529 results on '"Asthma -- Physiological aspects"'
Search Results
2. Data on Asthma Detailed by Researchers at Shanghai Jiao Tong University (Blockade of Nlrp3/caspase-1/il-1 Beta Regulated Th17/treg Immune Imbalance and Attenuated the Neutrophilic Airway Inflammation In an Ovalbumin-induced Murine Model of ...)
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Neutrophils -- Health aspects ,Albumin -- Health aspects ,Asthma -- Physiological aspects ,Health - Abstract
2022 JUL 16 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Lung Diseases and Conditions - Asthma is the subject [...]
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- 2022
3. Role of the TSLP--DC--OX40L pathway in asthma pathogenesis and airway inflammation in mice
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Feng, Shuang, Zhang, Li, Bian, Xu-Hua, Luo, Ying, Qin, Guang-Hui, and Shi, Rui-Ming
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Airway -- Health aspects ,Asthma -- Physiological aspects ,Biological sciences - Abstract
This study aimed to explore the effect of the TSLP-DC-OX40L pathway in asthma pathogenesis and airway inflammation in mice. For this, 65 male BALF/c mice were distributed among the control, asthma, immunoglobulin G (IgG) + asthma (IgG, 500 [micro]g/500 [micro]L, intratracheal injection of 50 [micro]L each time), LY294002 (OX40L inhibitor) + asthma (intratracheal injection of 2 mg/kg LY294002), and anti-TSLP + asthma (intratracheal injection of 500 [micro]g/500 [micro]L TSLP antibody, 50 [micro]L each time) groups. ELISA was applied to measure the serum levels of immunoglobulin E (IgE), ovalbumin (OVA)-sIgE, interleukin-4 (IL-4), IL-5, IL-13, and interferon-[gamma] (IFN-[gamma]); flow cytometry was employed to detect Treg cells and dendritic cell (DC) and lymphopoiesis. RT-qPCR and Western blot assays were used to measure the levels of TSLP, OX40L, T-bet, GATA-3, NF-[kappa]B, p38, and ERK. Treatment with LY294002 and anti-TSLP resulted in increases in the numbers of total cells, eosinophils, neutrophils, and lymphocytes in the bronchoalveolar lavage fluid; total serum levels of IgE, OVA-sIgE, IL-4, IL-5, and IL-13; levels of DC cells; lymphopoiesis; and levels of TSLP, OX40L, GATA-3, NF-[kappa]B, p38, and ERK, whereas there were decreases in the levels of IFN-[gamma] and CD[4.sup.+]CD[25.sup.+]Treg cells; CD[4.sup.+]Foxp[3.sup.+]Treg cells; and T-bet. The TSLP-DC-OX40L pathway may contribute to asthma pathogenesis and airway inflammation by modulating the levels of CD[4.sup.+]CD[25.sup.+]Treg cells and inflammatory cytokines. Key words: TSLP-DC-OX40L pathway, asthma, airway inflammation, pathogenesis, mouse model. Cette etude vise a explorer le role du sentier TSLP-CD-OX40L dans la pathogenese de l'asthme et l'inflammation des voies aeriennes chez la souris. Soixante cinq souris males BALB/c ont ete reparties en groupes controle, asthme, IgG + asthme (IgG, 500 [micro]g/500 [micro]L, injection intratracheale de 50 [micro]L a chaque fois), LY294002 (inhibiteur d'OX40L) + asthme (injection intratracheale de 2 mg/kg de LY294002) et anti-TSLP + asthme (injection intratracheale de 500 [micro]g/500 [micro]L d'anticorps anti-TSLP, 50 [micro]L a chaque fois). Un dosage par ELISA a ete realise pour mesurer les niveaux seriques d'IgE, d'ovalbumine (OVA)-sIgE, d'interleukine-4 (IL-4), d'IL-5, d'IL-13 et d'interferon-[gamma] (IFN-[gamma]). La cytometrie en flux a ete utilisee pour detecter les cellules Treg, les cellules dendritiques (CD) et la lymphopoiese. La qRT-PCR et le buvardage Western ont ete utilises pour detecter les niveaux de TSLP, d'OX40L, de T-bet, de GATA-3, de NF-[kappa]B, de p38 et de ERK. Le traitement au LY294002 et a l'anti-TSLP resultait en une augmentation du nombre de cellules totales, d'eosinophiles, de neutrophiles et de lymphocytes dans le liquide de LBA, des niveaux seriques d'IgE, d'OVA-sIgE, d'IL-4, d'IL-5 et d'IL-13, du nombre de CD, de la lymphopoiese, et des niveaux de TSLP, d'OX40L, de GATA-3, de NF-[kappa]B, de p38 et de ERK, et en une diminution des niveaux d'IFN-[gamma], du nombre de Treg CD[4.sup.