63 results on '"Asthmatic Airway Remodeling"'
Search Results
2. Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling.
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Zeng, Ling-Hui, Barkat, Muhammad Qasim, Syed, Shahzada Khurram, Shah, Shahid, Abbas, Ghulam, Xu, Chengyun, Mahdy, Amina, Hussain, Nadia, Hussain, Liaqat, Majeed, Abdul, Khan, Kashif-ur-Rehman, Wu, Ximei, and Hussain, Musaddique
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LUNGS , *LUNG development , *HEDGEHOG signaling proteins , *EMBRYOLOGY , *PULMONARY arterial hypertension , *RESPIRATORY organs , *WNT signal transduction , *FIBROBLASTS - Abstract
The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling
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Ling-Hui Zeng, Muhammad Qasim Barkat, Shahzada Khurram Syed, Shahid Shah, Ghulam Abbas, Chengyun Xu, Amina Mahdy, Nadia Hussain, Liaqat Hussain, Abdul Majeed, Kashif-ur-Rehman Khan, Ximei Wu, and Musaddique Hussain
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hedgehog signaling ,lung development ,asthmatic airway remodeling ,targets pathogen ,repairment in tissue and immune system ,Cytology ,QH573-671 - Abstract
The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.
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- 2022
- Full Text
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4. Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
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Yunxuan Zhang, Mengtian Shan, Meixuan Liu, and Zhongliang Guo
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autophagy ,Immunology ,house dust mite-induced asthma ,HMGB1 ,airway remodeling ,Downregulation and upregulation ,Fibrosis ,progranulin ,medicine ,Immunology and Allergy ,Sensitization ,Original Research ,House dust mite ,biology ,business.industry ,Autophagy ,respiratory system ,biology.organism_classification ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,biology.protein ,Journal of Inflammation Research ,business ,Airway - Abstract
Meixuan Liu,1,2 Mengtian Shan,1 Yunxuan Zhang,3 Zhongliang Guo1,2 1Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, Peopleâs Republic of China; 2Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, Peopleâs Republic of China; 3Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, Peopleâs Republic of ChinaCorrespondence: Zhongliang Guo Tel +86 18901681968Email drguozhl@163.comPurpose: Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms.Methods: In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β 1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms.Results: We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β 1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis.Conclusion: Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.Keywords: house dust mite-induced asthma, airway remodeling, progranulin, autophagy, HMGB1
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- 2021
5. Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling.
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Hussain, Musaddique, Xu, Chengyun, Lu, Meiping, Wu, Xiling, Tang, Lanfang, and Wu, Ximei
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CATENINS , *LUNG development , *ASTHMA treatment , *HYPERTROPHY , *THERAPEUTICS ,HYPERPLASIA treatment - Abstract
Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/β-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/β-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/β-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling. [ABSTRACT FROM AUTHOR]
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- 2017
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6. The Role of Macrophage Migration Inhibitory Factor (MIF) in Asthmatic Airway Remodeling
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Bo Xiao, Jianghong Wei, Jiange Zhang, Rui Zhou, Ruyi Li, Feiyun Wang, Dong Yao, Jingjie Wu, Libing Ma, Guofang Tang, Xueqiang Zhao, Huiren Lei, Haiming Huang, Yun Lin, Qian Lv, Lizong Rao, Biwen Mo, and Qing Xu
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Pulmonary and Respiratory Medicine ,autophagy ,CD74 ,animal diseases ,Immunology ,ATG5 ,Inflammation ,chemical and pharmacologic phenomena ,03 medical and health sciences ,airway remodeling ,0302 clinical medicine ,Smooth muscle ,otorhinolaryngologic diseases ,Immunology and Allergy ,Medicine ,030223 otorhinolaryngology ,Macrophage migration inhibitory factor ,Gene knockdown ,biology ,business.industry ,Autophagy ,respiratory system ,Cell biology ,Ovalbumin ,030228 respiratory system ,Asthmatic Airway Remodeling ,biology.protein ,Original Article ,medicine.symptom ,business - Abstract
Purpose Recent studies have demonstrated that macrophage migration inhibitory factor (MIF) is of importance in asthmatic inflammation. The role of MIF in modulating airway remodeling has not yet been thoroughly elucidated to date. In the present study, we hypothesized that MIF promoted airway remodeling by intensifying airway smooth muscle cell (ASMC) autophagy and explored the specific mechanisms. Methods MIF knockdown in the lung tissues of C57BL/6 mice was conducted by instilling intratracheally adeno-associated virus (AAV) vectors (MIF-mutant AAV9) into mouse lung tissues. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) was used to detect the role of autophagy in ovalbumin (OVA)-asthmatic murine models. Moreover, to block the expression of MIF and CD74 in vitro models, inhibitors, antibodies and lentivirus transfection techniques were employed. Results First, MIF knockdown in the lung tissues of mice showed markedly reduced airway remodeling in OVA murine mice models. Secondly, ASMC autophagy was increased in the OVA-challenged models. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) that were primed and challenged with OVA showed lower airway remodeling than genetically wild-type asthmatic mice. Thirdly, MIF can induce ASMC autophagy in vitro. Moreover, the cellular source of MIF which promoted ASMC autophagy was macrophages. Finally, MIF promoted ASMC autophagy in a CD74-dependent manner. Conclusions MIF can increase asthmatic airway remodeling by enhancing ASMC autophagy. Macrophage-derived MIF can promote ASMC autophagy by targeting CD74.
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- 2020
7. Bidirectional interaction of airway epithelial remodeling and inflammation in asthma
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Raju C. Reddy, Asoka Banno, Aravind T. Reddy, and Sowmya P. Lakshmi
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0301 basic medicine ,Inflammation ,Epithelium ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Anti-Asthmatic Agents ,Lung ,Asthma ,business.industry ,General Medicine ,respiratory system ,Airway obstruction ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,030228 respiratory system ,Asthmatic Airway Remodeling ,Immunology ,Airway Remodeling ,Respiratory epithelium ,Smooth muscle hypertrophy ,medicine.symptom ,Airway ,business - Abstract
Asthma is a chronic disease of the airways that has long been viewed predominately as an inflammatory condition. Accordingly, current therapeutic interventions focus primarily on resolving inflammation. However, the mainstay of asthma therapy neither fully improves lung function nor prevents disease exacerbations, suggesting involvement of other factors. An emerging concept now holds that airway remodeling, another major pathological feature of asthma, is as important as inflammation in asthma pathogenesis. Structural changes associated with asthma include disrupted epithelial integrity, subepithelial fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle hypertrophy/hyperplasia, and enhanced vascularity. These alterations are hypothesized to contribute to airway hyperresponsiveness, airway obstruction, airflow limitation, and progressive decline of lung function in asthmatic individuals. Consequently, targeting inflammation alone does not suffice to provide optimal clinical benefits. Here we review asthmatic airway remodeling, focusing on airway epithelium, which is critical to maintaining a healthy respiratory system, and is the primary defense against inhaled irritants. In asthma, airway epithelium is both a mediator and target of inflammation, manifesting remodeling and resulting obstruction among its downstream effects. We also highlight the potential benefits of therapeutically targeting airway structural alterations. Since pathological tissue remodeling is likewise observed in other injury- and inflammation-prone tissues and organs, our discussion may have implications beyond asthma and lung disease.
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- 2020
8. Editorial: Airway remodeling in asthma-what is new?
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Yamasaki A
- Abstract
Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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9. Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts
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Rakhee K. Ramakrishnan, Hauke Busch, Mahmood Y. Hachim, Saba Al Heialy, Ibrahim Y. Hachim, Khuloud Bajbouj, Noha Mousaad Elemam, Rifat Hamoudi, Ronald Olivenstein, and Qutayba Hamid
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0301 basic medicine ,Senescence ,Biology ,Cell and Developmental Biology ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Downregulation and upregulation ,Autocrine signalling ,Enhancer ,lcsh:QH301-705.5 ,Original Research ,remodeling ,in silco analysis ,Wnt signaling pathway ,Cell Biology ,asthma ,Embryonic stem cell ,030104 developmental biology ,lcsh:Biology (General) ,030228 respiratory system ,Asthmatic Airway Remodeling ,Cancer research ,transcriptome ,Wnt/b-catenin ,Developmental Biology - Abstract
Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based onin silicoanalysis and followed byin vitrovalidation. In summary, thein silicoanalysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.
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- 2021
10. Macrophage Migration Inhibitory Factor Promotes Asthmatic Airway Remodeling by Inducing Autophagy of Airway Smooth Muscle Cell
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Ruyi Li, Jiange Zhang, and B. Mo
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Chemistry ,Asthmatic Airway Remodeling ,Autophagy ,Macrophage migration inhibitory factor ,Airway smooth muscle cell ,Cell biology - Published
- 2020
11. Notch Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling
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Ximei Wu, Meiping Lu, Xiling Wu, Chengyun Xu, Lanfang Tang, Youping Yang, Musaddique Hussain, and Mashaal Ahmad
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0301 basic medicine ,Cell signaling ,Epithelial-Mesenchymal Transition ,Cellular differentiation ,Notch signaling pathway ,Embryonic Development ,Cell Communication ,Respiratory Mucosa ,Biology ,03 medical and health sciences ,Neuroendocrine Cells ,Pulmonary fibrosis ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Lung cancer ,Lung ,Pharmacology ,Receptors, Notch ,Cell Differentiation ,respiratory system ,medicine.disease ,Asthma ,respiratory tract diseases ,Pulmonary Alveoli ,030104 developmental biology ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,Microvessels ,Immunology ,Cancer research ,Airway Remodeling ,Molecular Medicine ,Goblet Cells ,Signal transduction ,Signal Transduction - Abstract
Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.
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- 2017
12. Macrophage migration inhibitory factor (MIF) promotes rat airway muscle cell proliferation and migration mediated by ERK1/2 and FAK signaling
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Xiefei Qi, Haibing Lan, Yu Chen, Nan Wang, Yuanqi Gong, Fang Yao, Ya-ling Luo, and Xiaojing Wang
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0301 basic medicine ,MAPK/ERK pathway ,medicine.medical_specialty ,Population ,chemical and pharmacologic phenomena ,Focal adhesion ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Cyclin D3 ,education ,education.field_of_study ,Chemistry ,Muscle cell proliferation ,Cell Biology ,General Medicine ,respiratory system ,Cell biology ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Asthmatic Airway Remodeling ,Macrophage migration inhibitory factor ,Signal transduction - Abstract
Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that contributes to asthmatic airway remodeling; however, little is known regarding the effects of MIF on airway smooth muscle cells (ASMCs). In the present study, we found that an enhanced expression of MIF promoted ASMC proliferation, increased the population of cells in the S/G2 phase, downregulated P21 expression, and upregulated cyclin D1, cyclin D3, and Cdk6 expression. In addition, the apoptosis of ASMCs was significantly decreased in response to MIF overexpression, compared with the negative control. Moreover, MIF facilitated the migration of ASMCs by upregulating the expression of matrix metalloproteinase (MMP)-2. Finally, we showed that MIF increased the phosphorylation of extracellular regulated protein kinases (ERK) 1/2 and focal adhesion kinase (FAK), which are associated with proliferation and migration. In conclusion, this study demonstrated that MIF overexpression promotes the proliferation and migration of ASMCs by upregulating the activity of the ERK1/2 and FAK signaling pathways in these cells, further indicating that inhibition of MIF may prove to be an effective strategy for treating asthma patients with airway remodeling.
