32 results on '"Priscilla C. Olsen"'
Search Results
2. Author response for 'MIF is essential to the establishment of house dust mite‐induced airway inflammation and tissue remodeling in mice'
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null Leticia Lintomen, null Luciana M. Kluppel, null Jamil Z. Kitoko, null Elena Montes‐Cobos, null Vinícius Mendes Vidal, null Luis Batista Tan, null José Nazioberto de Farias, null Heitor S. de Souza, null Priscilla C. Olsen, and null Marcelo T. Bozza
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- 2023
3. Multiple doses of adipose tissue‐derived mesenchymal stromal cells induce immunosuppression in experimental asthma
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Debora G. Xisto, Miquéias Lopes-Pacheco, Fernanda F. Cruz, Marcelo M. Morales, Jamil Z. Kitoko, Patricia R. M. Rocco, Ligia Lins de Castro, Herbert Leonel de Matos Guedes, and Priscilla C. Olsen
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0301 basic medicine ,medicine.medical_treatment ,Cell- and Tissue-Based Therapy ,Adipose tissue ,Inflammation ,lung ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Tissue Engineering and Regenerative Medicine ,Medicine ,Animals ,lcsh:QH573-671 ,Dexamethasone ,Immunosuppression Therapy ,lcsh:R5-920 ,immunosuppression ,medicine.diagnostic_test ,business.industry ,lcsh:Cytology ,Mesenchymal stem cell ,Immunosuppression ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,cellular therapy ,Eosinophil ,Asthma ,respiratory tract diseases ,adipose stem cells ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immunology ,Female ,Bone marrow ,medicine.symptom ,business ,mesenchymal stromal cells ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Developmental Biology ,medicine.drug - Abstract
In experimental house dust mite (HDM)‐induced allergic asthma, therapeutic administration of a single dose of adipose tissue‐derived mesenchymal stromal cells (MSCs) ameliorates lung inflammation but is unable to reverse remodeling. We hypothesized that multiple doses of MSCs might exert better therapeutic effects by reducing lung inflammation and remodeling but might also result in immunosuppressive effects in experimental asthma. HDM was administered intranasally in C57BL/6 mice. After the last HDM challenge, mice received two or three doses of MSCs (105 cells per day) or saline intravenously. An additional cohort of mice received dexamethasone as a positive control for immunosuppression. Two and three doses of MSCs reduced lung inflammation, levels of interleukin (IL)‐4, IL‐13, and eotaxin; total leukocyte, CD4+ T‐cell, and eosinophil counts in bronchoalveolar lavage fluid; and total leukocyte counts in bone marrow, spleen, and mediastinal lymph nodes. Two and three doses of MSCs also reduced collagen fiber content and transforming growth factor‐β levels in lung tissue; however, the three‐dose regimen was more effective, and reduced these parameters to control levels, while also decreasing α‐actin content in lung tissue. Two and three doses of MSCs improved lung mechanics. Dexamethasone, two and three doses of MSCs similarly increased galectin levels, but only the three‐dose regimen increased CD39 levels in the thymus. Dexamethasone and the three‐dose, but not the two‐dose regimen, also increased levels of programmed death receptor‐1 and IL‐10, while reducing CD4+CD8low cell percentage in the thymus. In conclusion, multiple doses of MSCs reduced lung inflammation and remodeling while causing immunosuppression in HDM‐induced allergic asthma., Multiple doses of mesenchymal stromal cells (MSCs) reduced lung inflammation and remodeling. However, three‐dose regimen was more effective at reducing remodeling parameters. Dexamethasone, two and three doses of MSCs similarly increased galectin levels, but only the three‐dose regimen increased CD39 levels in thymus. Dexamethasone and the three‐dose regimen, but not the two‐dose regimen, also increased levels of PD‐1 and IL‐10 in thymus.
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- 2020
4. Risk of Zika microcephaly correlates with features of maternal antibodies
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Priscilla C. Olsen, Rubens Belfort, Juliana A Lima, Charles M. Rice, Gustavo B. S Carvalho, David H. O’Connor, Heather A. Simmons, Michael Gale, Rebekah I. Keesler, Gracinda Archanjo, Stephanie A. Azzopardi, Antônio Raimundo Pinto de Almeida, Gustavo Carvalho, Isadora Cristina de Siqueira, Dawn M. Dudley, Federico Costa, Thiago Y. Oliveira, Pedro Fernando da Costa Vasconcelos, Anne D. Lewis, Lois M. A. Colgin, Adeolu Aromolaran, Anna Gazumyan, Jennifer Tisoncik-Go, Gielson Almeida do Sacramento, Kristina M. Adams Waldorf, Manoel Sarno, Ana P Alcântara, Nicole N. Haese, Albert I. Ko, Alec J. Hirsch, Elsio A. Wunder, Meredith A. Kelleher, Bruno de Paula Freitas, Jessica L. Smith, Mitermayer G. Reis, Davide F. Robbiani, Margaret R. MacDonald, Laksmi Rajagopal, Dina Daltro, Dennis Schaefer-Babajew, Ricardo Khouri, Rosemary J. Steinbach, Leonia Bozzacco, Qiao Wang, Daniele Freitas Henriques, Antonio E. Frias, Michel C. Nussenzweig, Lark L. Coffey, Adriana Mattos, Nivison Nery, Andres Mejia, Jaqueline S. Cruz, Licia Moreira, Kleber Pimentel, Daniel N. Streblow, João R. M. de Almeida, Victoria H. J. Roberts, Koen K. A. Van Rompay, Mateus Santana do Rosário, and Katiaci Araujo
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0301 basic medicine ,Microcephaly ,Microcefalia / gen?tica ,Immunology ,Physiology ,Antibodies, Viral ,Article ,Fetal brain ,Zika virus ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Pregnancy ,medicine ,Animals ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Pregnancy Complications, Infectious ,Maternal-Fetal Exchange ,Research Articles ,Fatores de risco ,biology ,Zika Virus Infection ,business.industry ,Brain ,Anomalias Cong?nitas ,Outbreak ,Zika Virus ,Virus zika / patogenicidade ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,3. Good health ,Titer ,030104 developmental biology ,Increased risk ,biology.protein ,Gravidez ,Female ,Macaca nemestrina ,Antibody ,K562 Cells ,business - Abstract
ZIKV infection during pregnancy causes microcephaly, but not all neonates are affected. This study shows that features of the maternal antibodies correlate with the risk of ZIKV-associated microcephaly., Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.
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- 2019
5. The Role of MIF on Eosinophil Biology and Eosinophilic Inflammation
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Priscilla C. Olsen, Marcelo T. Bozza, Leticia Lintomen, Jamil Z. Kitoko, and Claudia N. Paiva
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0301 basic medicine ,animal diseases ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Inflammation ,Immunoglobulin E ,CXCR4 ,Host-Parasite Interactions ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Bone Marrow ,Hypersensitivity ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,Eosinophilic esophagitis ,Macrophage Migration-Inhibitory Factors ,030203 arthritis & rheumatology ,biology ,General Medicine ,respiratory system ,Eosinophil ,medicine.disease ,biological factors ,Eosinophils ,Intramolecular Oxidoreductases ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Immunology ,biology.protein ,Macrophage migration inhibitory factor ,Disease Susceptibility ,medicine.symptom ,Biomarkers ,Signal Transduction - Abstract
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that participates in innate and adaptive immune responses. MIF contributes to the resistance against infection agents, but also to the cellular and tissue damage in infectious, autoimmune, and allergic diseases. In the past years, several studies demonstrated a critical role for MIF in the pathogenesis of type-2-mediated inflammation, including allergy and helminth infection. Atopic patients have increased MIF amounts in affected tissues, mainly produced by immune cells such as macrophages, Th2 cells, and eosinophils. Increased MIF mRNA and protein are found in activated Th2 cells, while eosinophils stock pre-formed MIF protein and secrete high amounts of MIF upon stimulation. In mouse models of allergic asthma, the lack of MIF causes an almost complete abrogation of the cardinal signs of the disease including mucus secretion, eosinophilic inflammation, and airway hyper-responsiveness. Additionally, blocking the expression of MIF in animal models leads to significant reduction of pathological signs of eosinophilic inflammation such as rhinitis, atopic dermatitis, eosinophilic esophagitis and helminth infection. A number of studies indicate that MIF is important in the effector phase of type-2 immune responses, while its contribution to Th2 differentiation and IgE production is not consensual. MIF has been found to intervene in different aspects of eosinophil physiology including differentiation, survival, activation, and migration. CD4+ T cells and eosinophils express CD74 and CXCR4, receptors able to signal upon MIF binding. Blockage of these receptors with neutralizing antibodies or small molecule antagonists also succeeds in reducing the signals of inflammation in experimental allergic models. Together, these studies demonstrate an important contribution of MIF on eosinophil biology and in the pathogenesis of allergic diseases and helminth infection.