+]CD[25.sup.+], de Treg CD[4.sup.+]Foxp[3.sup.+] et de T-bet. Le sentier TSLP-CD-OX40L peut contribuer a la pathogenese de l'asthme et a l'inflammation des voies aeriennes en modulant le nombre de cellules Treg CD[4.sup.+]CD[25.sup.+] et le contenu en cytokines pro-inflammatoires. [Traduit par la Redaction] Mots-cles : sentier TSLP-CD-OX40L, asthme, inflammation de voies aeriennes, pathogenese, modele de souris., Introduction Asthma is one of the most common chronic diseases around the world (Huerta-Yepez et al. 2011); a disease with chronic inflammation of lower airways and characteristics of recurrent airway [...]
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- 2018
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4. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction
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Dunican, Eleanor M., Elicker, Brett M., Gierada, David S., Nagle, Scott K., Schiebler, Mark L., Newell, John D., Raymond, Wilfred W., Lachowicz-Scroggins, Marrah E., Maio, Selena Di, Hoffman, Eric A., Castro, Mario, Fain, Sean B., Jarjour, Nizar N., Israel, Elliot, Levy, Bruce D., Erzurum, Serpil C., Wenzel, Sally E., Meyers, Deborah A., Bleecker, Eugene R., Phillips, Brenda R., Mauger, David T., Gordon, Erin D., Woodruff, Prescott G., Peters, Michael C., and Fahy, John V.
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Eosinophils -- Health aspects ,Mucus -- Health aspects ,Airway obstruction -- Risk factors ,Asthma -- Physiological aspects ,Health care industry - Abstract
BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in [greater than or equal to] 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by [H.sub.2][O.sub.2] to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428., Introduction Despite the prominence of mucus plugs in the pathophysiology of airflow obstruction in acute severe (fatal) asthma (1, 2), the role of mucus plugs in the pathophysiology of airflow [...]
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- 2018
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5. Rutgers University - The State University of New Jersey Researchers Provide New Insights into Rhinovirus (Rhinovirus induces airway remodeling: what are the physiological consequences?)
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Asthma -- Physiological aspects ,Health ,Rutgers, The State University of New Jersey - Abstract
2023 OCT 16 (NewsRx) -- By a News Reporter-Staff News Editor at Respiratory Therapeutics Week -- Investigators publish new report on rhinovirus. According to news reporting out of Rutgers University [...]
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- 2023
6. Researchers at Louisiana State University Release New Data on Lung Cancer (Mmp12 Is Upregulated by in utero Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer ...)
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Emphysema, Pulmonary -- Physiological aspects ,Oncology, Experimental -- Physiological aspects ,Smoking -- Physiological aspects ,Lung cancer -- Physiological aspects ,Cancer -- Research ,Cigarettes -- Physiological aspects ,Physical fitness -- Physiological aspects ,Asthma -- Physiological aspects ,Health - Abstract
2021 DEC 18 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators discuss new findings in lung cancer. According to news reporting from [...]
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- 2021
7. Tenovi Introduces Cellular FDA-Cleared Remote Peak Flow Meter for Advanced Remote Physiological Monitoring of Asthmatic Patients
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Patient compliance -- Physiological aspects ,Asthma -- Physiological aspects ,General interest ,News, opinion and commentary - Abstract
IRVINE, Calif.: Tenovi has issued the following news release: Remote patient monitoring (RPM) solutions leader Tenovi announced today that it is launching its cellular-enabled remote Peak Expiratory Flow Meter (PFM). [...]