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- 2017
13. EPO modified MSCs can inhibit asthmatic airway remodeling in an animal model
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Hai‐Feng Ou‐Yang, Chang-Gui Wu, Xin‐peng Han, Liang Liu, Xiang‐shu Tan, Fang‐qi Zhang, and Wen‐xian Ma
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0301 basic medicine ,Inflammation ,Mesenchymal Stem Cell Transplantation ,Biochemistry ,Mice ,03 medical and health sciences ,medicine ,Animals ,Erythropoietin ,Molecular Biology ,Interleukin 5 ,Interleukin 4 ,Mice, Inbred BALB C ,Chemistry ,Interleukins ,Lentivirus ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Genetic Therapy ,Cell Biology ,Molecular biology ,Asthma ,Blot ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Asthmatic Airway Remodeling ,Interleukin 13 ,Immunology ,Airway Remodeling ,medicine.symptom ,Bronchoalveolar Lavage Fluid ,Transforming growth factor - Abstract
There was no effective measures can be obtained at present to reverse or prevent airway remodeling. We investigated the therapeutic effect of Erythropoietin (EPO) gene modified mesenchymal stem cells (MSCs) on asthmatic airway remodeling and the possible underlied molecular mechanisms. EPO gene was transfected into MSCs via lentivirus vector. The transfected cells (EPO-MSCs) were identified by flow cytometry and the EPO secreting function was detected by PCR and Western blot. MSCs or EPO-MSCs were administrated to albumin (OVA)-induced chronic asthmatic mouse model via tail veins. The asthmatic phenotype was analyzed. Number of cells in bronchoalveolar lavage fluid (BALF) was counted using a hemocytometer. Histological findings of airways were evaluated by microscopic examination. The concentrations of interleukin 4(IL-4), interleukin 5(IL-5), and interleukin 13(IL-13) in lung homogenate were determined by ELISA. The activation state of transforming growth factor-β 1 (TGF-β1), Transforming growth factor beta-activated kinase 1 (TAK1), and p38 Mitogen Activated Protein Kinase (p38MAPK) signaling was detected by Real-Time PCR and Western blotting. EPO-MSCs were successfully constructed. EPO-MSCs showed a more potently suppressive effect on local asthmatic airway inflammation and the level of IL-4, IL-5, and IL-13 in lung tissue than MSCs. Moreover, the numbers of goblet cells, the thicknesses of smooth muscle layer, collagen density, percentage of proliferating cell nuclear antigen positive (PCNA+ ) mesenchymal cells, and von Willebrand factor positive(vWF+ ) vessels were also significantly inhibited by EPO-MSCs. Furthermore, EPO-MSCs could downregulate the expression of TGF-β1, TAK1, and p38MAPK in lung tissue both in mRNA level and in protein level. EPO gene modified MSCs may more efficiently attenuate asthmatic airway remodeling, which maybe related with the downregulation of TGF-β1-TAK1-p38MAPK pathway activity.
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- 2017
14. Coexisting COPD in elderly asthma with fixed airflow limitation: Assessment by DLco %predicted and HRCT
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Kazuto Matsunaga, Tsutomu Tamada, Keiji Kimura, Tsuneyuki Takahashi, Masakazu Ichinose, Uichiro Katsumata, Ken Ohta, and Hisatoshi Sugiura
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Cross-sectional study ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Japan ,DLCO ,Internal medicine ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,General hospital ,Intensive care medicine ,Aged ,Asthma ,COPD ,Lung ,Pulmonary Gas Exchange ,business.industry ,Smoking ,Middle Aged ,medicine.disease ,University hospital ,Respiratory Function Tests ,respiratory tract diseases ,Cross-Sectional Studies ,medicine.anatomical_structure ,030228 respiratory system ,Asthmatic Airway Remodeling ,Pediatrics, Perinatology and Child Health ,Airway Remodeling ,Female ,Tomography, X-Ray Computed ,business - Abstract
Asthma patients with fixed airflow limitation (FL) are theoretically classified into two phenotypes, that is, coexisting chronic obstructive pulmonary disease (COPD) and asthmatic airway remodeling. However, the precise percentages of such patients are not known.To assess the prevalence of patients with both FL and COPD components in elderly asthma.We evaluated patients by lung diffusion impairment and emphysematous findings in high-resolution computed tomography (HRCT) as candidates for COPD components, as a multicenter, cross-sectional survey. Asthma outpatients ≥ 50 years of age were enrolled from Tohoku University Hospital, Sendai, Japan, and four hospitals (Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai, JAPAN; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to November 30, 2014.The prevalence of patients with FEVNearly half of the patients with FL in elderly asthma show coexisting COPD components when assessed by DLco %predicted and LAA in HRCT.
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- 2017
15. Thymic stromal lymphopoietin induced early stage of epithelial-mesenchymal transition in human bronchial epithelial cells through upregulation of transforming growth factor beta 1
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Li-Fen Yang, Li Pan, Zhuang-Gui Chen, Liang-Ming Cai, Jing-Xin Qu, Yu-Qi Zhou, Zhen-Yuan Dai, Hui-Qing Ye, and Hong-tao Li
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Pulmonary and Respiratory Medicine ,Thymic stromal lymphopoietin ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Clinical Biochemistry ,Vimentin ,Bronchi ,Collagen Type I ,Cell Line ,Transforming Growth Factor beta1 ,Downregulation and upregulation ,medicine ,Humans ,Epithelial–mesenchymal transition ,Molecular Biology ,biology ,Chemistry ,Epithelial Cells ,Transforming growth factor beta ,Cadherins ,Asthma ,Fibronectins ,Up-Regulation ,Cytokine ,Asthmatic Airway Remodeling ,Cancer research ,biology.protein ,Airway Remodeling ,Cytokines ,Biomarkers ,Transforming growth factor - Abstract
Purpose: Epithelial-mesenchymal transition (EMT) involved in asthmatic airway remodeling. Thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine, was a key component in airway immunological response in asthma. But the role of TSLP in the EMT process was unknown. We aimed to access whether TSLP could induce EMT in airway epithelia and its potential mechanism. Materials and Methods: Human bronchial epithelial (HBE) cells were incubated with TSLP or transforming growth factor beta 1 (TGF-β1) or both. SB431542 was used to block TGF-β1 signal while TSLP siRNA was used to performed TSLP knockdown. Changes in E-cadherin, vimentin, collagen I and fibronectin level were measured by real-time PCR, western blot and immunofluorescence staining. Expressions of TGF-β after TSLP administration were measured by real-time PCR, western blot and ELISA. Results: TSLP induced changes of EMT relevant markers alone and promoted TGF-β1-induced EMT in HBEs. Intracellular and extracellular expression of TGF-β1 were upregulated by TSLP. SB431542 blocked changes of EMT relevant markers induced by TSLP. Knockdown of TSLP not only reduced TSLP and TGF-β1 expression but also inhibited changes of EMT relevant markers induced by TGF-β1 in HBEs. Conclusions: TSLP could induce early stage of EMT in airway epithelial cells through upregulation of TGF-β1. This effect may act as a targeting point for suppression of asthma.
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- 2019
16. Role of TRPC1 channels in pressure-mediated activation of airway remodeling
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Ye He, Qian Yu, Gang Yang, Minchao Li, and Na Li
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Male ,0301 basic medicine ,TRPC1 channel ,Ovalbumin ,Guinea Pigs ,Mechanotransduction, Cellular ,TRPC1 ,03 medical and health sciences ,Transient receptor potential channel ,0302 clinical medicine ,Pressure ,medicine ,Animals ,Humans ,Calcium Signaling ,Mechanotransduction ,Lung ,Cells, Cultured ,TRPC Cation Channels ,lcsh:RC705-779 ,biology ,Chemistry ,Research ,lcsh:Diseases of the respiratory system ,Airway remodeling ,respiratory system ,Asthma ,Cell biology ,Ca2+ ,030104 developmental biology ,030228 respiratory system ,Asthmatic Airway Remodeling ,biology.protein ,Bronchoconstriction ,Mechanosensitive channels ,Smooth muscle hypertrophy ,medicine.symptom - Abstract
Background Bronchoconstriction and cough, a characteristic of the asthmatic response, leads to development of compressive stresses in the airway wall. We hypothesized that progressively pathological high mechanical stress could act on mechanosensitive cation channels, such as transient receptor potential channel 1 (TRPC1) and then contributes to airway remodeling. Methods We imitate the pathological airway pressure in vitro using cyclic stretch at 10 and 15% elongation. Ca2+ imaging was applied to measure the activity of TRPC1 after bronchial epithelial cells exposed to cyclic stretch for 0, 0.5, 1, 1.5, 2, 2.5 h. To further clarify the function of channnel TRPC1 in the process of mechano-transduction in airway remodeling, the experiment in vivo was implemented. The TRPC1 siRNA and budesonide were applied separately to asthmatic models. The morphological changes were measured by HE and Massion method. The expression levels of TRPC1 were evaluated by real-time PCR, western blot and immunohistochemistry. The protein expression level of IL-13, TGF-β1 and MMP-9 in BALF were measured by ELISA. Results The result showed that cyclic stretch for 15% elongation at 1.5 h could maximize the activity of TRPC1 channel. This influx in Ca2+ was blocked by TRPC1 siRNA. Higher TRPC1 expression was observed in the bronchial epithelial layer of ovalbumin induced asthmatic models. The knockdown of TRPC1 with TRPC1 siRNA was associated with a hampered airway remodeling process, such as decreased bronchial wall thickness and smooth muscle hypertrophy/hyperplasia, a decreased ECM deposition area and inflammation infiltration around airway wall. Meantime, expression of IL-13, TGF-β1 and MMP-9 in OVA+TRPC1 siRNA also showed reduced level. TRPC1 intervention treatment showed similar anti-remodeling therapeutic effect with budesonide. Conclusions These results demonstrate that most TRPC1 channels expressed in bronchial epithelial cells mediate the mechanotransduction mechanism. TRPC1 inducing abnormal Ca2+ signal mediates receptor-stimulated and mechanical stimulus-induced airway remodeling. The inhibition of TRPC1 channel could produce similar therapeutic effect as glucocortisteroid to curb the development of asthmatic airway remodeling.
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- 2019
17. TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast
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Shuo Li, Junfei Wang, Jiping Zhao, Liuzhao Cao, Tian Liu, Fen Liu, Liang Dong, Jinxiang Wu, Yahui Liu, and Jiawei Xu
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,MAPK/ERK pathway ,STAT3 Transcription Factor ,Thymic stromal lymphopoietin ,MAP Kinase Signaling System ,medicine.medical_treatment ,Clinical Biochemistry ,Stat3 Signaling Pathway ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Thymic Stromal Lymphopoietin ,Medicine ,Animals ,Humans ,Fibroblast ,Molecular Biology ,Lung ,business.industry ,Epithelial Cells ,Receptor Cross-Talk ,respiratory system ,Fibroblasts ,Asthma ,respiratory tract diseases ,Crosstalk (biology) ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Asthmatic Airway Remodeling ,Cancer research ,Airway Remodeling ,Cytokines ,Airway ,business - Abstract
Thymic stromal lymphopoietin (TSLP) acts as a critical cytokine involved in asthmatic airway remodeling. Our study aimed to characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of Mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3).Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin (HE) and immunohistochemistry. Human lung fibroblasts were stimulated with human recombinant TSLP. The protein expression of phosphorylation of STAT3 (p-STAT3) and phosphorylation of MAPK as well as the expression of collagen I and alpha-smooth muscle actin (α-SMA) were detected by Western blotting and immunofluorescence. Co-culture was performed to detect the influence of TSLP secreted by airway epithelial cells on fibroblasts. An ovalbumin (OVA)-induced asthmatic murine model was established with or without intraperitoneal injection of SB203580 (inhibitor of p-38). Protein expression in lung tissue was detected by immunohistochemistry and western blotting.TSLP could activate MAPK in HLF-1. SB203580 could inhibit the activation of p38, attenuate phosphorylation of STAT3, and decrease the expression of collagen I and α-SMA consequently in human fibroblasts. Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and α-SMA and aggravates airway remodeling in fibroblasts. In vivo, expression of TSLP, collagen I, α-SMA, p-p38 and p-STAT3 was upregulated in airway tissue of OVA-challenged mice and downregulated in mice which were treated by SB203580. The tissue staining showed that airway structure change was attenuated by SB203580 compared with OVA challenged mice as well.TSLP might promote asthmatic airway remodeling via p38 MAPK-STAT3 axis activation and the crosstalk between airway epithelial cells and fibroblasts could aggravate remodeling. Blockade of p38 could alleviate airway remodeling which might provide a new therapeutic target for asthma.