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- 2019
6. Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma
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Patricia R. M. Rocco, Priscilla C. Olsen, Miquéias Lopes-Pacheco, Natalia G. Blanco, Ligia Lins de Castro, Marcelo M. Morales, Tainá Batista de Oliveira, Debora G. Xisto, Jamil Z. Kitoko, Daniel J. Weiss, and Soraia C. Abreu
- Subjects
Male ,0301 basic medicine ,Eotaxin ,Inflammation ,Mesenchymal Stem Cell Transplantation ,Cell therapy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Tissue Engineering and Regenerative Medicine ,Animals ,Medicine ,Lung ,House dust mite ,Mice, Inbred BALB C ,Interleukin-13 ,medicine.diagnostic_test ,biology ,business.industry ,Macrophages ,Bone marrow stromal cells ,Mesenchymal stem cell ,Interleukin ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,respiratory system ,biology.organism_classification ,Asthma ,Interleukin-10 ,Animal models ,respiratory tract diseases ,Eosinophils ,Disease Models, Animal ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immunology ,Female ,Tumor necrosis factor alpha ,Interleukin-4 ,Bone marrow ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Asthma is a chronic inflammatory disease characterized by airway inflammation and remodeling, which can lead to progressive decline of lung function. Although mesenchymal stromal cells (MSCs) have shown beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been limited. Mounting evidence suggests that prior exposure of MSCs to specific inflammatory stimuli or environments can enhance their immunomodulatory properties. Therefore, we investigated whether stimulating MSCs with bronchoalveolar lavage fluid (BALF) or serum from asthmatic mice could potentiate their therapeutic properties in experimental asthma. In a house dust mite (HDM) extract asthma model in mice, unstimulated, asthmatic BALF-stimulated, or asthmatic serum-stimulated MSCs were administered intratracheally 24 hours after the final HDM challenge. Lung mechanics and histology; BALF protein, cellularity, and biomarker levels; and lymph-node and bone marrow cellularity were assessed. Compared with unstimulated or BALF-stimulated MSCs, serum-stimulated MSCs further reduced BALF levels of interleukin (IL)-4, IL-13, and eotaxin, total and differential cellularity in BALF, bone marrow and lymph nodes, and collagen fiber content, while increasing BALF IL-10 levels and improving lung function. Serum stimulation led to higher MSC apoptosis, expression of various mediators (transforming growth factor-β, interferon-γ, IL-10, tumor necrosis factor-α-stimulated gene 6 protein, indoleamine 2,3-dioxygenase-1, and IL-1 receptor antagonist), and polarization of macrophages to M2 phenotype. In conclusion, asthmatic serum may be a novel strategy to potentiate therapeutic effects of MSCs in experimental asthma, leading to further reductions in both inflammation and remodeling than can be achieved with unstimulated MSCs. Stem Cells Translational Medicine 2019;8:301&312
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- 2018
7. Impact of one versus two doses of mesenchymal stromal cells on lung and cardiovascular repair in experimental emphysema
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Nazareth N. Rocha, Patricia R. M. Rocco, Marcelo M. Morales, Miquéias Lopes-Pacheco, Mariana A. Antunes, Jamil Z. Kitoko, Priscilla C. Olsen, Hananda A Poggio, and Fernanda F. Cruz
- Subjects
0301 basic medicine ,Pathology ,Lymphocyte ,Medicine (miscellaneous) ,Cardiovascular System ,chemistry.chemical_compound ,lcsh:QD415-436 ,Pancreatic elastase ,Lung ,lcsh:R5-920 ,medicine.diagnostic_test ,Elastase ,Heart ,respiratory system ,Animal models ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Pulmonary Emphysema ,Molecular Medicine ,Female ,Collagen ,Inflammation Mediators ,lcsh:Medicine (General) ,Bronchoalveolar Lavage Fluid ,medicine.medical_specialty ,Lymphoid Tissue ,Mesenchymal Stem Cell Transplantation ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,lcsh:Biochemistry ,03 medical and health sciences ,Collagen fiber ,Parenchyma ,medicine ,Animals ,Immunosuppression Therapy ,Inflammation ,Emphysema ,Wound Healing ,business.industry ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Elastic fiber ,Elastin ,respiratory tract diseases ,Mice, Inbred C57BL ,030104 developmental biology ,Bronchoalveolar lavage ,chemistry ,business ,Immunosuppression - Abstract
Background A single administration of mesenchymal stromal cells (MSCs) has been shown to reduce lung inflammation in experimental elastase-induced emphysema; however, effects were limited in terms of lung-tissue repair and cardiac function improvement. We hypothesized that two doses of MSCs could induce further lung and cardiovascular repair by mitigating inflammation and remodeling in a model of emphysema induced by multiple elastase instillations. We aimed to comparatively investigate the effects of one versus two doses of MSCs, administered 1 week apart, in a murine model of elastase-induced emphysema. Methods C57BL/6 mice were randomly divided into control (CTRL) and emphysema (E) groups. Mice in the E group received porcine pancreatic elastase (0.2 IU, 50 μL) intratracheally once weekly for four consecutive weeks; the CTRL animals received sterile saline (50 μL) using the same protocol. Three hours after the last instillation, the E group was further randomized to receive either saline (SAL) or murine MSCs (105 cells) intratracheally, in one or two doses (1 week apart). Fourteen days later, mice were euthanized, and all data analyzed. Results Both one and two doses of MSCs improved lung mechanics, reducing keratinocyte-derived chemokine and transforming growth factor-β levels in lung homogenates, total cell and macrophage counts in bronchoalveolar lavage fluid (BALF), and collagen fiber content in airways and blood vessels, as well as increasing vascular endothelial growth factor in lung homogenates and elastic fiber content in lung parenchyma. However, only the two-dose group exhibited reductions in tumor necrosis factor-α in lung tissue, BALF neutrophil and lymphocyte count, thymus weight, and total cellularity, as well as CD8+ cell counts and cervical lymph node CD4+ and CD8+ T cell counts, as well as further increased elastic fiber content in the lung parenchyma and reduced severity of pulmonary arterial hypertension. Conclusions Two doses of MSCs enhanced lung repair and improvement in cardiac function, while inducing T cell immunosuppression, mainly of CD8+ cells, in elastase-induced emphysema.