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- 2023
8. Tenovi Introduces Cellular FDA-Cleared Remote Peak Flow Meter for Advanced Remote Physiological Monitoring of Asthmatic Patients
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Patient compliance -- Physiological aspects ,Health care industry -- Physiological aspects ,Asthma -- Physiological aspects ,Health care industry ,Business ,News, opinion and commentary - Abstract
IRVINE, Calif., April 18, 2023 /PRNewswire/ -- Remote patient monitoring (RPM) solutions leader https://c212.net/c/link/?t=0&l=en&o=3839052-1&h=1276449901&u=https%3A%2F%2Ftenovi.com%2F&a=Tenovi announced today that it is launching its cellular-enabled remote https://c212.net/c/link/?t=0&l=en&o=3839052-1&h=2189090763&u=https%3A%2F%2Ftenovi.com%2Fpfm%2F&a=Peak+Expiratory+Flow+Meter(PFM). When combined with Tenovi's Cellular Gateway, [...]
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- 2023
9. Data from Department of Pulmonology Advance Knowledge in Asthma (Short-term and Long-term Effect of a High-intensity Pulmonary Rehabilitation Programme In Obese Patients With Asthma: a Randomised Controlled Trial)
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Obesity -- Physiological aspects ,Body mass index -- Physiological aspects ,Physical fitness -- Physiological aspects ,Asthma -- Physiological aspects ,Health - Abstract
2021 JUN 26 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on Lung Diseases and Conditions - Asthma have been presented. [...]
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- 2021
10. Recent Studies from Newcastle University Add New Data to Physiology (Advances in respiratory physiology in mouse models of experimental asthma)
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Asthma -- Physiological aspects ,Biological sciences ,Health - Abstract
2023 APR 4 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Investigators publish new report on physiology. According to news reporting from Newcastle, Australia, by [...]
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- 2023
11. New Asthma Study Findings Have Been Reported by Researchers at Uniformed Services University of the Health Sciences (ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function)
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Lipids -- Physiological aspects ,T cells -- Physiological aspects ,Physical fitness -- Physiological aspects ,Asthma -- Physiological aspects ,Health - Abstract
2020 DEC 26 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on asthma have been presented. According to news originating from [...]
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- 2020
12. Effect of the BMPR-II-SMAD3/MRTF complex on proliferation and migration of ASMCs and the mechanism in asthma
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Physical fitness -- Physiological aspects ,Cells (Biology) -- Physiological aspects ,Bone morphogenetic proteins -- Physiological aspects ,Asthma -- Physiological aspects ,Health - Abstract
2020 DEC 12 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- According to news reporting based on a preprint abstract, our journalists obtained [...]
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- 2020
13. Researchers' Work from Department of Pulmonology Focuses on Asthma (Short-term and Long-term Effect of a High-intensity Pulmonary Rehabilitation Programme In Obese Patients With Asthma: a Randomised Controlled Trial)
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Obesity -- Physiological aspects ,Physical fitness -- Physiological aspects ,Body mass index -- Physiological aspects ,Asthma -- Physiological aspects ,Health - Abstract
2020 SEP 12 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Fresh data on Lung Diseases and Conditions - Asthma are presented in [...]
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- 2020
14. Investigators at Queen Mary University of London Have Reported New Data on Chronic Obstructive Pulmonary Disease (Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease)
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Physical fitness -- Physiological aspects ,Medical research -- Physiological aspects ,Asthma -- Physiological aspects ,Vitamin D -- Physiological aspects ,Health ,University of London - Abstract
2020 AUG 22 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Lung Diseases and Conditions - Chronic Obstructive Pulmonary Disease [...]
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- 2020
15. Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma
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Bhatawadekar, Swati A., Leary, Del, and Maksym, Geoffrey N.