- Published
- 2018
18. D-4F, an apolipoprotein A-I mimetic, inhibits TGF-β1 induced epithelial-mesenchymal transition in human alveolar epithelial cell
- Author
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Chengwen Zhu, Jingyuan Xiong, Linshen Xie, Jintao Wang, and Jia You
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Apolipoprotein B ,Pulmonary Fibrosis ,Blotting, Western ,Vimentin ,030204 cardiovascular system & hematology ,Biology ,Toxicology ,Polymerase Chain Reaction ,Cell Line ,Pathology and Forensic Medicine ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,Pulmonary fibrosis ,medicine ,Humans ,Epithelial–mesenchymal transition ,A549 cell ,Apolipoprotein A-I ,Mesenchymal stem cell ,Cell Biology ,General Medicine ,medicine.disease ,Asthma ,030104 developmental biology ,Alveolar Epithelial Cells ,Asthmatic Airway Remodeling ,Cancer research ,biology.protein ,Transforming growth factor - Abstract
Emerging evidences support that transforming growth factor β1 (TGF-β1) induced epithelial-mesenchymal transition (EMT) participates in the pathogenesis of pulmonary fibrosis and asthmatic airway remodeling. Recent studies demonstrated that apolipoprotein A-I (Apo A-I) is the only known substance that can resolve established pulmonary fibrotic nodules, and Apo A-I mimetic D-4F (a synthetic polypeptide consisting of 18 amino acids) plays an inhibitory role in murine asthmatic model. However, cellular mechanisms for such therapeutic effects of Apo A-I and D-4F remain to be elucidated. This study evaluated the effects of D-4F on TGF-β1 induced EMT in human type II alveolar epithelial cell line A549. A549 cells treated with 10ng/ml of TGF-β1 manifested distinct EMT, including fibroblastic morphological changes, down-regulation of epithelial marker E-cadherin and up-regulation of mesenchymal marker vimentin. These EMT related changes were all inhibited by D-4F in a concentration dependent manner. Transcriptional investigation demonstrated clearly that D-4F dose-dependently compensated for the reduced E-cadherin mRNA level and the increased vimentin mRNA level in TGF-β1 treated A549 cells. Translational analysis revealed that D-4F significantly reversed the TGF-β1 induced changes of E-cadherin and vimentin levels. These results suggested that D-4F inhibits TGF-β1 induced EMT in human alveolar epithelial cell. Given the functional similarities between D-4F and Apo A-I, it is speculated that D-4F and Apo A-I are able to exert possible anti-fibrotic and anti-asthmatic effects via inhibiting alveolar EMT, and D-4F may possess beneficial clinical potential for patients suffering from pulmonary fibrosis and asthma.
- Published
- 2016
19. MicroRNA-133a alleviates airway remodeling in asthtama through PI3K/AKT/mTOR signaling pathway by targeting IGF1R
- Author
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Haiyan Li, Youyou Shao, Peng Lin, Changchong Li, Qiuping Wu, Lei Chong, and Lili Zhu
- Subjects
0301 basic medicine ,Physiology ,Ovalbumin ,Clinical Biochemistry ,Myocytes, Smooth Muscle ,Receptor, IGF Type 1 ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,microRNA ,Animals ,Protein kinase B ,Lung ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Insulin-like growth factor 1 receptor ,Mice, Inbred BALB C ,Phosphoinositide 3-kinase ,biology ,Airway Resistance ,TOR Serine-Threonine Kinases ,Cell Biology ,Actins ,Asthma ,Cell biology ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Asthmatic Airway Remodeling ,biology.protein ,Airway Remodeling ,Female ,Signal transduction ,Phosphatidylinositol 3-Kinase ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Asthma is characterized by chronic inflammation, and long-term chronic inflammation leads to airway remodeling. But the potential regulatory mechanism of airway remodeling is not clearly understood, and there is still no effective way to prevent airway remodeling. Present studies have confirmed the role of microRNAs (miRNAs) in the development of disease, which is known as suppressing translation or degradation of messenger RNA (mRNA) at the posttranscriptional stage. In this study, we described the role of miRNA-133a in asthma and demonstrated it in regulating airway remodeling of asthma through the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway by targeting IGF-1 receptor (IGF1R). IGF1R helps in mediating the intracellular signaling cascades. Asthmatic mice models were established by sensitization and Ovalbumin challenge. Adenovirus transfer vector carrying miR-133a or miR-133a sponge sequence was used to build the overexpression or downexpression of miR-133a modeling. Real-time polymerase chain reaction and Western blot were used to determine the alterations in the expression of miR-133a and mRNAs and their corresponding proteins. Results showed that miR-133a was downregulated in asthma. Upregulation of miR-133a expression in airway smooth muscle cells in vivo and in vitro could inhibit the activation of PI3K/AKT/mTOR pathway, and reduce the expression of α-smooth muscle actin (α-SMA), indicating that airway remodeling was inhibited. Functional studies based on luciferase reporter revealed miR-133a as a direct target of IGF1R mRNA. In conclusion, these data suggested that miR-133a regulated the expression of α-SMA through PI3K/AKT/mTOR signaling by targeting IGF1R. miR-133a plays a key role in airway remodeling of asthma and may serve as a potential therapeutic target for managing asthmatic airway remodeling.
- Published
- 2017
20. Effects of inhaled corticosteroids on the expression of TNF family molecules in murine model of allergic asthma
- Author
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Manhui Li, Aijun Shan, Fei Shi, Binbin Li, Ying Yang, Chen Qiu, Yarui Zhang, and Yi Xiong
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Budesonide ,Tumor Necrosis Factor Ligand Superfamily Member 14 ,Clinical Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Adrenal Cortex Hormones ,Lymphotoxin beta Receptor ,medicine ,Animals ,Receptor ,Molecular Biology ,Asthma ,Lung ,medicine.diagnostic_test ,business.industry ,respiratory system ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,030228 respiratory system ,Asthmatic Airway Remodeling ,Immunology ,Tumor Necrosis Factors ,Immunohistochemistry ,Tumor necrosis factor alpha ,business ,Receptors, Tumor Necrosis Factor, Member 14 ,medicine.drug - Abstract
Background: The tumor necrosis factor superfamily member LIGHT (the official gene symbol approved by NCBI Gene Database), an inflammatory factor secreted by T cells after allergen exposure, recently discovered to play crucial roles in asthmatic airway remodeling. However, it is unclear whether LIGHT could be controlled by inhaled corticosteroids, a key component of asthma management. This study was to investigate the effects and potential mechanisms of inhaled budesonide on the expressions of LIGHT and its receptors (LTβR and HVEM) of lung tissues in ovalbumin-sensitized mice. Materials and Methods: Thirty-three BALB/c mice were randomly divided into the control, asthma model, and budesonide treatment groups (11 in each group). Mice were sensitized and challenged by OVA to develop mouse model of chronic asthma, and treated with aerosolized budesonide before OVA challenge. Bronchoalveolar lavage fluid (BALF) and lungs were obtained after the final OVA challenge. Protein and mRNA Levels of LIGHT, LTβR, and HVEM in the lungs were investigated by immunohistochemistry, image analysis, and real-time PCR. Expressions of IL-6 and IFN-γ in BALF were measured by ELISA. Results: Inhaled budesonide significantly reduced protein and mRNA levels of lung LIGHT, LTβR, and HVEM in asthmatic mice. Correspondingly, the number of eosinophils and neutrophils and IL-6 levels in BALF after budesonide treatment were found to be decreased, whereas the IFN-γ levels in BALF were increased. Moreover, the expressions of LIGHT and HVEM mRNA showed positive correlation with IL-6 levels in the treatment group. Conclusions: Inhaled budesonide can down-regulate the expressions of LIGHT, LTβR, and HVEM in the lungs of asthmatic mice, and LIGHT/LTβR/HVEM interactions may be a potentially key target for asthma treatment.
- Published
- 2017
21. Contraction-dependent TGF-β1 activation is required for thrombin-induced remodeling in human airway smooth muscle cells
- Author
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Haojun Xie, Yating Huo, Rui-Jun Cai, Yuanxiong Cheng, Zhi-Hui Yao, Wen-Yan Lai, Jing Cao, and Ya-Lu Yuan
- Subjects
0301 basic medicine ,Contraction (grammar) ,Myocytes, Smooth Muscle ,Bronchi ,General Biochemistry, Genetics and Molecular Biology ,Extracellular matrix ,Transforming Growth Factor beta1 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Thrombin ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cells, Cultured ,Cytochalasin D ,Cell Proliferation ,Cell growth ,Chemistry ,General Medicine ,Cell biology ,030104 developmental biology ,030228 respiratory system ,Asthmatic Airway Remodeling ,Airway Remodeling ,Bronchoconstriction ,medicine.symptom ,Transforming growth factor ,medicine.drug ,Signal Transduction - Abstract
Aims Thrombin is a serine proteinase that is not only involved in coagulation cascade, but also mediates a number of biological responses relevant to tissues repair, and induces bronchoconstriction. TGF-β plays a pivotal role in airway remodeling due to its effects on airway smooth muscle proliferation and extracellular matrix (ECM) deposition. Recently, bronchoconstriction itself is found to constitute a form of strain and is highly relevant to asthmatic airway remodeling. However, the underlying mechanisms remain unknown. Here, we investigated the role of contraction- dependent TGF-β activation in thrombin-induced remodeling in human airway smooth muscle (HASM) cells. Materials and methods Primary HASM cells were treated with or without thrombin in the absence or presence of anti-TGF-β antibody, cytochalasin D and formoterol. CFSE labeling index or CCK-8 assay were performed to test cell proliferation. RT-PCR and Western blotting were used to examined ECM mRNA level and collagen Iα1, α-actin protein expression, respectively. Immunofluorescence was also used to confirm contraction induced by thrombin in HASM cells. Key finding Thrombin stimulation enhanced HASM cells proliferation and activated TGF-β signaling. Thrombin induced ECM mRNA and collagen Iα1 protein expression, and these effects are mediated by TGF-β. Abrogation of TGF-β activation by contraction inhibitors cytochalasin D and formoterol prevents the thrombin-induced effects. Significance These findings suggest that contraction-dependent TGF-β activation could be a mechanism by which thrombin leads to the development of asthmatic airway remodeling. Blocking physical forces with bronchodilator would be an intriguing way in reducing airway remodeling in asthma.
- Published
- 2017
22. Ultrastructural changes in rat airway epithelium in asthmatic airway remodeling
- Author
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Miao Li and Yun-Xiao Shang
- Subjects
Basement membrane ,Pathology ,medicine.medical_specialty ,Chemistry ,Epithelial Cells ,Cell Biology ,respiratory system ,Mitochondrion ,Lamellar granule ,Asthma ,Epithelium ,Mitochondria ,Pathology and Forensic Medicine ,medicine.anatomical_structure ,Microscopy, Electron, Transmission ,Asthmatic Airway Remodeling ,medicine ,Ultrastructure ,Airway Remodeling ,Animals ,Respiratory epithelium ,Female ,Rats, Wistar ,Airway - Abstract
Objectives To explore asthmatic rat airway epithelial cells mitochondrial ultrastructure changes. Methods Six female Wistar rats of the same weight (60–80 g) were randomly divided into two groups: the asthmatic group and the control group. According to the OVA inhaled method, the asthmatic airway remodeling rat model was established. Epithelial tissue of the rat trachea was taken from the two groups for transmission electron microscopy (TEM); we counted the number of mitochondria and observed the airway ciliated epithelium, intercellular collagen deposition in the two rat groups and mitochondrial ultrastructure change. Results Airway multilayer ciliated epithelium develops, with cilia fallen off; goblet cells increased and irregular, mitochondrial basement membrane density is decreased, mitochondrial crista is reduced, and the nucleus has more incisures and irregular shape in asthmatic rats; airway epithelial cell matrix collagen deposition increased; and lamellar body and mitochondrial cavity formation. Conclusions In the asthmatic rat airway, epithelial cells undergo apoptosis and the numbers of mitochondria increased compared with the ones in normal rat airway but lose normal structure.
- Published
- 2014
23. Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling
- Author
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Chengyun Xu, Meiping Lu, Ximei Wu, Musaddique Hussain, Xiling Wu, and Lanfang Tang
- Subjects
0301 basic medicine ,Embryonic Development ,WIF1 ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Airway resistance ,medicine ,Animals ,Humans ,Molecular Biology ,Lung ,Wnt Signaling Pathway ,Wnt signaling pathway ,respiratory system ,Embryonic stem cell ,Asthma ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Asthmatic Airway Remodeling ,Immunology ,Cancer research ,Molecular Medicine ,Airway Remodeling ,Lung morphogenesis ,Airway - Abstract
Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/β-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/β-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/β-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling.