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- 2018
8. A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates
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Jennifer R. Keeffe, Charles M. Rice, Stylianos Bournazos, Yu E. Lee, Jodie Usachenko, Stephanie A. Azzopardi, Dennis Schaefer-Babajew, Anil Singapuri, Davide F. Robbiani, Margaret R. MacDonald, Priscilla C. Olsen, Koen K. A. Van Rompay, Qiao Wang, Amir Ardeshir, Jennifer Watanabe, Mohsan Saeed, Michel C. Nussenzweig, Marianna Agudelo, Pamela J. Bjorkman, Lark L. Coffey, Anna Gazumyan, Thomas Eisenreich, Thiago Y. Oliveira, and Jackson B. Stuart
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0301 basic medicine ,medicine.drug_class ,030106 microbiology ,Viremia ,Dengue virus ,medicine.disease_cause ,Monoclonal antibody ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Article ,Zika virus ,03 medical and health sciences ,Epitopes ,Protein Domains ,medicine ,Animals ,Humans ,Antibody-dependent enhancement ,Amino Acid Sequence ,lcsh:QH301-705.5 ,Mice, Knockout ,biology ,Antibodies, Monoclonal ,Zika Virus ,Dengue Virus ,biology.organism_classification ,medicine.disease ,Virology ,Antibodies, Neutralizing ,Flavivirus ,030104 developmental biology ,HEK293 Cells ,lcsh:Biology (General) ,Mutation ,biology.protein ,Macaca ,Antibody - Abstract
Summary: Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV. : Passive administration of anti-Zika human monoclonal antibodies could be an efficacious and safe alternative to vaccines for at-risk populations. Keeffe et al. show that administration of a combination of two monoclonal antibodies to macaques followed by high-dose intravenous Zika challenge reduces viremia and prevents the emergence of viral escape mutations. Keywords: flavivirus, antibodies, crystal structure, escape, macaques, prophylaxis, protection, epitope, antibody dependent enhancement
- Published
- 2018
9. Critical role of CD4+ T cells and IFNγ signaling in antibody-mediated resistance to Zika virus infection
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Carolina Lucas, Pedro M. Pimentel-Coelho, Heitor A. Paula-Neto, Sharton Vinicius Antunes Coelho, Akiko Iwasaki, Cecilia B. Cavazzoni, Luciana Barros de Arruda, Fabricio M. Ferreira, Jamil Z. Kitoko, Michelle Premazzi Papa, Priscilla C. Olsen, Renata M. Pereira, Vinicius G. Suzart, Andre M. Vale, and Marcelo T. Bozza
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0301 basic medicine ,Adoptive cell transfer ,T cell ,viruses ,Science ,General Physics and Astronomy ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Cytotoxic T cell ,lcsh:Science ,Neutralizing antibody ,Multidisciplinary ,biology ,General Chemistry ,Acquired immune system ,Virology ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,lcsh:Q ,Antibody ,Viral load ,CD8 ,030215 immunology - Abstract
Protective adaptive immunity to Zika virus (ZIKV) has been mainly attributed to cytotoxic CD8+ T cells and neutralizing antibodies, while the participation of CD4+ T cells in resistance has remained largely uncharacterized. Here, we show a neutralizing antibody response, dependent on CD4+ T cells and IFNγ signaling, which we detected during the first week of infection and is associated with reduced viral load in the brain, prevention of rapid disease onset and survival. We demonstrate participation of these components in the resistance to ZIKV during primary infection and in murine adoptive transfer models of heterologous ZIKV infection in a background of IFNR deficiency. The protective effect of adoptively transferred CD4+ T cells requires IFNγ signaling, CD8+ T cells and B lymphocytes in recipient mice. Together, this indicates the importance of CD4+ T cell responses in future vaccine design for ZIKV.
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- 2018
10. Therapeutic administration of bone marrow-derived mesenchymal stromal cells reduces airway inflammation without up-regulating Tregs in experimental asthma
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Fernanda F. Cruz, P.R.M. Rocco, A. P. Nascimento, L.L. de Castro, M. Martins, Priscilla C. Olsen, Jamil Z. Kitoko, Ana Carolina S. Arantes, Soraia C. Abreu, Marcelo M. Morales, and Debora G. Xisto
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0301 basic medicine ,Biopsy ,Immunology ,Adipose tissue ,Mice, Transgenic ,Inflammation ,Cell Communication ,Lymphocyte Activation ,Mesenchymal Stem Cell Transplantation ,T-Lymphocytes, Regulatory ,Flow cytometry ,Immunomodulation ,Mice ,03 medical and health sciences ,medicine ,Animals ,Immunology and Allergy ,House dust mite ,Lung ,medicine.diagnostic_test ,biology ,business.industry ,Pyroglyphidae ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Allergens ,respiratory system ,biology.organism_classification ,Asthma ,Coculture Techniques ,Respiratory Function Tests ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Bone marrow ,medicine.symptom ,business - Abstract
Background Prophylactic administration of mesenchymal stromal cells (MSCs) derived from adipose (AD-MSC) and bone marrow tissue (BM-MSC) in ovalbumin-induced asthma hinders inflammation in a Treg-dependent manner. It is uncertain whether MSCs act through Tregs when inflammation is already established in asthma induced by a clinically relevant allergen. Objective Evaluate the effect of therapeutic administration of MSCs on inflammation and Treg cells in house dust mite (HDM)-induced asthma. Methods BM-MSCs and AD-MSCs were administered intratracheally to C57BL/6 mice 1 day after the last HDM challenge. Lung function, remodelling and parenchymal inflammation were assayed 3 or 7 days after MSCs treatment, through invasive plethysmography and histology, respectively. Bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes (mLNs) were assessed regarding the inflammatory profile by flow cytometry, ELISA and qRT-PCR. MSCs were studied regarding their potential to induce Treg cells from primed and unprimed lymphocytes in vitro. Results BM-MSCs, but not AD-MSCs, reduced lung influx of eosinophils and B cells and increased IL-10 levels in HDM-challenged mice. Neither BM-MSCs nor AD-MSCs reduced lung parenchymal inflammation, airway hyperresponsiveness or mucus hypersecretion. BM-MSCs and AD-MSCs did not up-regulate Treg cell counts within the airways and mLNs, but BM-MSCs decreased the pro-inflammatory profile of alveolar macrophages. Co-culture of BM-MSCs and AD-MSCs with allergen-stimulated lymphocytes reduced Treg cell counts in a cell-to-cell contact-independent manner, although co-culture of both MSCs with unprimed lymphocytes up-regulated Treg cell counts. Conclusions MSCs therapeutically administered exert anti-inflammatory effects in the airway of HDM-challenged mice, but do not ameliorate lung function or remodelling. Although MSC pre-treatment can increase Treg cell numbers, it is highly unlikely that the MSCs will induce Treg cell expansion when lymphocytes are allergenically primed in an established lung inflammation.
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- 2017
11. Bone Marrow, Adipose, and Lung Tissue-Derived Murine Mesenchymal Stromal Cells Release Different Mediators and Differentially Affect Airway and Lung Parenchyma in Experimental Asthma
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Elga Bandeira, Almair Ferreira de Araujo, Fernanda F. Cruz, Soraia C. Abreu, Ludmilla Dellatorre-Texeira, Debora G. Xisto, Jamil Z. Kitoko, Vivian C. Branco, Bruno L. Diaz, Daniel J. Weiss, Patricia R. M. Rocco, Priscilla C. Olsen, Marcelo M. Morales, and Mariana A. Antunes
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Male ,0301 basic medicine ,Pathology ,Macrophage ,Mesenchymal stromal cells ,Adipose tissue ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Translational Research Articles and Reviews ,Bone Marrow Stem Cells ,Lung ,General Medicine ,respiratory system ,Trachea ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Adipose Tissue ,Disease Models (Animal/Cell) ,Inflammation / Inflammatory Disease ,Female ,Inflammation Mediators ,medicine.symptom ,medicine.medical_specialty ,Adipose Stem Cells/VSF ,Bone Marrow Cells ,Inflammation ,Lung injury ,Mesenchymal Stem Cell Transplantation ,03 medical and health sciences ,Tissue Engineering and Regenerative Medicine ,Parenchyma ,medicine ,Animals ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Eosinophil ,Fibrosis ,Asthma ,respiratory tract diseases ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Immunology ,business ,Biomarkers ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Mesenchymal stromal cells (MSCs) from different sources have differential effects on lung injury. To compare the effects of murine MSCs from bone marrow (BM), adipose tissue (AD), and lung tissue (LUNG) on inflammatory and remodeling processes in experimental allergic asthma, female C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) or saline (C). Twenty-four hours after the last challenge, mice received either saline (50 µl, SAL), BM-MSCs, AD-MSCs, or LUNG-MSCs (105 cells per mouse in 50 µl total volume) intratracheally. At 1 week, BM-MSCs produced significantly greater reductions in resistive and viscoelastic pressures, bronchoconstriction index, collagen fiber content in lung parenchyma (but not airways), eosinophil infiltration, and levels of interleukin (IL)-4, IL-13, transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF) in lung homogenates compared to AD-MSCs and LUNG-MSCs. Only BM-MSCs increased IL-10 and interferon (IFN)-γ in lung tissue. In parallel in vitro experiments, BM-MSCs increased M2 macrophage polarization, whereas AD-MSCs and LUNG-MSCs had higher baseline levels of IL-4, insulin-like growth factor (IGF), and VEGF secretion. Exposure of MSCs to serum specimens obtained from asthmatic mice promoted reductions in secretion of these mediators, particularly in BM-MSCs. Intratracheally administered BM-MSCs, AD-MSCs, and LUNG-MSCs were differentially effective at reducing airway inflammation and remodeling and improving lung function in the current model of allergic asthma. In conclusion, intratracheal administration of MSCs from BM, AD, and LUNG were differentially effective at reducing airway inflammation and remodeling and improving lung function comparably reduced inflammation and fibrogenesis in this asthma model. However, altered lung mechanics and lung remodeling responded better to BM-MSCs than to AD-MSCs or LUNG-MSCs. Moreover, each type of MSC was differentially affected in a surrogate in vitro model of the in vivo lung environment.