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Asthma -- Physiological aspects ,Airway (Medicine) -- Health aspects ,Biological sciences - Abstract
Ventilation heterogeneity is an important marker of small airway dysfunction in asthma. The frequency dependence of respiratory system resistance ([R.sub.rs]) from oscillometry is used as a measure of this heterogeneity. However, this has not been quantitatively assessed or compared with other outcomes from oscillometry, including respiratory system reactance ([X.sub.rs]) and the associated elastance ([E.sub.rs]). Here, we used a multibranch model of the human lung, including an upper airway shunt, to match previously reported respiratory mechanics in mild to severe asthma. We imposed heterogeneity by narrowing a proportion of the peripheral airways to account for patient [E.sub.rs] at 5 Hz, and then narrowed central airways to account for the remaining [R.sub.rs] at 18 Hz. The model required >75% of the small airways to be occluded to reproduce severe asthma. While the model produced frequency dependence in [R.sub.rs], it was upward-shifted below 5 Hz compared with in-vivo results, indicating that other factors, including more distributed airway narrowing or central airway wall compliance, are required. However, [E.sub.rs] quantitatively reflected the imposed heterogeneity better than the frequency dependence of [R.sub.rs], independent of the frequency range for the estimation, and thus was a more robust measure of small-airway function. Thus, [E.sub.rs] appears to have greater potential as a clinical measure of early small-airway disease in asthma. Key words: small airway heterogeneity, ventilation defects, elastance, frequency dependence of resistance, oscillometry. L'heterogeneite ventilatoire constitue un marqueur important de la dysfonction des petites voies respiratoires dans l'asthme. La dependance en fonction de la frequence de la resistance du systeme respiratoire ([R.sub.rs]) a partir de l'oscillometrie est utilisee pour mesurer cette heterogeneite. Cependant, elle n'a pas ete evaluee de maniere quantitative ou comparee a d'autres resultats de l'oscillometrie, incluant la reactance du systeme respiratoire ([X.sub.rs]) et l'elastance associee ([E.sub.rs]). Les auteurs ont utilize ici un modele ramifie de poumon humain incluant une obstruction des voies aeriennes superieures qui reproduit la mecanique respiratoire de l'asthme leger a severe rapportee precedemment. Les auteurs ont impose une heterogeneite en retrecissant une partie des voies respiratoires peripheriques pour representer l'[E.sub.rs] a 5 Hz d'un patient, et en retrecissant ensuite les voies respiratoires centrales pour representer la [R.sub.rs] residuelle a 18 Hz. Une occlusion de >75 % des petites voies respiratoires etait necessaire pour representer l'asthme severe. Alors que le modele produisait une dependance en fonction de la frequence de la [R.sub.rs], elle se deplacait sous les 5 Hz relativement a la situation in vivo, indiquant que d'autres facteurs sont requis, incluant une meilleure distribution du retrecissement des voies respiratoires ou une compliance des parois des voies respiratoires centrales. Cependant, la [E.sub.rs] refletait quantitativement l'heterogeneite imposee davantage que la dependance en fonction de la frequence de la [R.sub.rs], de maniere independante du spectre de frequence pour l'estimation, et constituait ainsi une mesure plus robuste de la fonction des petites voies respiratoires. La [E.sub.rs] semble alors avoir un meilleur potentiel comme mesure clinique de la maladie precoce des petites voies respiratoires dans l'asthme. [Traduit par la Redaction] Mots-cles: heterogeneite des petites voies respiratoires, defauts de ventilation, elastance, dependance en fonction de la frequence de la resistance, oscillometrie., Introduction Heterogeneous airway narrowing is a hallmark feature of asthma; a fact also supported by the occurrence of 'patchy ventilation,' characterized by ventilation defects in asthmatic subjects as seen in [...]
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- 2015
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16. Vitamin D improves corticosteroid efficacy and attenuates its side-effects in an animal model of asthma
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Mehta, Anita A., Agrawal, Ashok D., Appanna, Vasu, and Chaudagar, Kiranj K.