- Published
- 2017
24. Deletion of Shp2 in bronchial epithelial cells impairs IL-25 production in vitro, but has minor influence on asthmatic inflammation in vivo
- Author
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Yuanrong Dai, Xuejun Qin, Songmin Ying, Jiesen Zhou, Fang Liu, Zhihua Chen, Wen Li, Huahao Shen, Yuehai Ke, and Zhangwei Qiu
- Subjects
Lipopolysaccharides ,0301 basic medicine ,Pulmonology ,Physiology ,MAP Kinase Kinase 4 ,lcsh:Medicine ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Pathology and Laboratory Medicine ,Toxicology ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,Epithelium ,Mice ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Small interfering RNAs ,RNA, Small Interfering ,lcsh:Science ,Immune Response ,Surfactant homeostasis ,Mice, Knockout ,Innate Immune System ,Multidisciplinary ,Interleukin ,Animal Models ,respiratory system ,Cell biology ,Nucleic acids ,Experimental Organism Systems ,Asthmatic Airway Remodeling ,Cytokines ,Female ,Cellular Types ,Anatomy ,medicine.symptom ,Research Article ,p38 mitogen-activated protein kinases ,Immunology ,Immunoblotting ,Molecular Probe Techniques ,Mouse Models ,Bronchi ,Inflammation ,In Vitro Techniques ,Biology ,Research and Analysis Methods ,Cell Line ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,In vivo ,Genetics ,medicine ,Animals ,Humans ,Non-coding RNA ,Molecular Biology Techniques ,Molecular Biology ,Toxicity ,030102 biochemistry & molecular biology ,Interleukins ,lcsh:R ,Biology and Life Sciences ,Epithelial Cells ,Cell Biology ,Molecular Development ,Asthma ,In vitro ,Gene regulation ,Enzyme Activation ,Mice, Inbred C57BL ,Biological Tissue ,030104 developmental biology ,Cell culture ,Immune System ,RNA ,lcsh:Q ,Gene expression ,Developmental Biology - Abstract
Shp2 played an important role in cigarette-smoke-mediated inflammation, surfactant homeostasis and asthmatic airway remodeling. However, whether shp2 plays a key role in epithelium-associated allergic reaction is still unknown. In this study, LPS and OVA were observed to induce the production of IL-25 in bronchial epithelial cells in vitro via the activation of MAPK p38 and JNK. Furthermore, blockage of Shp2 by its specific inhibitor PHPS1 or by siRNA-mediated depletion was found to reduce the production of IL-25 in epithelial cells as well as the up-regulated LPS-triggered activation of JNK but not p38. To confirm the role of intra-bronchial epithelial Shp2 in OVA-induced allergic reaction, we generated CC10-rtTA/(tetO)7-Cre/Shp2f/f mice, where Shp2 was conditionally knocked out in bronchial epithelial cells. Surprisingly, specific deletion of Shp2 in bronchial epithelial cells showed a mild but insignificant effect on the expressions of epithelium-derived cytokines as well as TH2 and TH17 polarization following allergen-induced murine airway inflammation. Collectively, our data suggested that deletion of Shp2 impaired IL-25 production in bronchial epithelial cells in vitro, but might yet have minor influence on OVA-induced allergic reaction in vivo.
- Published
- 2017
25. β-catenin as a regulator and therapeutic target for asthmatic airway remodeling
- Author
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Tim Koopmans, Kuldeep Kumawat, and Reinoud Gosens
- Subjects
PROTEIN CBP ,Bronchoconstriction ,SMOOTH-MUSCLE-CELLS ,Clinical Biochemistry ,Regulator ,FOCAL ADHESION KINASE ,catenin ,EXTRACELLULAR-MATRIX PRODUCTION ,WNT ,LUNG-CANCER ,Drug Discovery ,medicine ,Animals ,Humans ,Anti-Asthmatic Agents ,Molecular Targeted Therapy ,MATERNAL SMOKING ,Wnt Signaling Pathway ,beta Catenin ,Tissue homeostasis ,Cell Proliferation ,Pharmacology ,business.industry ,PULMONARY-FIBROSIS ,Wnt signaling pathway ,Cell Differentiation ,respiratory system ,asthma ,airway smooth muscle ,EPITHELIAL-MESENCHYMAL TRANSITION ,Extracellular Matrix ,respiratory tract diseases ,Catenin ,Asthmatic Airway Remodeling ,Immunology ,Airway Remodeling ,Molecular Medicine ,MOUSE LUNG ,medicine.symptom ,Signal transduction ,business ,Airway ,PRESCHOOL WHEEZERS - Abstract
Introduction: Pathological alteration in the airway structure, termed as airway remodeling, is a hallmark feature of individuals with asthma and has been described to negatively impact lung function in asthmatics. Recent studies have raised considerable interest in the regulatory role of beta-catenin in remodeling asthmatic airways. The WNT/beta-catenin signaling pathway is the key to normal lung development and tightly coordinates the maintenance of tissue homeostasis under steady-state conditions. Several studies indicate the crucial role of beta-catenin signaling in airway remodeling in asthma and suggest that this pathway may be activated by both the growth factors and mechanical stimuli such as bronchoconstriction. Areas covered: In this review, we discuss recent literature regarding the mechanisms of beta-catenin signaling activation and its mechanistic role in asthmatic airway remodeling. Further, we discuss the possibilities of therapeutic targeting of beta-catenin. Expert opinion: The aberrant activation of beta-catenin signaling by both WNT-dependent and -independent mechanisms in asthmatic airways plays a key role in remodeling the airways, including cell proliferation, differentiation, tissue repair and extracellular matrix production. These findings are interesting from both a mechanistic and therapeutic perspective, as several drug classes have now been described that target beta-catenin signaling directly.
- Published
- 2014
26. Notch signaling regulates col1α1 and col1α2 expression in airway fibroblasts
- Author
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Xin-Ting Xu, Ping Wang, Shuo-Yao Qu, Mei Hu, Hai-Feng Ou-Yang, and Chang-Gui Wu
- Subjects
Chromatin Immunoprecipitation ,congenital, hereditary, and neonatal diseases and abnormalities ,Notch signaling pathway ,Biology ,Collagen Type I ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,Genes, Reporter ,Fibrosis ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Humans ,HES1 ,Promoter Regions, Genetic ,Homeodomain Proteins ,Binding Sites ,Receptors, Notch ,Fibroblasts ,medicine.disease ,Cell biology ,Gene Expression Regulation ,Notch proteins ,Hes3 signaling axis ,Asthmatic Airway Remodeling ,Immunology ,Mutagenesis, Site-Directed ,Transcription Factor HES-1 ,Cyclin-dependent kinase 8 ,Type I collagen ,Protein Binding ,Signal Transduction - Abstract
Subepithelial fibrosis is one of the common pathological features of asthmatic airway remodeling. During subepithelial fibrosis, type I collagen becomes the most abundant extracellular protein component. Studies have shown that Notch signaling participates in the progression of fibrosis; however, whether Notch signaling is involved in regulating type I collagen expression in airway fibroblasts remains unclear. The aim of the present study was to examine whether Notch signaling can regulate type I collagen expression in airway fibroblasts and to explore the underlying molecular mechanisms. Here, the expression of Notch signaling components was examined in mouse L929 cells and human MRC-5 cells. After upregulating or downregulating Notch signaling in these cell lines, col1α1 and col1α2 expression was examined. Using gene reporter assays, site-directed mutagenesis, and ChIP assays, the role of Hes1 binding sites in both the mouse and human COL1A1 and COL1A2 promoters was investigated. This study revealed that Notch signaling-related molecules (including Notch1, Hes1, and others) are expressed in L929 and MRC-5 cells and that Notch signaling regulates the expression of col1α1 and col1α2 in both cell lines. Additionally, over-expression of the Notch intracellular domain resulted in activation of the COL1A1 and COL1A2 promoters, and site-directed mutagenesis reporter assays revealed that Hes1 proteins might augment both mouse and human COL1A1 and COL1A2 promoter activity. Furthermore, ChIP assays confirmed that Hes1 binds to the COL1A1 and COL1A2 promoters in both L929 and MRC-5 cells. Therefore, it is reasonable to assume that Notch signaling can directly upregulate COL1A1 and COL1A2 promoter activity through a Hes1-dependent mechanism, which could serve as a possible target for pharmacotherapy of airway subepithelial fibrosis.
- Published
- 2014
27. Effect of Tumor Necrosis Factor Family Member LIGHT (TNFSF14) on the Activation of Basophils and Eosinophils Interacting with Bronchial Epithelial Cells
- Author
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Huai Na Qiu, Christopher W.K. Lam, Zhe Cai, Jie Dong, and Chun-Kwok Wong
- Subjects
Tumor Necrosis Factor Ligand Superfamily Member 14 ,Chemokine ,Herpesvirus entry mediator ,Article Subject ,medicine.medical_treatment ,Immunology ,Bronchi ,Cell Line ,Cell surface receptor ,Cell Adhesion ,Hypersensitivity ,lcsh:Pathology ,medicine ,Humans ,Cell adhesion ,biology ,Interleukin-6 ,Cell adhesion molecule ,Macrophages ,Cell Membrane ,Interleukin-8 ,Epithelial Cells ,Cell Biology ,Asthma ,Coculture Techniques ,Recombinant Proteins ,Basophils ,Cell biology ,Eosinophils ,Cytokine ,Matrix Metalloproteinase 9 ,Microscopy, Fluorescence ,Asthmatic Airway Remodeling ,biology.protein ,Tumor necrosis factor alpha ,Research Article ,Signal Transduction ,lcsh:RB1-214 - Abstract
Allergic asthma can cause airway structural remodeling, involving the accumulation of extracellular matrix and thickening of smooth muscle. Tumor necrosis factor (TNF) family ligand LIGHT (TNFSF14) is a cytokine that binds herpesvirus entry mediator (HVEM)/TNFRSF14 and lymphotoxinβreceptor (LTβR). LIGHT induces asthmatic cytokine IL-13 and fibrogenic cytokine transforming growth factor-βrelease from allergic asthma-related eosinophils expressing HVEM and alveolar macrophages expressing LTβR, respectively, thereby playing crucial roles in asthmatic airway remodeling. In this study, we investigated the effects of LIGHT on the coculture of human basophils/eosinophils and bronchial epithelial BEAS-2B cells. The expression of adhesion molecules, cytokines/chemokines, and matrix metalloproteinases (MMP) was measured by flow cytometry, multiplex, assay or ELISA. Results showed that LIGHT could significantly promote intercellular adhesion, cell surface expression of intercellular adhesion molecule-1, release of airway remodeling-related IL-6, CXCL8, and MMP-9 from BEAS-2B cells upon interaction with basophils/eosinophils, probably via the intercellular interaction, cell surface receptors HVEM and LTβR on BEAS-2B cells, and extracellular signal-regulated kinase, p38 mitogen activated protein kinase, and NF-κB signaling pathways. The above results, therefore, enhance our understanding of the immunopathological roles of LIGHT in allergic asthma and shed light on the potential therapeutic targets for airway remodeling.
- Published
- 2014
28. A role for WNT1-inducible signaling protein-1 in airway remodeling in a rat asthma model
- Author
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Youfan Jiang, Yuanyin Liu, Xin Zhao, Mingjin Yang, Xuemei Ran, and Yu Tian
- Subjects
Male ,Ovalbumin ,Inositol Phosphates ,Immunology ,Collagen Type I ,Cell Line ,CCN Intercellular Signaling Proteins ,Rats, Sprague-Dawley ,Fibrosis ,In vivo ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Immunology and Allergy ,Antibodies, Blocking ,Fibroblast ,Lung ,Protein kinase B ,Cell Proliferation ,Phosphoinositide-3 Kinase Inhibitors ,Pharmacology ,biology ,Akt/PKB signaling pathway ,Fibroblasts ,medicine.disease ,Asthma ,In vitro ,Rats ,Collagen Type I, alpha 1 Chain ,Disease Models, Animal ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,biology.protein ,Airway Remodeling - Abstract
Over-expression of WISP1 has been described in multi-organ fibrosis and tissue remodeling. Moreover, it has recently been found that polymorphism of WISP1 gene is related with the change of lung function in asthmatic subjects. Therefore, we hypothesized that WISP1 might be closely linked to occurrence and development of asthmatic airway remodeling. Aim of this study was to examine the roles of WISP1 in an asthmatic model with airway remodeling and assess the specific effects of WISP1 on human lung fibroblast in vitro. Animal models were developed by challenged with ovalbumin. The levels of WISP1 expression in animal models were assessed by real-time PCR and immunohistochemistry. To examine the specific effects of WISP1 on airway remodeling, WISP1 was depleted by neutralizing α-WISP1 antibodies in vivo. Moreover, human lung fibroblast (HFL-1) was challenged with WISP1 in the presence and absence of SH-5 in vitro. Our study showed that OVA exposure increased the levels of WISP1 expression in a rat asthma model. WISP1 depletion could partially inhibit OVA-induced airway remodeling. In vitro, WISP1-treated HFL-1 cells presented abnormal proliferation and over-expression of Col1a1 and Fn1. However, WISP1-induced collagen release from HFL-1 cells could be attenuated by pretreatment with an Akt inhibitor. Moreover, the levels of p-Akt and p-GSK-3β in WISP1-treated HFL-1 cells were also significantly elevated. In summary, WISP1 might initiate and perpetuate the pathological remodeling of asthma by inducing fibroblast proliferation and ECM deposition. The specific effects of WISP1 were likely due to activation of pulmonary Akt/GSK-3β signaling.