- Published
- 2017
12. Effects of crystalloid, hyper-oncotic albumin, and iso-oncotic albumin on lung and kidney damage in experimental acute lung injury
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Gisele A. Padilha, Renata de S. Mendes, Marcos V. S. Fernandes, Pedro L. Silva, Patricia R. M. Rocco, Lígia de A. Maia, Paolo Pelosi, Nazareth N. Rocha, Priscilla C. Olsen, Vera Luiza Capelozzi, Marcelo Gama de Abreu, Cintia L. Santos, Milena V. Oliveira, and Fernanda F. Cruz
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Male ,Oncotic pressure ,medicine.medical_specialty ,Urology ,Context (language use) ,Lung injury ,Inferior vena cava ,Pulmonary function testing ,Random Allocation ,Albumins ,Acute lung injury ,medicine ,Animals ,Hemodynamic ,Rats, Wistar ,Diffuse alveolar damage ,Albumin ,Inflammation ,Kidney damage ,Lung damage ,lcsh:RC705-779 ,business.industry ,Research ,Acute kidney injury ,Crystalloid Solutions ,lcsh:Diseases of the respiratory system ,Acute Kidney Injury ,medicine.disease ,Rats ,medicine.vein ,business - Abstract
Background Conflicting data have reported beneficial effects of crystalloids, hyper-oncotic albumin (20%ALB), and iso-oncotic albumin (5%ALB) in critically ill patients. Although hyper-oncotic albumin may minimize lung injury, recent studies have shown that human albumin may lead to kidney damage proportional to albumin concentration. In this context, we compared the effects of Ringer’s lactate (RL), 20%ALB, and 5%ALB, all titrated according to similar hemodynamic goals, on pulmonary function, lung and kidney histology, and molecular biology in experimental acute lung injury (ALI). Methods Male Wistar rats received Escherichia coli lipopolysaccharide intratracheally (n = 24) to induce ALI. After 24 h, animals were anesthetized and randomly assigned to receive RL, 20%ALB, or 5%ALB (n = 6/group) to maintain hemodynamic stability (distensibility index of inferior vena cava 65 mmHg). Rats were then mechanically ventilated for 6 h. Six animals, which received neither ventilation nor fluids (NV), were used for molecular biology analyses. Results The total fluid volume infused was higher in RL compared to 5%ALB and 20%ALB (median [interquartile range], 10.8[8.2–33.2] vs. 4.8[3.6–7.7] and 4.3[3.9–6.6] mL, respectively; p = 0.02 and p = 0.003). B-line counts on lung ultrasound (p
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- 2019
13. Glucagon reduces airway hyperreactivity, inflammation, and remodeling induced by ovalbumin
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Nathalia Santos Magalhães, Renato S.B. Cordeiro, Cynthia Machado Cascabulho, Patrícia M.R. e Silva, Diego de Sá Coutinho, Vinicius F. Carvalho, Bruno L. Diaz, Carolina Trindade de Azevedo, Daniella B. R. Insuela, Maximiliano Ruben Ferrero, Priscilla C. Olsen, Tatiana P. T. Ferreira, Marco A. Martins, and Andrea Henriques-Pons
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,medicine.medical_specialty ,Ovalbumin ,lcsh:Medicine ,Mice, Inbred Strains ,Inflammation ,Glucagon ,Article ,Bronchospasm ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Receptors, Glucagon ,medicine ,Animals ,lcsh:Science ,Receptor ,Lung ,CCL11 ,Cell Proliferation ,Multidisciplinary ,biology ,Chemistry ,Respiration ,lcsh:R ,Chemokine CCL24 ,Pneumonia ,Chronic inflammation ,respiratory system ,Asthma ,respiratory tract diseases ,030104 developmental biology ,Endocrinology ,biology.protein ,Airway Remodeling ,Cytokines ,lcsh:Q ,Tumor necrosis factor alpha ,Bronchial Hyperreactivity ,medicine.symptom ,CCL24 ,Bronchoalveolar Lavage Fluid ,030217 neurology & neurosurgery - Abstract
Glucagon has been shown to be beneficial as a treatment for bronchospasm in asthmatics. Here, we investigate if glucagon would prevent airway hyperreactivity (AHR), lung inflammation, and remodeling in a murine model of asthma. Glucagon (10 and 100 µg/Kg, i.n.) significantly prevented AHR and eosinophilia in BAL and peribronchiolar region induced by ovalbumin (OVA) challenge, while only the dose of 100 µg/Kg of glucagon inhibited subepithelial fibrosis and T lymphocytes accumulation in BAL and lung. The inhibitory action of glucagon occurred in parallel with reduction of OVA-induced generation of IL-4, IL-5, IL-13, TNF-α, eotaxin-1/CCL11, and eotaxin-2/CCL24 but not MDC/CCL22 and TARC/CCL17. The inhibitory effect of glucagon (100 µg/Kg, i.n.) on OVA-induced AHR and collagen deposition was reversed by pre-treatment with indomethacin (10 mg/Kg, i.p.). Glucagon increased intracellular cAMP levels and inhibits anti-CD3 plus anti-CD28-induced proliferation and production of IL-2, IL-4, IL-10, and TNF- α from TCD4+ cells in vitro. These findings suggest that glucagon reduces crucial features of asthma, including AHR, lung inflammation, and remodeling, in a mechanism probably associated with inhibition of eosinophils accumulation and TCD4+ cell proliferation and function. Glucagon should be further investigated as an option for asthma therapy.