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Corticosteroids -- Health aspects ,Alfacalcidol -- Health aspects ,Calcifediol -- Health aspects ,Vitamin D -- Health aspects ,Asthma -- Physiological aspects ,Biological sciences - Abstract
The subacute use of corticosteroids has side-effects such as glucose intolerance, dyslipidemia, anxiety, and depression, which could be halted with vitamin D, which is an immunomodulatory vitamin. Thus, we aimed to study the anti-asthmatic efficacy and side-effects profile of vitamin D, the corticosteroid dexamethasone, and their combination on ovalbumin-induced airway inflammation in rats. For this, 2 different doses of vitamin D (50 IU/kg, daily for 2 weeks, or and 60000 IU/kg, bolus dose, by intraperitoneal injection (i.p.)) were administered in combination with dexamethasone (2.5 mg/kg, i.p., for 2 weeks) prior to challenge with ovalbumin. At the end of the therapy, the asthmatic parameters such as differential white blood cell counts, serum levels of immunoglobulin E, bronchoalveolar lavaged fluid, and interleukin-5, as well as serum levels of nitric oxide were significantly increased after allergen challenges in asthmatic rats as compared with the controls. Such increases were significantly attenuated by monotherapy with vitamin D and with combination therapy of vitamin D and dexamethasone, where the combination therapy was superior to the monotherapy. Dexamethasone-induced hyperglycemia, hyperlipidemia, and behavioral abnormalities in the allergic rats were attenuated with vitamin D. The daily dose was better for controlling serum levels of immunoglobulin E than the bolus dose, whereas the bolus was superior for reducing dexamethasone-induced psychotropic abnormalities. There were no significant changes in other parameters between the daily and the bolus dose. In conclusion, a daily dose of vitamin D in combination with dexamethasone is more efficacious for treating asthma in allergic rats than monotherapy. Key words: ovalbumin, dexamethasone, single dose, bolus dose. L'utilisation subaigue de corticosteroides provoque des effets secondaires comme l'intolerance au glucose, la dyslipidemie, l'anxiete et la depression, qui pourraient etre contrecarres par la vitamine D, une vitamine immuno-modulatrice. Les auteurs avaient pour but d'etudier l'efficacite antiasthmatique et le profil des effets secondaires de la vitamine D, de la dexamethasone et de leur combinaison, dans un modele d'inflammation des voies respiratoires induite par l'ovalbumine chez le rat. Deux doses differentes de vitamine D (50 UI/kg, i.p., quotidiennement pendant 2 semaines et 60000 UI/kg bolus) ont ete administrees en combinaison avec la dexamethasone (2,5 mg/kg, i.p. pendant 2 semaines) avant une provocation a l'ovalbumine. A la fin de la therapie, les parametres asthmatiques comme la numeration differentielle des globules blancs, les IgE du serum et du liquide de lavage broncho-alveolaire, l'IL-5 et le NO du serum etaient significativement accrus a la suite de la provocation chez les rats asthmatiques comparativement aux controles. Un tel accroissement etait significativement attenue par la combinaison ou monotherapie de vitamine D et de dexamethasone, la therapie combinee etant superieure a la monotherapie. L'hyperglycemie, l'hyperlipidemie et les troubles de comportements induits chez les rats allergiques par la dexamethasone etaient attenues par la vitamine D. La dose quotidienne etait plus efficace pour controler les IgE que le bolus, alors que le bolus etait plus efficace pour reduire les troubles du comportement que la dose quotidienne. Il n'y avait pas de changements significatifs des autres parametres entre la dose quotidienne et le bolus. En conclusion, une dose quotidienne de vitamine D combines a la dexamethasone est plus efficace pour traiter l'asthme chez les rats allergiques que la monotherapie. [Traduit par la Redaction] Mots-cles: ovalbumine, dexamethasone, dose unique, dose bolus., Introduction Asthma is one of the most common chronic inflammatory diseases, and is ranked among the top 10 prevalent conditions. It affects about 300 million people worldwide and is projected [...]
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- 2015
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17. KETONE BODIES REDUCE MARKERS OF ASTHMA IN OBESE MICE
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Asthma -- Physiological aspects ,News, opinion and commentary - Abstract
ROCKVILLE, Md. -- The following information was released by the American Physiological Society (APS): Findings point to potential therapeutic for treatment-resistant asthma Rockville, Md. (February 25, 2022)--Over half of people [...]