- Published
- 2013
29. 1,25-Dihydroxyvitamin D3(1,25-(OH)2D3) Attenuates Airway Remodeling in a Murine Model of Chronic Asthma
- Author
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Jing-Fang Hong, Guo-xiang Lai, Changgui Wu, and Ying-Fang Song
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Ovalbumin ,medicine.medical_treatment ,Blotting, Western ,Intraperitoneal injection ,Mice ,Immune system ,Calcitriol ,NF-KappaB Inhibitor alpha ,Western blot ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,RNA, Messenger ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Transcription Factor RelA ,respiratory system ,Immunohistochemistry ,Asthma ,Blot ,Reverse transcription polymerase chain reaction ,Disease Models, Animal ,IκBα ,Endocrinology ,Asthmatic Airway Remodeling ,Chronic Disease ,Pediatrics, Perinatology and Child Health ,biology.protein ,Airway Remodeling ,I-kappa B Proteins ,business - Abstract
1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) has immune- and inflammation-modulating properties in asthma, but its possible effects on asthmatic airway remodeling remain uncertain. In this study, we investigated the effects of 1,25-(OH)(2)D(3) on airway remodeling in a murine model of chronic asthma and investigated its role in regulating nuclear factor-κB (NF-κB) activation.BALB/c mice were sensitized to ovalbumin (OVA) and subsequently exposed to intranasal OVA challenges for 9 weeks. Some mice also received an intraperitoneal injection of 1,25-(OH)(2)D(3) at the time of challenge. At the end of the challenge period, mice were evaluated for chronic airway inflammation and airway remodeling. Nuclear translocation of NF-κB p65 in lung tissue was examined by Western blot. Inhibitor of NF-κB alpha (IκBα) expression was determined by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western blot. Phosphorylated IκBα protein expression was also determined by Western blot.1,25-(OH)(2)D(3) treatment reduced OVA-induced chronic inflammation in lung tissue and attenuated established structural changes of the airways, including subepithelial collagen deposition, goblet cell hyperplasia, and increased airway smooth muscle mass. 1,25-(OH)(2)D(3) also inhibited the nuclear translocation of NF-κB p65 in lung tissue. Concurrently, 1,25-(OH)(2)D(3) induced increased IκBα protein levels via inducing increased IκBα mRNA levels and decreased IκBα phosphorylation.1,25-(OH)(2)D(3) could attenuate asthmatic airway remodeling and its inhibition of NF-κB activation may underlie this protective effect.
- Published
- 2012
30. Effect of compound Maqin decoction on TGF-β1/Smad proteins and IL-10 and IL-17 content in lung tissue of asthmatic rats
- Author
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Xuefeng Li, Peng Qian, Yiqin Wang, Xue-Liang Li, Zhaoxia Xu, and Yan-Hong Xie
- Subjects
0301 basic medicine ,Male ,Ephedra ,SMAD ,Dexamethasone ,Rats, Sprague-Dawley ,0302 clinical medicine ,Anti-Asthmatic Agents ,Lung ,Elaeagnaceae ,biology ,Interleukin-17 ,Interleukin ,General Medicine ,Berberidaceae ,Interleukin-10 ,Interleukin 10 ,Asthmatic Airway Remodeling ,Airway Remodeling ,Interleukin 17 ,medicine.drug ,Scutellaria baicalensis ,Signal Transduction ,medicine.medical_specialty ,Ovalbumin ,Smad7 Protein ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Animals ,Smad3 Protein ,Molecular Biology ,Dose-Response Relationship, Drug ,business.industry ,Plant Extracts ,Xanthium ,Asthma ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,biology.protein ,business ,030215 immunology ,Transforming growth factor - Abstract
In this research, compound Maqin decoction (CMD) has been shown to positively affect in airway inflammation of asthma models. We evaluated the effects of CMD on the expression of transforming growth factor (TGF)-β1/Smad proteins, interleukin (IL)-17, and IL-10 in lung tissue of asthmatic rats. Asthma was induced in a rat model using ovalbumin. After a 4-week treatment with CMD, rats were killed to evaluate the expression of TGF-β1 and Smad proteins in lung tissue. IL-10 and IL-17 levels in lung tissue homogenates were determined by ELISA. The expression of TGF-β1 and Smad3 protein increased, whereas expression of Smad7 protein decreased upon high-dose or low-dose treatment with CMD or by intervention with dexamethasone, compared to the control. There was a significant difference between treatment with a high dose CMD and the control treatment, but no significant difference was found between high-dose CMD treatment and dexamethasone intervention. The expression of TGF-β1 and Smad7 protein increased, whereas the expression of Smad3 protein decreased in the model group compared to other groups. In the CMD high-dose group, low-dose group, and dexamethasone intervention group, the IL-17 concentrations in lung tissue homogenates were decreased, while IL-10 levels were increased. Again, there was a significant difference between CMD high-dose and control treatment, but not between CMD high-dose treatment and dexamethasone intervention. Thus, positive effects of CMD against asthmatic airway remodeling may be due to its regulatory effect on TGF-β1, Smad3, and Smad7 protein levels and on cytokines such as IL-10 and IL-17.
- Published
- 2016
31. Airway architect Adam33 in asthma
- Author
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Mallar Bhattacharya
- Subjects
House dust mite ,education.field_of_study ,medicine.diagnostic_test ,biology ,business.industry ,ADAM33 ,Population ,General Medicine ,respiratory system ,Eosinophil ,medicine.disease ,biology.organism_classification ,respiratory tract diseases ,Allergic inflammation ,medicine.anatomical_structure ,Bronchoalveolar lavage ,Bronchial hyperresponsiveness ,Asthmatic Airway Remodeling ,Immunology ,medicine ,education ,business - Abstract
In asthma, inflammation results in bronchial constriction, mucus hypersecretion, and airway remodeling. This pathology is thought to stem from a collusion of genetic predisposition and environmental factors, such as viruses or allergens, but specific airway molecules that choreograph the interaction between genes and environment remain unidentified. Genetic polymorphisms in ADAM33, a membrane-anchored protease expressed in multiple airway cell types, have been associated in population studies with asthma susceptibility and bronchial hyperresponsiveness. Davies et al. explored the pathobiology of this protein and have discovered a link between ADAM33 and allergic inflammation. The authors first found that the expression of enzymatically active ADAM33 was increased in bronchoalveolar lavage fluid from patients with asthma and in mice sensitized and challenged with house dust mite extract, a model of allergic airway inflammation. Interestingly, inducible overexpression of soluble ADAM33 in the airway of both embryonic and adult mice increased lung expression of genes associated with asthmatic airway remodeling. Human fetal lung explants treated with recombinant ADAM33 had similar gene expression changes but not when treated with a recombinant mutant lacking protease activity. Interestingly, ADAM33 overexpression alone did not increase inflammatory genes or cause bronchial hyperresponsiveness. However, the authors found an interaction between ADAM33 and the allergic stimulus: induction of soluble ADAM33 overexpression in the house dust mite model increased bronchial hyperresponsiveness, bronchoalveolar lavage eosinophilia, and lung expression of genes associated with T helper 2 (TH2) inflammation compared with the house dust mite model alone. Furthermore, ADAM33–/– mice in the house dust mite model were protected from airway remodeling and also had decreased bronchial hyperresponsivness, bronchoalveolar lavage eosinophil count, and lung expression of TH2 genes. Of note, airway remodeling could be reversed with cessation of transgene induction, which suggests that inhibition of ADAM33 could reverse airway pathology related to allergic inflammation. Taken together, these studies establish that ADAM33 mediates the airway inflammatory and remodeling effects of allergen and is a potential therapeutic target for asthma. Future studies aiming for clinical translation should devise strategies for inhibition of ADAM33 in vivo and test its role in other models of asthmatic airway inflammation. E. R. Davies et al. , Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight 1 , e87632 (2016). [[Full Text]][1] [1]: https://insight.jci.org/articles/view/87632
- Published
- 2016
32. Calpain-activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma
- Author
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Ju Fang, Jie Yang, Peng-Cheng Cai, Fei Liu, Qian Zhang, Peter A. Greer, Yunchao Su, Huan-Zhong Shi, Yu Zeng, Shan-Shan Rao, Wan-Li Ma, Qing Mu, Lin-Jie Song, Li-Ling Zhou, Hong Ye, Feng‐Zhi Li, Yu Xia, and Yu‐Xiu Lin
- Subjects
0301 basic medicine ,Immunology ,Myocytes, Smooth Muscle ,Inflammation ,Mechanistic Target of Rapamycin Complex 2 ,Biology ,mTORC2 ,Collagen Type I ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Animals ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Mice, Knockout ,Akt/PKB signaling pathway ,Calpain ,Muscle, Smooth ,Dipeptides ,Asthma ,respiratory tract diseases ,3. Good health ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Rapamycin-Insensitive Companion of mTOR Protein ,030220 oncology & carcinogenesis ,Asthmatic Airway Remodeling ,Knockout mouse ,biology.protein ,Airway Remodeling ,Cytokines ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Background Allergic asthma is characterized by inflammation and airway remodeling. Airway remodeling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in airway smooth muscle remodeling remains unknown. Objective To investigate the role of calpain in asthmatic airway remodeling as well as the underling mechanism. Methods The mouse asthma model was made by ovalbumin sensitization and challenge. Calpain conditional knockout mice were studied in the model. Airway smooth muscle cells (ASMCs) were isolated from smooth muscle bundles in airway of rats. Cytokines IL-4, IL-5, TNF-α and TGF-β1, and serum from asthmatic patients were selected to treated ASMCs. Collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs were analyzed. Results Inhibition of calpain using calpain knockout mice attenuated airway smooth muscle remodeling in mouse asthma models. Cytokines IL-4, IL-5, TNF-α and TGF-β1, and serum from asthmatic patients increased collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs, which were blocked by the calpain inhibitor MDL28170. Moreover, MDL28170 reduced cytokine-induced increases in Rictor protein which is the most important component of mammalian target of rapamycin complex 2 (mTORC2). Blockage of the mTORC2 signal pathway prevented cytokine-induced phosphorylation of Akt, collagen-I synthesis and cell proliferation of ASMCs, and attenuated airway smooth muscle remodeling in mouse asthma models. Conclusions Our results indicate that calpain mediates cytokine-induced collagen-I synthesis and proliferation of ASMCs via the mTORC2/Akt signaling pathway, thereby regulating airway smooth muscle remodeling in asthma. This article is protected by copyright. All rights reserved.
- Published
- 2015
33. Integrin αvβ5-Mediated TGF-β Activation by Airway Smooth Muscle Cells in Asthma
- Author
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Gisli Jenkins, Linhua Pang, Dean Sheppard, Amanda L. Tatler, Anthony Habgood, Xiaozhu Huang, Lisa Jolly, Alison E. John, J Porte, Alan J. Knox, and Christopher E. Brightling
- Subjects
medicine.medical_treatment ,Blotting, Western ,Myocytes, Smooth Muscle ,Respiratory System ,Immunology ,Integrin ,Enzyme-Linked Immunosorbent Assay ,Cell Separation ,Real-Time Polymerase Chain Reaction ,Transfection ,Article ,Cell Line ,Extracellular matrix ,Mice ,Transforming Growth Factor beta ,medicine ,Animals ,Humans ,Immunoprecipitation ,Immunology and Allergy ,Myocyte ,Receptors, Vitronectin ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Transforming growth factor beta ,respiratory system ,Flow Cytometry ,Immunohistochemistry ,Asthma ,respiratory tract diseases ,Cell biology ,Cytokine ,Asthmatic Airway Remodeling ,biology.protein ,Airway Remodeling ,Bronchoconstriction ,medicine.symptom - Abstract
Severe asthma is associated with airway remodeling, characterized by structural changes including increased smooth muscle mass and matrix deposition in the airway, leading to deteriorating lung function. TGF-β is a pleiotropic cytokine leading to increased synthesis of matrix molecules by human airway smooth muscle (HASM) cells and is implicated in asthmatic airway remodeling. TGF-β is synthesized as a latent complex, sequestered in the extracellular matrix, and requires activation for functionality. Activation of latent TGF-β is the rate-limiting step in its bioavailability. This study investigated the effect of the contraction agonists LPA and methacholine on TGF-β activation by HASM cells and its role in the development of asthmatic airway remodeling. The data presented show that LPA and methacholine induced TGF-β activation by HASM cells via the integrin αvβ5. Our findings highlight the importance of the β5 cytoplasmic domain because a polymorphism in the β5 subunit rendered the integrin unable to activate TGF-β. To our knowledge, this is the first description of a biologically relevant integrin that is unable to activate TGF-β. These data demonstrate that murine airway smooth muscle cells express αvβ5 integrins and activate TGF-β. Finally, these data show that inhibition, or genetic loss, of αvβ5 reduces allergen-induced increases in airway smooth muscle thickness in two models of asthma. These data highlight a mechanism of TGF-β activation in asthma and support the hypothesis that bronchoconstriction promotes airway remodeling via integrin mediated TGF-β activation.