- Published
- 2019
14. Glutamine Therapy Reduces Inflammation and Extracellular Trap Release in Experimental Acute Respiratory Distress Syndrome of Pulmonary Origin
- Author
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Elvira M. Saraiva, Heloísa Lopes dos Santos, Pedro L. Silva, Phillipe de Souza Lima-Gomes, Paolo Pelosi, Gisele Pena de Oliveira, Antonio Galina, Marcelo M. Morales, Jamil Z. Kitoko, Eduarda Gabrielle Lopes Martins, Felipe M. Ornellas, Carla Cristina de Araújo, Helena D’Anunciação de Oliveira, Pâmella Nowaski Lugon, Natalia C. Rochael, Priscilla C. Olsen, and Patricia R. M. Rocco
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Male ,0301 basic medicine ,ARDS ,Lipopolysaccharide ,Glutathione reductase ,lung mechanics ,Leukocyte Count ,chemistry.chemical_compound ,0302 clinical medicine ,Lung ,chemistry.chemical_classification ,reactive oxygen species ,Mice, Inbred BALB C ,Respiratory Distress Syndrome ,Nutrition and Dietetics ,medicine.diagnostic_test ,Glutathione peroxidase ,respiratory system ,Interleukin-10 ,Glutathione Reductase ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,glutamine ,Female ,medicine.symptom ,lcsh:Nutrition. Foods and food supply ,extracellular traps ,medicine.medical_specialty ,Inflammation ,pulmonary acute respiratory distress syndrome ,lcsh:TX341-641 ,Article ,Interferon-gamma ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Peroxidase ,Glutathione Peroxidase ,business.industry ,DNA ,Pneumonia ,medicine.disease ,respiratory tract diseases ,Endotoxins ,Pulmonary Alveoli ,Glutamine ,Disease Models, Animal ,030104 developmental biology ,Bronchoalveolar lavage ,Endocrinology ,chemistry ,Extracellular traps ,Lung mechanics ,Pulmonary acute respiratory distress syndrome ,Reactive oxygen species ,Food Science ,business - Abstract
The innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS). Glutamine (Gln) decreases lung inflammation in experimental ARDS, but its impact on the formation of extracellular traps (ETs) in the lung is unknown. In a mouse model of endotoxin-induced pulmonary ARDS, the effects of Gln treatment on leukocyte counts and ET content in bronchoalveolar lavage fluid (BALF), inflammatory profile in lung tissue, and lung morphofunction were evaluated in vivo. Furthermore, ET formation, reactive oxygen species (ROS) production, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were tested in vitro. Our in vivo results demonstrated that Gln treatment reduced ET release (as indicated by cell-free-DNA content and myeloperoxidase activity), decreased lung inflammation (reductions in interferon-&gamma, and increases in interleukin-10 levels), and improved lung morpho-function (decreased static lung elastance and alveolar collapse) in comparison with ARDS animals treated with saline. Moreover, Gln reduced ET and ROS formation in BALF cells stimulated with lipopolysaccharide in vitro, but it did not alter GPx or GR activity. In this model of endotoxin-induced pulmonary ARDS, treatment with Gln reduced pulmonary functional and morphological impairment, inflammation, and ET release in the lung.
- Published
- 2019
15. The tyrosine kinase inhibitor dasatinib reduces lung inflammation and remodelling in experimental allergic asthma
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Marcelo M. Morales, P.R.M. Rocco, M. Martins, Fernanda F. Cruz, Priscilla C. Olsen, A. L. da Silva, Vivian C. Branco, Tatiana P. T. Ferreira, R.F. Magalhães, Johnatas D. Silva, and Patrícia Maria Sens Marques
- Subjects
0301 basic medicine ,Pharmacology ,Lung ,business.industry ,medicine.drug_class ,Context (language use) ,Inflammation ,respiratory system ,medicine.disease ,Pathophysiology ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,Dasatinib ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Medicine ,medicine.symptom ,business ,Dexamethasone ,medicine.drug ,Asthma - Abstract
Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the TK inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma.
- Published
- 2016
16. JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties
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Amanda C. Cotias, Katharinne Ingrid Moraes de Carvalho, Gina C. Couto, Camila R. Pão, Patrícia M.R. e Silva, Edna A. Anjos-Valotta, Josiane S. Neves, Robson Xavier Faria, Priscilla C. Olsen, Renato S.B. Cordeiro, Magda F. Serra, Marco A. Martins, and Jorge Carlos Santos da Costa
- Subjects
0301 basic medicine ,Lung ,Contraction (grammar) ,Carbachol ,Lidocaine ,business.industry ,Inflammation ,Lymphocyte proliferation ,Pharmacology ,Eosinophil ,Bronchospasm ,03 medical and health sciences ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Anesthesia ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
Background Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model. Methods The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na+ current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice. Results The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P < 0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P < 0.001] for Ca2+; mean ± SD; n = 9 each) but lower in Na+ current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P < 0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P < 0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P < 0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 104/μm2 (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 104/μm2 (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1. Conclusion These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.
- Published
- 2016
17. Critical role of CD4
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Carolina G O, Lucas, Jamil Z, Kitoko, Fabricio M, Ferreira, Vinicius G, Suzart, Michelle P, Papa, Sharton V A, Coelho, Cecilia B, Cavazzoni, Heitor A, Paula-Neto, Priscilla C, Olsen, Akiko, Iwasaki, Renata M, Pereira, Pedro M, Pimentel-Coelho, Andre M, Vale, Luciana B, de Arruda, and Marcelo T, Bozza
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Zika Virus Infection ,Body Weight ,Zika Virus ,Adaptive Immunity ,Antibodies, Viral ,Adoptive Transfer ,Antibodies, Neutralizing ,Article ,Interferon-gamma ,Mice ,Immunoglobulin G ,Chlorocebus aethiops ,Animals ,Female ,Vero Cells - Abstract
Protective adaptive immunity to Zika virus (ZIKV) has been mainly attributed to cytotoxic CD8+ T cells and neutralizing antibodies, while the participation of CD4+ T cells in resistance has remained largely uncharacterized. Here, we show a neutralizing antibody response, dependent on CD4+ T cells and IFNγ signaling, which we detected during the first week of infection and is associated with reduced viral load in the brain, prevention of rapid disease onset and survival. We demonstrate participation of these components in the resistance to ZIKV during primary infection and in murine adoptive transfer models of heterologous ZIKV infection in a background of IFNR deficiency. The protective effect of adoptively transferred CD4+ T cells requires IFNγ signaling, CD8+ T cells and B lymphocytes in recipient mice. Together, this indicates the importance of CD4+ T cell responses in future vaccine design for ZIKV., Characterization of protective immunity to Zika virus has largely focussed on CD8+ T cells and antibody-mediated protection. Here the authors show roles for CD4+ T cells and the associated IFNγ signaling in antibody-mediated resistance to Zika virus infection.
- Published
- 2018
18. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice
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Μ.A. Martins, Priscilla C. Olsen, Ana Carolina S. Arantes, C.T. de-Azevedo, Jamil Z. Kitoko, and Tatiana P. T. Ferreira
- Subjects
Male ,Budesonide ,Ovalbumin ,Cell Count ,Thymus Gland ,T-Lymphocytes, Regulatory ,Dexamethasone ,Flow cytometry ,Mice ,medicine ,Animals ,Glucocorticoids ,Lung ,Asthma ,Pharmacology ,medicine.diagnostic_test ,business.industry ,Pyroglyphidae ,Pneumonia ,respiratory system ,medicine.disease ,Interleukin-10 ,respiratory tract diseases ,Lymphatic system ,medicine.anatomical_structure ,Immunology ,Cytokine secretion ,business ,Glucocorticoid ,medicine.drug - Abstract
Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients.
- Published
- 2015
19. Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico
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Priscilla C. Olsen, Antônio Raimundo Pinto de Almeida, Pamela J. Bjorkman, Gustavo Reyes-Terán, Mohsan Saeed, Davide F. Robbiani, Marina Caskey, Anna Gazumyan, Roshni Patel, Jennifer R. Keeffe, Joy A. Pai, Edgar E. Sevilla-Reyes, Marianna Agudelo, Nivison Nery, Albert I. Ko, Federico Costa, Cibele Orge, Margaret R. MacDonald, Daniel M. Weinberger, Michel C. Nussenzweig, Mitermayer G. Reis, Ricardo Khouri, Thiago Y. Oliveira, Lilian Nogueira, Yu E. Lee, Charles M. Rice, Santiago Ávila-Ríos, Gielson Almeida do Sacramento, Neena M. Thomas, Stephanie A. Azzopardi, Anthony P. West, Lion F.K. Uhl, Arlene Hurley, Kai Hui Yao, Harry B. Gristick, Dennis Schaefer-Babajew, Jovana Golijanin, Elsio A. Wunder, Leonia Bozzacco, and Thomas Eisenreich
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0301 basic medicine ,Male ,Biology ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,Neutralization ,Virus ,Article ,Dengue fever ,Serology ,Zika virus ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Neutralizing antibody ,Mexico ,B-Lymphocytes ,Zika Virus Infection ,medicine.disease ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Titer ,030104 developmental biology ,Immunology ,biology.protein ,Leukocytes, Mononuclear ,Female ,Antibody ,Immunologic Memory ,030217 neurology & neurosurgery ,Brazil - Abstract
Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.