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- 2022
18. Astragalus membranaceus modulates Th1/2 immune balance and activates PPARγ in a murine asthma model
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Chen, Shih-Ming, Tsai, Yau-Sheng, Lee, Su-Wen, Liu, Ya-Hui, Liao, Shuen-Kuei, Chang, Wen-Wei, and Tsai, Pei-Jane
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Immune response -- Research ,Protein research ,Medicinal plants -- Health aspects ,Transcription factors -- Health aspects ,Asthma -- Physiological aspects ,Biological sciences - Abstract
Astragalus membranaceus, a traditional Chinese herb, has been used to improve airway inflammation and asthma. The present study investigated whether A. membranaceus has immunotherapeutic effects on asthma, a chronic inflammatory mucosal disease that is associated with excess production of IgE, eosinophilia, T helper 2 (Th2) cytokines, and bronchial hyperresponsiveness. An ovalbumin (OVA)-induced, chronic inflammatory airway murine asthma model was used to examine the status of pulmonary inflammation after the administration of A. membranaceus. The IgE levels in serum and bronchoalveolar lavage fluid showed a tendency to decrease after the administration of A. membranaceus. The number of eosinophils decreased and infiltration of inflammatory cells and collagen deposition declined in lung sections after A. membranaceus administration. The RNA and protein levels of Th2 cytokines and the ratio of the GATA3/T-bet mRNA levels decreased after A. membranaceus treatment. Furthermore, the mRNA level of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor, increased in the lung tissues of A. membranaceus-treated mice. Finally, an A. membranaceus water extract activated PPARγ activity in either human embryonic kidney 293 (HEK293) or A549 cells in a PPARγ-responsive element-containing luciferase reporter assay. These results indicate that A. membranaceus has an inhibitory effect on airway inflammation in a murine model of asthma through modulating the imbalanced relationship between Th1 and Th2 cytokines. Key words: Astragalus membranaceus, PPARγ, asthma, murine model. Astragalus membranaceus (AM), une plante medicinale traditionnelle chinoise, a ete utilisee pour attenuer l'inflammation des voies respiratoires et l'asthme. La presente etude a examine si AM exer^ait des effets immunotherapeutiques sur l'asthme, une maladie inflammatoire chronique de la muqueuse associee a une production excessive d'lgE, une eosinophilie, une production de cytokines Th2 et une hyperreactivite bronchique. Un modele d'asthme consistant en une inflammation chronique des voies aeriennes induite par l'OVA a ete utilise chez la souris afin d'examiner l'etat d'inflammation pulmonaire a la suite de l'administration d'AM. Les niveaux d'lgE dans le serum et le liquide de lavage broncho-alveolaire tendaient a diminuer apres l'administration d'AM. Le nombre d'eosinophiles diminuait, et l'infiltration des cellules inflammatoires et le depot de collagene etaient abaisses dans les coupes de poumons a la suite de l'administration d'AM. Les niveaux des cytokines Th2 et de leur ARNm correspondant, ainsi que le rapport des niveaux d'ARNm de GATA3/T-bet diminuait apres l'administration d'un traitement avec AM. De plus, le niveau d'ARNm de PPARγ, un recepteur hormonal nucleaire, etait accru dans les tissus pulmonaires des souris traitees avec AM. Finalement, un extrait aqueux d'AM activait PPARγ chez les cellules HEK293 ou A549 selon un dosage de l'activite luciferase d'un gene rapporteur comportant un element de reponse au PPARγ. Ces resultats indiquent que AM exerce un effet inhibiteur de l'inflammation des voies respiratoires dans un modele d'asthme chez la souris en modulant la relation debalancee entre les cytokines Th1 et Th2. [Traduit par la Redaction] Mots-cles: Astragalus membranaceus, PPARγ, asthme, modele chez la souris., Introduction Asthma is the most common chronic inflammatory airway disease and is characterized by bronchoconstriction, pulmonary inflammation, and airway remodeling (Hansel and Barnes 2001). The prevalence of asthma is increasing [...]