- Published
- 2011
34. The Role of Bone Marrow-Derived Adult Stem Cells in a Transgenic Mouse Model of Allergic Asthma
- Author
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Xinpeng Han, Hai-Feng Ou-Yang, Chang-Gui Wu, Xin-Yu Ti, and Feng Zhao
- Subjects
Pulmonary and Respiratory Medicine ,Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Cellular differentiation ,Bone Marrow Cells ,Mice, Transgenic ,Inflammation ,Mice ,Immunity ,Hypersensitivity ,medicine ,Animals ,Asthma ,Immunity, Cellular ,business.industry ,Cell Differentiation ,respiratory system ,Flow Cytometry ,Hematopoietic Stem Cells ,medicine.disease ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,Immunology ,Airway Remodeling ,Female ,Bone marrow ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,Adult stem cell - Abstract
Background: Asthmatic airway remodeling is an abnormal injury/repair process of the small airways caused by chronic inflammation in which the quantities of multiple cells increase dramatically. However, the origin of these proliferative cells is still undetermined. Objective: The aim of this study was to examine whether bone marrow (BM)-derived adult stem cells are responsible for the proliferative cells in asthmatic airway remodeling. Methods: Adult mice were durably engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. Using GFP BM chimera mice, an ovalbumin (OVA)-induced chronic asthma mouse model was established. The distribution of BM-derived GFP+ cells in the lungs of chronic asthma mice was detected by fluorescence microscopy. The phenotype of BM-derived GFP+ cells in the lung tissues of chronic asthma mice was analyzed by flow cytometry. Results: BM chimera mice were successfully generated, with no detectable radioactive inflammation observed. Using BM chimera mice, we established a mouse model of chronic asthma characterized by a significant increase in the thickness of the airway subepithelial basement membrane and smooth muscle layers. OVA treatment caused many GFP+ cells to appear at sites of small airway inflammation. The extravascular localization of some GFP+ cells and their morphology were not consistent with leukocytes. Flow cytometric analysis of lung cells revealed a significant increase in type I collagen (Col I)+GFP+ cells and α-smooth muscle actin (α-SMA)+GFP+ cells in OVA-treated GFP BM chimera mice. Conclusions: Considerable numbers of Col I- and α-SMA-producing cells originated from BM in the lung tissues of mice with OVA-induced chronic asthma.
- Published
- 2011
35. Airway remodeling in asthma
- Author
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Qutayba Hamid, Rabih Halwani, and Saleh Al-Muhsen
- Subjects
Pathology ,medicine.medical_specialty ,Mild asthma ,Inflammation ,Severity of Illness Index ,Drug Discovery ,medicine ,Animals ,Humans ,Asthma ,Pharmacology ,business.industry ,Decreased pulmonary function ,respiratory system ,medicine.disease ,Pathophysiology ,respiratory tract diseases ,Airway wall ,Asthmatic Airway Remodeling ,Immunology ,Bronchial Hyperreactivity ,Inflammation Mediators ,medicine.symptom ,Airway ,business - Abstract
Asthmatic airway remodeling is the pathophysiological modifications of the normal airway wall structure which include changes in the composition and organization of its cellular and molecular constituents. These modifications are the major cause of the symptoms associated with decreased pulmonary function. Airway remodeling is partially reversible in mild asthma but mostly irreversible in chronic severe asthma. It is initiated as a repair process in response to airway wall injuries caused by inflammation; however, dysregulation of this process leads to airway remodeling. In this review, we will summarize the most recent findings about the different structural changes in airways of asthmatics as well as mediators involved in this process.
- Published
- 2010
36. Allergen-induced, eotaxin-rich, proangiogenic bone marrow progenitors: A blood-borne cellular envoy for lung eosinophilia
- Author
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Kewal Asosingh, Serpil C. Erzurum, Mark A. Aronica, Jodi Hanson, and Georgiana Cheng
- Subjects
Adult ,Chemokine CCL11 ,Male ,Pathology ,medicine.medical_specialty ,Endothelium ,Ovalbumin ,Angiogenesis ,Immunology ,Neovascularization, Physiologic ,Bone Marrow Cells ,Endothelial progenitor cell ,Article ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Pulmonary Eosinophilia ,Chemoattractant activity ,Mice, Inbred BALB C ,business.industry ,Stem Cells ,Allergens ,respiratory system ,Eosinophil ,Asthma ,respiratory tract diseases ,Eosinophils ,Endothelial stem cell ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,cardiovascular system ,Airway Remodeling ,Female ,Bone marrow ,business - Abstract
Background Eosinophilic inflammation is closely related to angiogenesis in asthmatic airway remodeling. In ovalbumin (OVA)–sensitized mice bone marrow–derived, proangiogenic endothelial progenitor cells (EPCs) are rapidly recruited into the lungs after OVA aerosol challenge and promptly followed by mobilization and recruitment of eosinophils. Objective We hypothesized that bone marrow–derived EPCs initiate the recruitment of eosinophils through expression of the eosinophil chemoattractant eotaxin-1. Methods EPCs were isolated from an OVA murine model of allergic airway inflammation and from asthmatic patients. Endothelial and smooth muscle cells were isolated from mice. Eotaxin-1 expression was analyzed by means of immunofluorescence, real-time PCR, or ELISA. In vivo recruitment of eosinophils by EPCs was analyzed in mice. Results Circulating EPCs of asthmatic patients had higher levels of eotaxin-1 compared with those seen in control subjects. In the murine model OVA allergen exposure augmented eotaxin-1 mRNA and protein levels in EPCs. The EPCs from OVA-sensitized and OVA-challenged mice released high levels of eotaxin-1 on contact with lung endothelial cells from sensitized and challenged mice but not from control animals and not on contact with cardiac or hepatic endothelial cells from sensitized and challenged mice. Intranasal administration of the eotaxin-rich media overlying cultures of EPCs caused recruitment into the lungs, confirming functional chemoattractant activity. Conclusions Bone marrow–derived EPCs are early responders to environmental allergen exposures and initiate a parallel switch to a proangiogenic and proeosinophilic environment in the lungs of asthmatic patients.
- Published
- 2010
37. Cultured Lung Fibroblasts from Ovalbumin-Challenged 'Asthmatic' Mice Differ Functionally from Normal
- Author
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Lijun Mao, Shinsaku Togo, Hisatoshi Sugiura, Fenghai Duan, Shin Kawasaki, Thomas B. Casale, Ronald F. Ertl, Stephen I. Rennard, Koichiro Kamio, Xingqi Wang, Youngsoo Ahn, A.I. Berro, Xiangde Liu, and Tom Bargar
- Subjects
Vascular Endothelial Growth Factor A ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Ovalbumin ,Clinical Biochemistry ,Bronchial Provocation Tests ,Transforming Growth Factor beta1 ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Fibroblast ,Lung ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,Chemotaxis ,Articles ,Cell Biology ,Fibroblasts ,Actins ,Asthma ,Fibronectins ,Rats ,Vascular endothelial growth factor ,Fibronectin ,Disease Models, Animal ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Asthmatic Airway Remodeling ,Immunology ,biology.protein ,Female ,Collagen ,Smooth muscle hypertrophy ,Gels ,Transforming growth factor - Abstract
Asthmatic airway remodeling is characterized by goblet cell hyperplasia, angiogenesis, smooth muscle hypertrophy, and subepithelial fibrosis. This study evaluated whether acquired changes in fibroblast phenotype could contribute to this remodeling. Airway and parenchymal fibroblasts from control or chronically ovalbumin (OVA)-sensitized and challenged "asthmatic" mice were assessed for several functions related to repair and remodeling +/- exogenous transforming growth factor (TGF)-beta. All OVA-challenged mouse fibroblasts demonstrated augmented gel contraction (P < 0.05) and chemotaxis (P < 0.05); increased TGF-beta(1) (P < 0.05), fibronectin (P < 0.05), and vascular endothelial growth factor (P < 0.05) release; and expressed more alpha-smooth muscle actin (P < 0.05). TGF-beta(1) stimulated both control and asthmatic fibroblasts, which retained all differences from control fibroblasts for all features(P < 0.05, all comparisons). Parenchymal fibroblasts proliferated more rapidly (P < 0.05), while airway fibroblasts proliferated similarly compared with control fibroblasts (P = 0.25). Thus, in this animal model, OVA-challenged mouse fibroblasts acquire a distinct phenotype that differs from control fibroblasts. The augmented profibrotic activity and mediator release of asthmatic fibroblasts could contribute to airway remodeling in asthma.
- Published
- 2007
38. FSTL1 PROMOTES ASTHMATIC AIRWAY REMODELING BY INDUCING ONCOSTATIN M
- Author
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David H. Broide, Peter Rosenthal, Seema S. Aceves, Michael Croft, Qutayba Hamid, Sudipta Das, Alexa Pham, Taylor A. Doherty, Andrew Beppu, Fazila Chouiali, Christine Vuong, Xu Zhang, Bruce L. Zuraw, Xiang Gao, Maya R. Karta, Marina Miller, and Dae J.in Song
- Subjects
Male ,Follistatin-Related Proteins ,medicine.medical_treatment ,Immunology ,Inflammation ,Oncostatin M ,Article ,Antibodies ,Mice ,Pulmonary fibrosis ,medicine ,Immunology and Allergy ,Animals ,Humans ,Asthma ,Lung ,biology ,business.industry ,Macrophages ,fungi ,respiratory system ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Cytokine ,Asthmatic Airway Remodeling ,biology.protein ,Airway Remodeling ,Female ,medicine.symptom ,Airway ,business ,Signal Transduction - Abstract
Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cretg /Fstl1Δ/Δ mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma.
- Published
- 2015
39. Effect of nuclear factor-κB on airway remodeling in asthmatic rats
- Author
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Zhang Zhenxiang, Ni Wang, Xu Shuyun, XU Yong-jian, and Chen Shi-xin
- Subjects
medicine.medical_specialty ,Pathology ,Pyrrolidines ,Ovalbumin ,Respiratory System ,Biomedical Engineering ,Biochemistry ,Epithelium ,Biomaterials ,Mice ,chemistry.chemical_compound ,Western blot ,Pyrrolidine dithiocarbamate ,Thiocarbamates ,Internal medicine ,Genetics ,medicine ,Animals ,Electrophoretic mobility shift assay ,Rats, Wistar ,Lung ,Earth-Surface Processes ,Basement membrane ,biology ,medicine.diagnostic_test ,Chemistry ,NF-kappa B ,Transcription Factor RelA ,respiratory system ,Asthma ,Rats ,medicine.anatomical_structure ,Endocrinology ,Asthmatic Airway Remodeling ,biology.protein ,Immunohistochemistry ,I-kappa B Proteins ,Rabbits ,Airway - Abstract
In order to investigate the effect of nuclear factor-kappaB (NF-kappaB) on airway remodeling in asthmatic rats, 18 Wistar rats were divided into three groups: asthmatic group; pyrrolidine dithiocarbamate (PDTC) group, in which rats were injected intraperitoneally with NF-kappaB specific inhibitor PDTC (100 mg/kg) before ovalbumin (OVA) challenge; control group. The NF-kappaB activity and the expression of inhibitory protein kappaBalpha (I-kappaBalpha) in airway were detected by electrophoretic mobility shift assay (EMSA), Western blot and immunohistochemistry respectively. The infiltration of inflammatory cells, the number of Goblet cells, the area of collagen and smooth muscle in airway were measured by means of image analysis system. The results showed that with the up-regulation of airway NF-kappaB activity in asthmatic group, the number of goblet cells (3.084 +/- 0.86/100 microm basement membrane (BM)), the area of collagen (24.71 +/- 4.24 microm2/microm BM) and smooth muscle (13.81 +/- 2.11 microm2/microm BM) in airway were significantly increased (P0.05) as compared with control group (0.14 +/- 0.05/100 microm BM, 14.31 +/- 3.16 microm2/microm BM and 7.67 +/- 2.35 microm2/microm BM respectively) and PDTC group (0.33 +/- 0.14/100 microm BM, 18.16 +/- 2.85 microm/microm BM and 8.95 +/- 2.16 microm2/microm BM respectively). However, there was no significant difference between PDTC group and control group (P0.05). It was concluded that the activity of NF-kappaB is increased in airway of asthmatic rats. Inhibition of NF-kappaB activation can attenuate constructional changes in asthma airway, suggesting NF-kappaB may contribute to asthmatic airway remodeling.