- Published
- 2017
20. Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis
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Priscila J. Carneiro, Vera Luiza Capelozzi, Priscilla C. Olsen, Jamil Z. Kitoko, Gisele A. Padilha, Johnatas D. Silva, Patricia R. M. Rocco, Fernanda F. Cruz, and Amanda L. Clevelario
- Subjects
lymphocytes ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,macrophage polarization ,Population ,lung mechanics ,regulatory T cells ,03 medical and health sciences ,tyrosine kinase inhibitor ,0302 clinical medicine ,Silicosis ,Fibrosis ,Physiology (medical) ,Parenchyma ,Pulmonary fibrosis ,medicine ,Occupational lung disease ,education ,Original Research ,education.field_of_study ,Lung ,business.industry ,lung fibrosis ,respiratory system ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business ,Bosutinib ,medicine.drug - Abstract
Silicosis is an occupational lung disease for which no effective therapy exists. We hypothesized that bosutinib, a tyrosine kinase inhibitor, might ameliorate inflammatory responses, attenuate pulmonary fibrosis, and thus improve lung function in experimental silicosis. For this purpose, we investigated the potential efficacy of bosutinib in the treatment of experimental silicosis induced in C57BL/6 mice by intratracheal administration of silica particles. After 15 days, once disease was established, animals were randomly assigned to receive DMSO or bosutinib (1 mg/kg/dose in 0.1 mL 1% DMSO) by oral gavage, twice daily for 14 days. On day 30, lung mechanics and morphometry, total and differential cell count in alveolar septa and granuloma, levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, transforming growth factor (TGF)-β, and vascular endothelial growth factor in lung homogenate, M1 and M2 macrophages, total leukocytes, and T cells in BALF, lymph nodes, and thymus, and collagen fiber content in alveolar septa and granuloma were analyzed. In a separate in vitro experiment, RAW264.7 macrophages were exposed to silica particles in the presence or absence of bosutinib. After 24 h, gene expressions of arginase-1, IL-10, IL-12, inducible nitric oxide synthase (iNOS), metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and caspase-3 were evaluated. In vivo, in silicotic animals, bosutinib, compared to DMSO, decreased: (1) fraction area of collapsed alveoli, (2) size and number of granulomas, and mononuclear cell granuloma infiltration; (3) IL-1β, TNF-α, IFN-γ, and TGF-β levels in lung homogenates, (4) collagen fiber content in lung parenchyma, and (5) viscoelastic pressure and static lung elastance. Bosutinib also reduced M1 cell counts while increasing M2 macrophage population in both lung parenchyma and granulomas. Total leukocyte, regulatory T, CD4+, and CD8+ cell counts in the lung-draining lymph nodes also decreased with bosutinib therapy without affecting thymus cellularity. In vitro, bosutinib led to a decrease in IL-12 and iNOS and increase in IL-10, arginase-1, MMP-9, and TIMP-1. In conclusion, in the current model of silicosis, bosutinib therapy yielded beneficial effects on lung inflammation and remodeling, therefore resulting in lung mechanics improvement. Bosutinib may hold promise for silicosis; however, further studies are required.
- Published
- 2017
21. Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma
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Debora G. Xisto, Marco A. Martins, Jamil Z. Kitoko, Daniel J. Weiss, Ligia Lins de Castro, Patrícia Redondo, Marcelo M. Morales, Fernanda F. Cruz, Priscilla C. Olsen, Patricia R. M. Rocco, and Tatiana P. T. Ferreira
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,T cell ,Mesenchymal stromal cells ,Medicine (miscellaneous) ,Adipose tissue ,Inflammation ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,lcsh:Biochemistry ,03 medical and health sciences ,Mice ,Parenchyma ,medicine ,Animals ,Humans ,lcsh:QD415-436 ,Lung ,lcsh:R5-920 ,medicine.diagnostic_test ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Eosinophil ,respiratory system ,Extracellular vesicles ,Asthma ,Remodeling ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,Bronchoalveolar lavage ,Adipose Tissue ,Immunology ,Respiratory Mechanics ,Molecular Medicine ,Heterografts ,Female ,medicine.symptom ,lcsh:Medicine (General) - Abstract
Background Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. Methods C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 105 human AD-MSCs, or EVs (released by 105 AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. Results In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3+CD4+ T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3+CD4+ T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3+CD4+ T cells in the mediastinal lymph nodes. Conclusions In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different mechanisms of action of AD-MSCs versus their EVs.
- Published
- 2017
22. MIF in Eosinophilic Inflammation
- Author
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Marcelo T. Bozza, Claudia N. Paiva, and Priscilla C. Olsen
- Subjects
business.industry ,animal diseases ,chemical and pharmacologic phenomena ,Inflammation ,Atopic dermatitis ,respiratory system ,Eosinophil ,medicine.disease ,Proinflammatory cytokine ,medicine.anatomical_structure ,Immune system ,Eosinophilic ,Immunology ,otorhinolaryngologic diseases ,medicine ,Macrophage migration inhibitory factor ,medicine.symptom ,business ,Eosinophilic esophagitis - Abstract
Eosinophils are granular leukocytes known to have a central role in the effector arm of Th2 immune responses elicited in allergic diseases and parasitic inflammation. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine that not only contributes to the immune response to infection but also promotes tissue damage in sterile inflammation, and infectious conditions, is important in Th2 immune responses. Activated Th2 cells have increased MIF mRNA and protein, while eosinophils have mRNA and the preformed protein and secrete high quantities of MIF upon stimulation. In animal models of eosinophilic inflammation such as asthma, rhinitis, dermatitis, eosinophilic esophagitis, and helminth infection, the blockage or the genetic lack of MIF causes a significant reduction of the cardinal signs observed in these diseases. Importantly, atopic patients have increased MIF in affected tissues. MIF also affects several aspects of eosinophil physiology including differentiation, survival, activation, and migration. In this chapter, we reviewed the current knowledge of the role of MIF in eosinophil biology and in eosinophilic inflammatory conditions.
- Published
- 2017
23. Eicosapentaenoic acid enhances mesenchymal stromal cell effects in experimental allergic asthma
- Author
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Vanessa Martins, Natália R. T. Amorim, Marcelo M. Morales, Natalia G. Blanco, T.B. de Oliveira, Fernanda F. Cruz, Hugo C. Castro Faria-Neto, Cassiano Felippe Gonçalves-de-Albuquerque, Priscilla C. Olsen, Bruno L. Diaz, Andréia Cristina Lopes Frazão da Silva, Soraia C. Abreu, Debora G. Xisto, Daniel J. Weiss, P.R.M. Rocco, and J.J. Kitoko
- Subjects
Cancer Research ,Transplantation ,Stromal cell ,Experimental allergic ,business.industry ,Immunology ,Mesenchymal stem cell ,Cell Biology ,medicine.disease ,Eicosapentaenoic acid ,Oncology ,medicine ,Immunology and Allergy ,business ,Genetics (clinical) ,Asthma - Published
- 2018
24. IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice
- Author
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Cory M. Hogaboam, Caio Victor M. F. do Nascimento, Priscilla C. Olsen, Patrícia M.R. e Silva, Patricia G. Trentin, Marco A. Martins, Patricia R. M. Rocco, Raj K. Puri, Ana Carolina Santos de Arantes, and Tatiana P. T. Ferreira
- Subjects
Male ,medicine.medical_treatment ,Silicosis ,Immunology ,Exotoxins ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Immunotoxin ,Pseudomonas ,Respiratory Hypersensitivity ,medicine ,Animals ,Immunology and Allergy ,Occupational lung disease ,Lung ,Lymphotoxin-alpha ,Administration, Intranasal ,Cells, Cultured ,Methacholine Chloride ,Cell Proliferation ,030304 developmental biology ,Inflammation ,A549 cell ,0303 health sciences ,Granuloma ,Interleukin-13 ,Tumor Necrosis Factor-alpha ,business.industry ,Interleukin-8 ,Receptors, Interleukin-13 ,Interleukin-4 Receptor alpha Subunit ,Fibroblasts ,respiratory system ,Silicon Dioxide ,medicine.disease ,Recombinant Proteins ,Up-Regulation ,3. Good health ,Cytokine ,030220 oncology & carcinogenesis ,Interleukin 13 ,business - Abstract
Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13–PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13–PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13–PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13–PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13–PE. In addition, IL-13–PE inhibited both IL-13–induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13–PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.