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- 2014
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19. Study Results from University of Adelaide Update Understanding of Physiology (Maternal Allergic Asthma During Pregnancy Alters Fetal Lung and Immune Development In Sheep: Potential Mechanisms for Programming Asthma and Allergy)
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Career development -- Physiological aspects ,Physical fitness -- Physiological aspects ,Sheep -- Physiological aspects ,Asthma -- Physiological aspects ,Pregnant women -- Physiological aspects ,Surface active agents ,Editors ,Social science research ,Infrastructure (Economics) ,Health - Abstract
2019 AUG 31 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on Life Science Research - Physiology is now available. [...]
- Published
- 2019
20. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling
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Doherty, Taylor A., Soroosh, Pejman, Khorram, Naseem, Fukuyama, Satoshi, Rosenthal, Peter, Cho, Jae Youn, Norris, Paula S., Choi, Heonsik, Scheu, Stefanie, Pfeffer, Klaus, Zuraw, Bruce L., Ware, Carl F., Broide, David H., and Croft, Michael
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Tumor necrosis factor -- Physiological aspects ,Asthma -- Physiological aspects ,Airway (Medicine) -- Physiological aspects ,Biological sciences ,Health - 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., Individuals with chronic asthma show evidence of structural remodeling of the airways, including accumulation of extracellular matrix proteins such as collagen and thickening of smooth muscle. Current therapies for asthma [...]
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- 2011
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21. Study Data from U.S. Food and Drug Administration (FDA) Provide New Insights into Molecular Science (Evaluating the Sub-Acute Toxicity of Formaldehyde Fumes in an In Vitro Human Airway Epithelial Tissue Model)
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United States. Food and Drug Administration ,Formaldehyde -- Physiological aspects ,Asthma -- Physiological aspects ,Business ,Health ,Health care industry - Abstract
2022 MAR 29 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Weekly -- Researchers detail new data in molecular science. According to news originating from the U.S. Food [...]
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- 2022
22. Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma
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Klein, Elizabeth, Weigel, Jason, Buford, Mary C., Holian, Andrij, and Wells, Sandra M.
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Inflammation -- Physiological aspects ,Inflammation -- Care and treatment ,Immunohistochemistry -- Methods ,Asthma -- Models ,Asthma -- Physiological aspects ,Asthma -- Care and treatment ,Nitric oxide -- Health aspects ,Arginine -- Properties ,Biological sciences - Abstract
Nitric oxide (NO), formed by nitric oxide synthase (NOS), is an important mediator of lung inflammation in allergic asthma. Asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of NOS, is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Elevated ADMA has been shown to affect lung function in mice, and by inhibiting NOS it alters NO and reactive oxygen species production in mouse lung epithelial cells. However, the effects of altered ADMA levels during lung inflammation have not been explored. A model of allergen-induced airway inflammation was utilized in combination with the modulation of endogenous circulating ADMA levels in mice. Airway inflammation was assessed by quantifying inflammatory cell infiltrates in lung lavage and by histology. Lung DDAH expression was assessed by quantitative PCR and immunohistochemistry. Nitrite levels were determined in lung lavage fluid as a measure of NO production, iNOS expression was determined by immunohistochemistry, immunofluorescence, Western blot, and quantitative PCR. NF-[kappa]B binding activity was assessed by a transcription factor binding assay. Allergen-induced lung inflammation was potentiated in mice with elevated circulating ADMA and was reduced in mice overexpressing DDAH. Elevated ADMA reduced nitrite levels in lung lavage fluid in both allergen-challenged and control animals. ADMA increased iNOS expression in airway epithelial cells in vivo following allergen challenge and in vitro in stimulated mouse lung epithelial cells. ADMA also increased NF-[kappa]B binding activity in airway epithelial cells in vitro. These data support that ADMA may play a role in inflammatory airway diseases such as asthma through modulation of iNOS expression in lung epithelial cells. airway; dimethylarginine dimethylaminohydrolase; inducible nitric oxide synthase doi: 10.1152/ajplung.00188.2010.