- Published
- 2004
40. Airway Structural Alterations Selectively Associated with Severe Asthma
- Author
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Anne Druilhe, Michel Aubier, Marina Pretolani, Marie-Christine Dombret, and Laurent Benayoun
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Myosin light-chain kinase ,macromolecular substances ,Critical Care and Intensive Care Medicine ,Risk Assessment ,Sensitivity and Specificity ,Severity of Illness Index ,Muscle hypertrophy ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,Sex Factors ,Reference Values ,medicine ,Humans ,Aged ,Probability ,Asthma ,Bronchus ,Lung ,business.industry ,Airway Resistance ,Biopsy, Needle ,Respiratory disease ,Age Factors ,Muscle, Smooth ,Middle Aged ,respiratory system ,Eosinophil ,medicine.disease ,Immunohistochemistry ,Respiratory Function Tests ,respiratory tract diseases ,medicine.anatomical_structure ,Case-Control Studies ,Asthmatic Airway Remodeling ,Multivariate Analysis ,Regression Analysis ,Female ,Bronchial Hyperreactivity ,business ,Bronchoalveolar Lavage Fluid - Abstract
To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins alpha-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.
- Published
- 2003
41. Interleukin-20 promotes airway remodeling in asthma
- Author
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Qian Dong, Chunyan Xing, Jiping Zhao, Qi Chu, Liang Dong, Wenbin Gong, Xin Wang, Guicheng Wang, Yuguo Zhang, Yuanyuan Zhang, Junfei Wang, Tian Liu, and Junqing Hao
- Subjects
Adult ,Male ,medicine.medical_treatment ,Immunology ,Lupus nephritis ,Mice ,Young Adult ,Interleukin 20 ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Receptor ,Cells, Cultured ,Asthma ,Mice, Inbred BALB C ,business.industry ,Interleukins ,respiratory system ,medicine.disease ,respiratory tract diseases ,Cytokine ,Asthmatic Airway Remodeling ,Respiratory epithelium ,Airway Remodeling ,Cytokines ,Female ,Airway ,business - Abstract
Previous studies have demonstrated that interleukin-20 (IL-20) is a pro-inflammatory cytokine, and it has been implicated in psoriasis, lupus nephritis, rheumatoid arthritis, atherosclerosis, and ulcerative colitis. Little is known about the effects of IL-20 in airway remodeling in asthma. The aim of our study was to demonstrate the function of IL-20 in airway remodeling in asthma. To identify the expression of IL-20 and its receptor, IL-20R1/IL-20R2, in the airway epithelium in bronchial tissues, bronchial biopsy specimens were collected from patients and mice with asthma and healthy subjects and stained with specific antibodies. To characterize the effects of IL-20 in asthmatic airway remodeling, we silenced and stimulated IL-20 in cell lines isolated from mice by shRNA and recombinant protein approaches, respectively, and detected the expression of α-SMA and FN-1 by Western blot analysis. First, overexpression of IL-20 and its receptor, IL-20R1/IL-20R2, was detected in the airway epithelium collected from patients and mice with asthma. Second, IL-20 increased the expression of fibronectin-1 and α-SMA, and silencing of IL-20 in mouse lung epithelial (MLE)-12 cells decreased the expression of fibronectin-1 and α-SMA. IL-20 may be a critical cytokine in airway remodeling in asthma. This study indicates that targeting IL-20 and/or its receptors may be a new therapeutic strategy for asthma.
- Published
- 2014
42. IL-33 promotes airway remodeling and is a marker of asthma disease severity
- Author
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Shuying Liu, Jiping Zhao, Jinxiang Wu, Zhi Guo, Fen Liu, Liquan Bi, Liang Dong, and Yingjian Chen
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,Immunoglobulin E ,Severity of Illness Index ,Pulmonary function testing ,Immunology and Allergy ,Medicine ,Bronchial Biopsy ,Humans ,Asthma ,biology ,business.industry ,Interleukins ,medicine.disease ,Interleukin-33 ,respiratory tract diseases ,Interleukin 33 ,Asthmatic Airway Remodeling ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Sputum ,Airway Remodeling ,Female ,medicine.symptom ,Airway ,business ,Biomarkers - Abstract
To investigate the function of interleukin-33 (IL-33) in the asthmatic airway remodeling and the relationship between IL-33 and asthma severity.IL-33 levels, sputum eosinophils percentage (EOS%), pulmonary function and total immunoglobulin (IgE) were measured for 45 patients with asthma and 40 non-allergic controls. Asthma severity was assessed. The expressions of IL-33 and reticular basement membrane (RBM) on bronchial biopsy specimens from eight asthma patients and eight non-allergic controls were observed after hematoxylin-eosin staining (HE) and immunohistochemical staining. In vitro experiments, real-time polymerase chain reactions and western blotting analysis were used to identify the specific effects of IL-33 administration.Serum IL-33 levels in patients with asthma were higher than those in non-allergic controls. Moreover, in asthmatic patients, serum IL-33 levels were negatively correlated to forced expiratory volume in one second (FEV1, % predicted), and positively correlated to asthma severity. Increased expression of IL-33 and RBM thickening were observed on bronchial biopsy specimens obtained from patients with asthma. Serum IL-33 levels were positively correlated to basement membrane thickness. The production of fibronectin1 and type I collagen in human lung fibroblasts (HLF-1) increased at 24 h after IL-33 treatment in vitro. Pre-treatment with anti-ST2 antibody or fluticasone propionate (FP) suppressed the production of fibronectin1 and types I collagen induced by IL-33.IL-33 is a marker of asthma severity, and may contribute to airway remodeling in asthma by acting on human lung fibroblasts.
- Published
- 2014
43. Effect of TRPV1 channel on proliferation and apoptosis of airway smooth muscle cells of rats
- Author
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Limin Zhao, Hong-yan Kuang, Xiao-yu Zhang, Jizhen Wu, Xian-liang Chen, Luo-xian Zhang, and Lijun Ma
- Subjects
medicine.medical_specialty ,Myocytes, Smooth Muscle ,Biomedical Engineering ,TRPV1 ,TRPV Cation Channels ,Apoptosis ,Bronchi ,Biology ,Biochemistry ,Calcium in biology ,Biomaterials ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,Genetics ,medicine ,Myocyte ,Animals ,MTT assay ,Calcium Signaling ,Earth-Surface Processes ,Cell Proliferation ,Antipruritics ,Cell biology ,Rats ,Endocrinology ,chemistry ,Capsaicin ,Asthmatic Airway Remodeling ,lipids (amino acids, peptides, and proteins) ,Capsazepine - Abstract
Airway remodeling is an important pathological feature of asthma and the basis of severe asthma. Proliferation of airway smooth muscle cells (ASMCs) is a major contributor to airway remodeling. As an important Ca(2+) channel, transient receptor potential vanilloid 1 (TRPV1) plays the key role in the cell pathological and physiological processes. This study investigated the expression and activity of TRPV1 channel, and further clarified the effect of TRPV1 channel on the ASMCs proliferation and apoptosis in order to provide the scientific basis to treat asthmatic airway remodeling in clinical practice. Immunofluorescence staining and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the expression of TRPV1 in rat ASMCs. Intracellular Ca(2+) was detected using the single cell confocal fluorescence microscopy measurement loaded with Fluo-4/AM. The cell cycles were observed by flow cytometry. MTT assay and Hoechst 33258 staining were used to detect the proliferation and apoptosis of ASMCs in rats respectively. The data showed that: (1) TRPV1 channel was present in rat ASMCs. (2) TRPV1 channel agonist, capsaicin, increased the Ca(2+) influx in a concentration-dependent manner (EC50=284.3±58 nmol/L). TRPV1 channel antagonist, capsazepine, inhibited Ca(2+) influx in rat ASMCs. (3) Capsaicin significantly increased the percentage of S+G2M ASMCs and the absorbance of MTT assay. Capsazepine had the opposite effect. (4) Capsaicin significantly inhibited the apoptosis, whereas capsazepine had the opposite effect. These results suggest that TRPV1 is present and mediates Ca(2+) influx in rat ASMCs. TRPV1 activity stimulates proliferation of ASMCs in rats.
- Published
- 2013
44. Effects of baicalin on airway remodeling in asthmatic mice
- Author
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Jing Sun, Yubao Lv, Qingli Luo, Jingcheng Dong, Baojun Liu, Weiyi Gong, Lulu Li, Jinfeng Wu, and Xiao-Hong Duan
- Subjects
MAPK/ERK pathway ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Ovalbumin ,Pharmaceutical Science ,Inflammation ,Analytical Chemistry ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Mice ,Internal medicine ,Drug Discovery ,medicine ,Extracellular ,Animals ,Anti-Asthmatic Agents ,Extracellular Signal-Regulated MAP Kinases ,Lung ,Plethysmography, Whole Body ,Pharmacology ,Flavonoids ,Mice, Inbred BALB C ,Interleukin-13 ,medicine.diagnostic_test ,biology ,business.industry ,Organic Chemistry ,respiratory system ,Asthma ,Vascular endothelial growth factor ,Disease Models, Animal ,Endocrinology ,Bronchoalveolar lavage ,Complementary and alternative medicine ,chemistry ,Asthmatic Airway Remodeling ,biology.protein ,Molecular Medicine ,Airway Remodeling ,Cytokines ,Female ,medicine.symptom ,business ,Baicalin ,Bronchoalveolar Lavage Fluid - Abstract
Airway remodeling is an important characteristic of asthma, linking inflammation with airway hyperresponsiveness. Baicalin, a major active component, was isolated from Radix Scutellariae. Many studies show that baicalin has anti-inflammatory, anti-bacterial, and anti-allergic effects. Here we investigate the influence of baicalin on asthmatic airway remodeling and the mechanism underlining the anti-remodeling effect in vivo. Asthmatic airway remodeling mice model was established by ovalbumin exposure. Seventy female BALB/c mice were randomly assigned to seven experimental groups: blank, ovalbumin, hexadecadrol, control, and baicalin (25 mg/kg, 50 mg/kg, 100 mg/kg) groups. Pulmonary function was measured using a whole-body plethysmograph in conscious and unrestrained mice. The lung pathology was observed and measured. The production of cytokines in bronchoalveolar lavage fluid and serum was measured using enzyme-labeled immunosorbent assay kits, and the expression levels of transforming growth factor-β 1 and vascular endothelial growth factor were detected by immunohistochemistry. The protein expression levels of transforming growth factor-β 1, vascular endothelial growth factor, extracellular signal–regulated kinase, and p21ras were measured using Western blot. The results show that ovalbumin exposure significantly increased the expression of interleukin-13 in BALF and serum, and transforming growth factor-β 1, vascular endothelial growth factor, extracellular signal–regulated kinase and p21ras expressions in the lungs. Baicalin attenuated the effects of ovalbumin significantly. It can be concluded that baicalin has significant anti-remodeling effect on ovalbumin-induced asthmatic airway remodeling mice model by decreasing expression of transforming growth factor-β 1, interleukin-13, and vascular endothelial growth factor and inhibiting the activation of the extracellular signal–regulated kinase pathway.