- Published
- 2013
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25. JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties: Implications for New Bronchospasm Therapy
- Author
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Magda F, Serra, Josiane S, Neves, Gina C, Couto, Amanda C, Cotias, Camila R, Pão, Priscilla C, Olsen, Katharinne I Moraes, de Carvalho, Edna A, Anjos-Valotta, Robson X, Faria, Jorge C S, Costa, Renato S B, Cordeiro, Patricia M R, Silva, and Marco A, Martins
- Subjects
Inflammation ,Trachea ,Disease Models, Animal ,Mice ,Bronchial Spasm ,Anti-Inflammatory Agents ,Animals ,Lidocaine ,Anesthetics, Local ,Rats, Wistar ,Rats - Abstract
Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model.The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice.The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P0.001] for Ca; mean ± SD; n = 9 each) but lower in Na current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 10/μm (n = 6; P0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 10/μm (n = 7; P0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1.These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.
- Published
- 2015
26. Lidocaine-derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the function and survival of T cells
- Author
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Patrícia M.R. e Silva, Marco A. Martins, Magda F. Serra, Bruna de Paula Fonseca e Fonseca, Priscilla C. Olsen, Jorge Carlos Santos da Costa, João P. B. Viola, Francisco Alves Farias-Filho, Tatiana P. T. Ferreira, and Renato S.B. Cordeiro
- Subjects
Inhalation ,Lidocaine ,biology ,business.industry ,Immunology ,Inflammation ,Pharmacology ,Ovalbumin ,medicine.anatomical_structure ,Mechanism of action ,medicine ,biology.protein ,Immunology and Allergy ,Bronchoconstriction ,medicine.symptom ,Airway ,business ,medicine.drug ,Respiratory tract - Abstract
Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1.
- Published
- 2010
27. NFAT1 Transcription Factor Regulates Pulmonary Allergic Inflammation and Airway Responsiveness
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Heitor Siffert Pereira de Souza, Priscilla C. Olsen, Tatiana P. T. Ferreira, Marco A. Martins, Luciana P. Coelho, Bruna de Paula Fonseca e Fonseca, and João P. B. Viola
- Subjects
Pulmonary and Respiratory Medicine ,Clinical Biochemistry ,Inflammation ,medicine.disease_cause ,Allergic inflammation ,Mice ,Respiratory Hypersensitivity ,Animals ,Humans ,Medicine ,Eosinophilia ,Molecular Biology ,Asthma ,Mice, Knockout ,NFATC Transcription Factors ,business.industry ,Muscle, Smooth ,NFAT ,Pneumonia ,Cell Biology ,respiratory system ,medicine.disease ,Receptors, Muscarinic ,respiratory tract diseases ,Mice, Inbred C57BL ,Immunology ,Allergic response ,Bronchoconstriction ,Methacholine ,Bronchial Hyperreactivity ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,Muscle Contraction ,medicine.drug - Abstract
Allergic asthma is a chronic inflammatory disease of the lung whose incidence and morbidity continues to rise in developed nations. Despite being a hallmark of asthma, the molecular mechanisms that determine airway hyperresponsiveness (AHR) are not completely established. Transcription factors of the NFAT family are involved in the regulation of several asthma-related genes. It has been shown that the absence of NFAT1 leads to an increased pleural eosinophilic allergic response accompanied by an increased production of Th2 cytokines, suggesting a role for NFAT1 in the regulation of allergic diseases. Herein, we analyze NFAT1-/- mice to address the role of NFAT1 in a model of allergic airway inflammation and its influence in AHR. NFAT1-/- mice submitted to airway inflammation display a significant exacerbation of several features of the allergic disease, including lung inflammation, eosinophilia, and serum IgE levels, which were concomitant with elevated Th2 cytokine production. However, in spite of the increased allergic phenotype, NFAT1-/- mice failed to express AHR after methacholine aerosol. Refractoriness of NFAT1-/- mice to methacholine was confirmed in naïve mice, suggesting that this refractoriness occurs in an intrinsic way, independent of the lung inflammation. In addition, NFAT1-/- mice exhibit increased AHR in response to serotonin inhalation, suggesting a specific role for NFAT1 in the methacholine pathway of bronchoconstriction. Taken together, these data add support to the interpretation that NFAT1 acts as a counterregulatory mechanism to suppress allergic inflammation. Moreover, our findings suggest a novel role for NFAT1 protein in airway responsiveness mediated by the cholinergic pathway.
- Published
- 2009
28. Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema
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Nazareth N. Rocha, Isalira P R G Freitas, Priscilla C. Olsen, Bruno L. Diaz, Fernanda F. Cruz, Soraia C. Abreu, Marcelo M. Morales, Ana Clara Teixeira, Elga Bandeira, Patricia R. M. Rocco, Miquéias Lopes-Pacheco, Christina Maeda Takyia, Vera Luiza Capelozzi, Mariana A. Antunes, Debora G. Xisto, and Daniel J. Weiss
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Pulmonary and Respiratory Medicine ,Male ,Pathology ,medicine.medical_specialty ,Stromal cell ,Macrophage ,Mesenchymal stromal cells ,Adipose tissue ,Bone Marrow Cells ,Mesenchymal Stem Cell Transplantation ,Mice ,Random Allocation ,chemistry.chemical_compound ,Elastase ,medicine ,Animals ,Pancreatic elastase ,Cells, Cultured ,Emphysema ,Lung ,business.industry ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Remodeling ,Mice, Inbred C57BL ,Endothelial stem cell ,Vascular endothelial growth factor ,Treatment Outcome ,medicine.anatomical_structure ,Pulmonary Emphysema ,chemistry ,business - Abstract
We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2.
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- 2014
29. Effects of bone marrow mononuclear cells from healthy or ovalbumin-induced lung inflammation donors on recipient allergic asthma mice
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Bruno Diaz Paredes, Patricia R. M. Rocco, Priscilla C. Olsen, Lucas Wilson de Mendonça, Elga Bernardo Bandeira de Melo, Debora G. Xisto, Marcelo M. Morales, Daniel J. Weiss, Bruno L. Diaz, Soraia C. Abreu, Vivian C. Branco, and Mariana A. Antunes
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Ovalbumin ,Cell- and Tissue-Based Therapy ,Medicine (miscellaneous) ,Bone Marrow Cells ,Inflammation ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Peripheral blood mononuclear cell ,Immunophenotyping ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Medicine ,Bone Marrow Transplantation ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Research ,Interleukin ,Pneumonia ,Cell Biology ,respiratory system ,Eosinophil ,Asthma ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,13. Climate action ,030220 oncology & carcinogenesis ,Immunology ,Leukocytes, Mononuclear ,biology.protein ,Molecular Medicine ,Female ,Bone marrow ,Stem cell ,medicine.symptom ,business - Abstract
Introduction: Asthma is characterized by a chronic inflammatory process which may lead to several changes in bone marrow cell composition. We hypothesized that bone marrow mononuclear cells (BMMCs) obtained from ovalbumin (OVA)-induced lung inflammation mice may promote different effects compared to BMMCs from healthy donors in a model of allergic asthma. Methods: C57BL/6 mice were randomly assigned to two groups. In the OVA group, mice were sensitized and challenged with ovalbumin, while healthy animals (control group) received saline using the same protocol. BMMCs were analyzed by flow cytometry 24 hours after the last challenge. After BMMC characterization, another group of OVA mice were further randomized into three subgroups to receive intratracheal saline (BMMC-SAL), BMMCs from control or BMMCs from OVA mice (BMMC-Control and BMMC-OVA, respectively; 2x10 6 cells/mouse), 24 hours after the last challenge. Results: BMMC-OVA exhibited an increased percentage of eosinophils, monocytes and hematopoietic precursors, while mesenchymal stem cells decreased, as compared with BMMC-Control. BMMCs from both donor groups reduced airway resistance, alveolar collapse, bronchoconstriction index, eosinophil infiltration, collagen fiber content in alveolar septa and levels of interleukin (IL)-4, IL-5, IL-13, interferon-γ, transforming growth factor-β, and vascular endothelial growth factor in lung homogenates. However, the benefits of BMMCs were significantly more pronounced when cells were obtained from control donors. Conclusion: Both BMMC-Control and BMMC-OVA reduced the inflammatory and remodeling processes; nevertheless, BMMC-Control led to a greater improvement in lung morphofunction, which may be due to different BMMC composition and/or properties.
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- 2014
30. Nebulized lidocaine prevents airway inflammation, peribronchial fibrosis, and mucus production in a murine model of asthma
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Amanda C. Cotias, Patricia Barbosa Jurgilas, Gina C. Couto, Camila R. Pão, Edna A. Anjos-Valotta, Marco A. Martins, Tatiana P. T. Ferreira, Ana Carolina S. Arantes, Priscilla C. Olsen, Renato S.B. Cordeiro, Magda F. Serra, Ana Lucia A. Pires, and Patrícia M.R. e Silva
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Male ,Lidocaine ,T-Lymphocytes ,Inflammation ,Bronchi ,GATA3 Transcription Factor ,Proinflammatory cytokine ,Mice ,Fibrosis ,medicine ,Animals ,Anesthetics, Local ,Lung ,medicine.diagnostic_test ,biology ,business.industry ,Nebulizers and Vaporizers ,respiratory system ,Eosinophil ,medicine.disease ,Mucus ,Asthma ,Ovalbumin ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Immunology ,biology.protein ,medicine.symptom ,business ,medicine.drug - Abstract
Background Evidence suggests that nebulized lidocaine is beneficial in asthma therapy, but to what extent and the mechanisms underlying this effect remain poorly understood. The aim of this study was to assess the impact of lidocaine treatment using a murine model of allergic asthma characterized by expression of pivotal features of the disease: inflammation, mucus production, and lung remodeling. Methods A/J mice sensitized with ovalbumin were treated with inhaled lidocaine or vehicle immediately after ovalbumin intranasal challenges. Lung function, total and differential leukocytes in bronchoalveolar lavage fluid, peribronchial eosinophil density, interleukin (IL)-4, IL-5 and eotaxin-1 levels, epithelial mucus, collagen, extracellular-matrix deposition, matrix metalloproteinase-9 activity, and GATA-3 expression were evaluated. Between five and eight animals per group were used. Results Inhaled lidocaine inhibited ovalbumin-induced airway hyperreactivity to methacholine, and accumulation of lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid 24 h after the last allergen provocation. Lidocaine administration also prevented other pathophysiological changes triggered by ovalbumin in lung tissue, including peribronchial eosinophil and neutrophil infiltration, subepithelial fibrosis, increased content of collagen and mucus, matrix metalloproteinase-9 activity, and increased levels of IL-4, IL-5, IL-13, and eotaxin-1. Furthermore, inhaled lidocaine inhibited lung tissue GATA-3 expression in ovalbumin-challenged mice. We also demonstrated that lidocaine inhibited the expression of GATA-3 in ovalbumin-stimulated T cells in vitro. Conclusions Inhaled lidocaine prevents eosinophilic inflammation, overproduction of mucus, and peribronchial fibrosis in a murine model of asthma, and impaired airway hyperreactivity, possibly by inhibiting allergen-evoked GATA-3 expression and the subsequent up-regulation of proinflammatory cytokines and chemokines.
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- 2012
31. Two for one: cyclic AMP mediates the anti-inflammatory and anti-spasmodic properties of the non-anesthetic lidocaine analog JMF2-1
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Luciana P. Coelho, Jorge Carlos Santos da Costa, Priscilla C. Olsen, Marco A. Martins, Renato S.B. Cordeiro, and Patrícia M.R. e Silva
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Male ,T-Lymphocytes ,Respiratory System ,Anti-Inflammatory Agents ,Apoptosis ,Epithelium ,chemistry.chemical_compound ,Mice ,Cyclic AMP ,Caspase 8 ,Mice, Inbred BALB C ,Forskolin ,JMF2-1 ,Smooth muscle contraction ,Trachea ,medicine.anatomical_structure ,NG-Nitroarginine Methyl Ester ,medicine.symptom ,Intracellular ,Muscle contraction ,medicine.drug ,Adenylyl Cyclases ,Muscle Contraction ,medicine.medical_specialty ,Carbachol ,Cell Survival ,T cell ,Guinea Pigs ,Myocytes, Smooth Muscle ,Inflammation ,Nitric Oxide ,Internal medicine ,cAMP ,Airway smooth muscle cell ,medicine ,Animals ,Rats, Wistar ,Cell Proliferation ,Pharmacology ,Cell growth ,business.industry ,Colforsin ,Lidocaine ,Parasympatholytics ,Asthma ,Rats ,Endocrinology ,chemistry ,Lymph Nodes ,business - Abstract
Inhalation of JMF2-1, an analog of lidocaine with reduced anesthetic activity, prevents airway contraction and lung inflammation in experimental asthma models. We sought to test if the JMF2-1 effects are a consequence of increased intracellular cAMP levels in asthma cell targets, such as smooth muscle cells and T cells. Functional effect of JMF2-1 on carbachol-induced contraction of intact or epithelial-denuded rat trachea was assessed in conventional organ baths. cAMP was quantified by radioimmunoassay in cultured guinea pig tracheal smooth muscle cells, as well as lymph node cells from BALB/c mice, exposed to JMF2-1. We found that JMF2-1 (0.1–1mM) concentration-dependently inhibited epithelium-intact tracheal ring contraction induced by carbachol challenge. The antispasmodic effect remained unaltered following epithelium removal or pretreatment with NG-nitro-L-arginine methyl ester (100μM), but it was clearly sensitive to 9-(tetrahydro-2-furyl) adenine (SQ22,536, 100μM), an adenylate cyclase inhibitor. JMF2-1 (300 and 600μM) also dose-dependently increased cAMP intracellular levels of both cultured airway smooth muscle cells and T lymphocytes. This effect was consistently abrogated by SQ22,536 and reproduced by forskolin in both systems. JMF2-1 induced apoptosis of anti-CD3 activated T cells in a mechanism sensitive to zIETD, indicating that JMF2-1 mediates caspase-8-dependent apoptosis. Furthermore, forskolin also inhibited anti-CD3 induced T cell proliferation and survival. Our results suggest that JMF2-1 inhibits respiratory smooth muscle contraction as well as T cell proliferation and survival through enhancement of intracellular cAMP levels. These findings may help to explain the anti-inflammatory and antispasmodic effects of JMF2-1 observed in previous studies.
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- 2011
32. JMF2-1, a lidocaine derivative acting on airways spasm and lung allergic inflammation in rats
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Magda F. Serra, Debora G. Xisto, Patrícia M.R. e Silva, Rodrigo de Azeredo Siqueira, Jorge Carlos Santos da Costa, Robson Xavier Faria, Vinicius F. Carvalho, Marco A. Martins, Priscilla C. Olsen, Patricia R. M. Rocco, Luiz Anastacio Alves, and Renato S.B. Cordeiro
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Allergy ,Lidocaine ,medicine.drug_class ,Ovalbumin ,Immunology ,Anti-Inflammatory Agents ,Sodium Channels ,Allergic inflammation ,Cell Line ,chemistry.chemical_compound ,Leukocyte Count ,Mice ,Seizures ,medicine ,Respiratory Hypersensitivity ,Immunology and Allergy ,Animals ,Anti-Asthmatic Agents ,Rats, Wistar ,Lung ,Anesthetics ,Local anesthetic ,business.industry ,Eosinophil ,medicine.disease ,Rats ,Trachea ,medicine.anatomical_structure ,chemistry ,Anesthesia ,Anesthetic ,Methacholine ,business ,Histamine ,medicine.drug ,Sodium Channel Blockers - Abstract
Background Prior reports show that nebulized lidocaine might be an effective treatment for asthma. Objective We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity. Methods Blockade of Na + currents was assayed in cultured GH 3 cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro . Results The 50% inhibitory concentration values for blockade of Na + currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue. Conclusion Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung. Clinical implications Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.
- Published
- 2006
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