- Published
- 2013
45. Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice
- Author
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Zhangwei Qiu, Xuejun Qin, Y.-W. Li, Huahao Shen, Pingli Wang, Gensheng Zhang, Xue Zhang, Qiang-min Xie, Yuehai Ke, James J. Lee, and Wei Li
- Subjects
Male ,Chemokine ,Ovalbumin ,Immunology ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Inflammation ,Respiratory Mucosa ,Article ,Allergic inflammation ,Transforming Growth Factor beta1 ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myofibroblasts ,Lung ,Mice, Knockout ,biology ,Allergens ,Fibroblasts ,respiratory system ,Asthma ,respiratory tract diseases ,Disease Models, Animal ,Gene Expression Regulation ,Asthmatic Airway Remodeling ,Gene Targeting ,biology.protein ,Airway Remodeling ,Respiratory epithelium ,Female ,Collagen ,Smooth muscle hypertrophy ,medicine.symptom ,Signal transduction ,Airway - Abstract
Asthma remains a common chronic inflammatory disease whose incidence has markedly increased over the past two decades. In addition, the chronic inflammation associated with a given patient is often linked with the remodeling of airway structure that may impair lung function [1, 2]. These changes include peribronchial fibrosis, fibroblast proliferation and conversion to myofibroblasts, and smooth muscle hypertrophy [3]. Although these features are well recognized, the mechanisms leading to remodeling and the effect of therapy on preventing or reversing these changes are largely unknown. A variety of cells, cytokines, chemokines, and growth factors that are released from inflammatory and structural cells in the airway have been implicated in promoting airway inflammation and, in turn, remodeling events. Furthermore, the cross-talk between epithelium and the underlying mesenchyme appears to be critical for driving remodeling responses in asthma. Findings from long-term patient studies, which have been ongoing for more than a decade, have indicated that transforming growth factor-β1 (TGF-β1) may be an important mediator of allergic inflammation and airway remodeling. TGF-β1 is produced by various cell types in the lung, such as airway epithelial cells and leukocytes comprising the pulmonary pro-inflammatory cell infiltrate [4, 5], and more recent studies suggested that this pulmonary TGF-β1 contributes to subepithelial fibrosis and airway smooth muscle remodeling linked with many asthma patients [6, 7]. An important positive regulator of many growth factor signaling pathways, including TGF-β, is the protein tyrosine phosphatase SHP2. SHP2 is a cytoplasmic phosphotyrosine phosphatase with two SH2 domains (N-SHP2 and C-SHP2) that is widely expressed in the airway epithelium [8]. Studies of allergic respiratory inflammation have also identified SHP2 as both a positive and negative regulator of key pulmonary immune signaling pathways. These SHP2 functions include fine-tuning of cellular response to cytokines [9–12], effects on inhibitory receptor signaling [13–15], and mediating T-cell development and function [16–18]. In the present study, the role of SHP2 expression in airway epithelial cells was defined further using a mouse model of chronic allergen exposure that is accompanied by characteristic airway remodeling events. These studies avoid the early embryonic lethality associated with homozygous shp2 knockout mice [19, 20] and instead exploit an inducible shp2 knockout strategy to specifically delete the expression in the mouse airway epithelia. Airway epithelial cell shp2 expression was linked with the airway remodeling events following chronic allergen exposure. Subsequent cell culture studies with BEAS-2B airway epithelial cells showed that the shp2-mediated airway remodeling occurring in mice may be mediated by the regulation of airway epithelial TGF-β1 production. These data suggest that shp2 may be a key regulator of airway remodeling events and thus a previously underappreciated therapeutic target.
- Published
- 2012
46. Inhibiting or blocking LIGHT, a TNF superfamily member, for treating airway remodeling
- Author
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Mario Cazzola, Maria Gabriella Matera, Cazzola, and Matera, Maria Gabriella
- Subjects
Pulmonary and Respiratory Medicine ,Lung ,business.industry ,Settore MED/10 - Malattie dell'Apparato Respiratorio ,Public Health, Environmental and Occupational Health ,Smooth muscle hyperplasia ,respiratory system ,medicine.disease ,respiratory tract diseases ,Blockade ,medicine.anatomical_structure ,Fibrosis ,Asthmatic Airway Remodeling ,Immunology ,medicine ,Immunology and Allergy ,Eosinophilia ,Tumor necrosis factor alpha ,medicine.symptom ,Airway ,business - Abstract
Evaluation of: Doherty TA, Soroosh P, Khorram N et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat. Med. 17, 596–603 (2011).Individuals with chronic asthma demonstrate a progressive decline in lung function that is thought to be due to structural remodeling of the airways, characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we report on a recent publication showing that the tumor necrosis factor family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin-β-receptor reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung TGF-β and IL-13, cytokines implicated...
- Published
- 2011
47. Tissue remodeling in patients with eosinophilic esophagitis: what lies beneath the surface?
- Author
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Seema S. Aceves
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Muscularis mucosae ,Immunology ,Anti-Inflammatory Agents ,Gene Expression ,Fibrosis ,Biopsy ,Immunology and Allergy ,Medicine ,Humans ,Eosinophilic esophagitis ,Lamina propria ,medicine.diagnostic_test ,business.industry ,Hypereosinophilic syndrome ,Eosinophilic Esophagitis ,medicine.disease ,Esophageal Tissue ,Androstadienes ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,Cytokines ,Fluticasone ,Female ,Collagen ,business - Abstract
The concept of eosinophil-associated tissue remodeling and fibrosis has its roots in the hypereosinophilic syndrome and asthmatic airways. In asthmatic patients TH2-associated eotaxins and interleukins activate eosinophils to release granule products and growth factors that propagate inflammation and cause tissue damage. Continual and recurrent dysregulated repair leads to tissue remodeling with subsequent fibrosis and end-organ dysfunction. The reversibility, natural history, and clinical consequences of eosinophil-associated remodeling have been largely debated, especially in human disease, in which the paucity of tissue for repeated analysis has been a rate-limiting factor in our understanding. The availability of adequate surrogate markers in patients with disorders such as asthma has obviated any clinical requirement for direct tissue assessment. In contrast, eosinophilic esophagitis (EoE), a relatively recently described antigen-driven disease of increasing worldwide prevalence, by its definition requires microscopic esophageal tissue evaluation for its diagnosis and management. This necessity for repeated histologic analysis allows EoE to function as a new model for studying allergic, eosinophil-associated remodeling over time. Although asthmatic airway remodeling has been hypothesized to begin in early childhood, the ability to study airway tissue in children remains elusive. EoE, on the other hand, affords the potential to monitor the genesis and evolution of remodeling in young children. However, despite readily available esophageal tissue, remodeling analysis in patients with EoE still has its challenges. Esophageal biopsy specimens are small, approximately 3 mm. Although the esophageal epithelium is uniformly available from all biopsy specimens, only the minority of biopsy specimens contain adequate subepithelial lamina propria (LP) and muscularis mucosa for analysis. Because a large number of remodeling events, including fibrosis and angiogenesis, occur in the LP, this can generally only be studied in a subset of patients with EoE. Whether this required selection of biopsy
- Published
- 2011
48. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling
- Author
-
Naseem Khorram, Taylor A. Doherty, Klaus Pfeffer, Pejman Soroosh, Michael Croft, David H. Broide, Stefanie Scheu, Peter Rosenthal, Heonsik Choi, Jae Youn Cho, Paula S. Norris, Satoshi Fukuyama, Bruce L. Zuraw, and Carl F. Ware
- Subjects
Tumor Necrosis Factor Ligand Superfamily Member 14 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Mice ,Fibrosis ,Transforming Growth Factor beta ,medicine ,Animals ,Humans ,Lung ,Mice, Knockout ,Interleukin-13 ,Lymphotoxin alpha1, beta2 Heterotrimer ,General Medicine ,Smooth muscle hyperplasia ,Transforming growth factor beta ,respiratory system ,medicine.disease ,Asthma ,respiratory tract diseases ,Disease Models, Animal ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,Immunology ,Interleukin 13 ,biology.protein ,Airway Remodeling ,Tumor necrosis factor alpha ,Inflammation Mediators ,Transforming growth factor ,Signal Transduction - Abstract
Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.
- Published
- 2010
49. Corticosteroids and montelukast: effects on airway epithelial and human umbilical vein endothelial cells
- Author
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Z. Servetnyk, Karin Andersson, Eyman Shebani, Godfried M. Roomans, and N. Makeeva
- Subjects
Pulmonary and Respiratory Medicine ,Cyclopropanes ,Pathology ,medicine.medical_specialty ,Umbilical Veins ,Necrosis ,Endothelium ,Apoptosis ,macromolecular substances ,Respiratory Mucosa ,Acetates ,Sulfides ,Umbilical vein ,Cell Line ,Adrenal Cortex Hormones ,medicine ,Humans ,Anti-Asthmatic Agents ,Montelukast ,business.industry ,Desmosomes ,Intercellular Adhesion Molecule-1 ,Asthma ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,Immunology ,Quinolines ,Respiratory epithelium ,Cytokines ,Leukotriene Antagonists ,Endothelium, Vascular ,medicine.symptom ,Airway ,business ,medicine.drug - Abstract
Our primary objective was to investigate the possible contribution of controller medications to asthmatic airway remodeling, by (1) comparing the apoptotic and necrotic effects of several corticosteroids and montelukast on cultured airway human bronchial surface epithelial (16HBE) and submucosal (Calu3) cells; (2) measuring epithelial shedding potential and desmosome length in response to a cytokine challenge, with or without co-administered corticosteroids; and (3) studying corticosteroids and montelukast effects on inter-cellular adhesion molecule (ICAM) expression in both 16HBE and human umbilical vein endothelial cells (HUVEC). For this purpose, apoptosis, necrosis, and ICAM expression were quantified by flow cytometry, with 16HBE cells sensitive to both the apoptotic and necrotic effects of dexamethasone and montelukast; Calu3 cells sensitive only to budesonide. Transmission electron microscopy revealed decreased desmosome length in the presence of cytokines (TNF-alpha and INF-gamma), with corticosteroids counteracting this reduction. Dexamethasone, beclomethasone, and montelukast decreased versus increased ICAM-1 expression in airway epithelial cells and HUVEC, respectively. For conclusions, bronchial surface epithelial and submucosal cells exhibit a different sensitivity profile toward dexamethasone, budesonide, and montelukast, with corticosteroids preventing cytokineinduced desmosomal damage in 16HBE cells. The studied drugs led to increased ICAM-1 expression in endothelium, potentially facilitating inflammatory cell migration into lung tissue.
- Published
- 2009
50. Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthma
- Author
-
Serpil C. Erzurum, Shadi Swaidani, Kewal Asosingh, and Mark A. Aronica
- Subjects
Adult ,Male ,Angiogenic Switch ,Angiogenesis ,Immunology ,Antigens, CD34 ,Mice, Transgenic ,Endothelial progenitor cell ,Immunophenotyping ,Neovascularization ,Mice ,Th2 Cells ,Antigens, CD ,Cell Movement ,medicine ,Immunology and Allergy ,Animals ,Humans ,AC133 Antigen ,Progenitor cell ,Glycoproteins ,Mice, Inbred BALB C ,Lung ,Neovascularization, Pathologic ,business.industry ,Stem Cells ,Endothelial Cells ,respiratory system ,Th1 Cells ,Asthma ,respiratory tract diseases ,Endothelial stem cell ,medicine.anatomical_structure ,Asthmatic Airway Remodeling ,embryonic structures ,cardiovascular system ,Female ,medicine.symptom ,business ,Peptides ,circulatory and respiratory physiology - Abstract
Increased numbers of submucosal vessels are a consistent pathologic component of asthmatic airway remodeling. However, the relationship between new vessel formation and asthmatic inflammatory response is unknown. We hypothesized that angiogenesis is a primary event during the initiation of airway inflammation and is linked to the recruitment of bone marrow-derived endothelial progenitor cells (EPC). To test this hypothesis, circulating EPC and EPC-derived endothelial cell colony formation of individuals with asthma or allergic rhinitis and health controls was evaluated. Circulating EPC were increased in asthma, highly proliferative, and exhibited enhanced incorporation into endothelial cell tubes as compared with controls. In an acute allergen challenge murine asthma model, EPC mobilization occurred within hours of challenge and mobilized EPC were selectively recruited into the challenged lungs of sensitized animals, but not into other organs. EPC recruitment was Th1 and Th2 dependent and was temporally associated with an increased microvessel density that was noted within 48 h of allergen challenge, indicating an early switch to an angiogenic lung environment. A chronic allergen challenge model provided evidence that EPC recruitment to the lung persisted and was associated with increasing microvessel density over time. Thus, a Th1- and Th2-dependent angiogenic switch with EPC mobilization, recruitment, and increased lung vessel formation occurs early but becomes a sustained and cumulative component of the allergen-induced asthmatic response.
- Published
- 2007
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