- Published
- 2010
23. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model
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Bonfield, Tracey L., Koloze, Mary, Lennon, Donald P., Zuchowski, Brandon, Yang, Sung Eun, and Caplan, Arnold I.
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Cellular therapy -- Methods ,Airway (Medicine) -- Physiological aspects ,Asthma -- Physiological aspects ,Asthma -- Care and treatment ,Biological sciences - Abstract
Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases, hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma. models of asthma; stem cell therapy doi: 10.1152/ajplung.00182.2009.
- Published
- 2010
24. [LTD.sub.4] induces HB-EGF-dependent CXCL8 release through EGFR activation in human bronchial epithelial cells
- Author
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McGovern, Toby, Risse, Paul-Andre, Tsuchiya, Kimitake, Hassan, Muhannad, Frigola, Gerard, and Martin, James G.
- Subjects
Asthma -- Care and treatment ,Asthma -- Physiological aspects ,Epithelial cells -- Properties ,Bronchi -- Properties ,Biological sciences - Abstract
Airway epithelial cells release proinflammatory mediators that may contribute to airway remodeling and leukocyte recruitment. We explored the hypothesis that leukotriene [D.sub.4] ([LTD.sub.4]) may trigger the release of proremodeling factors through activation of the EGF receptor (EGFR). We particularly focused on the effects of [LTD.sub.4] on release of heparin-binding EGF-like factor (HB-EGF) and IL-8 (CXCL8), a potent neutrophil chemoattractant that may be released downstream of EGFR activation. To address this hypothesis, both primary (NHBE) and transformed bronchial human epithelial cells (BEAS-2B) were grown on an air-liquid interface and stimulated with [LTD.sub.4]. HB-EGF and CXCL8 were evaluated by ELISA in cell culture supernatants. To explore the EGFR signaling pathway, we used a broad-spectrum matrix metalloproteinase (MMP) inhibitor, GM-6001, two selective EGFR tyrosine kinase inhibitors, AG-1478 and PD-153035, an HB-EGF neutralizing antibody, and a specific small interfering RNA (siRNA) against the EGFR. Expression of the [CysLT.sub.1] cysteinyl leukotriene receptor was demonstrated by RT-PCR and immunocytochemistry in both BEAS-2B and NHBE cells. Four hours after stimulation with [LTD.sub.4], HB-EGF and CXCL8 were significantly increased in cell culture supernatant. GM-6001 and montelukast, a specific [CysLT.sub.1] receptor antagonist, blocked the [LTD.sub.4]-induced increase in HB-EGF. All inhibitors/antagonists decreased [LTD.sub.4]-induced CXCL8 release, siRNA against EGFR abrogated CXCL8 release following stimulation with LTD4 and exogenous HB-EGF. These findings suggest [LTD.sub.4] induced EGFR transactivation through the release of HB-EGF in human bronchial epithelial cells with downstream release of CXCL8. These effects may contribute to epithelial-mediated airway remodeling in asthma and other conditions associated with cysteinyl leukotriene release. cysteinyl leukotrienes; heparin-binding-epidermal growth factor-like factor; interleukin-8; leukotriene [D.sub.4] doi: 10.1152/ajplung.00438.2009.
- Published
- 2010
25. Calcium transient evoked by TRPV1 activators is enhanced by tumor necrosis factor-[alpha] in rat pulmonary sensory neurons
- Author
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Hu, Youmin, Gu, Qihai, Lin, Ruei-Lung, Kryscio, Richard, and Lee, Lu-Yuan
- Subjects
Tumor necrosis factor -- Properties ,Asthma -- Physiological aspects ,Asthma -- Care and treatment ,Neurons -- Physiological aspects ,Calcium, Dietary -- Health aspects ,Biological sciences - Abstract
TNF[alpha] a proinflammatory cytokine known to be involved in the pathogenesis of allergic asthma, has been shown to induce hyperalgesia in somatic tissue via a sensitizing effect on dorsal root ganglion neurons expressing transient receptor potential vanilloid type 1 receptor (TRPV1). Because TRPVl-expressing pulmonary sensory neurons play an important role in regulating airway function, this study was carried out to determine whether TNF[alpha] alters the sensitivity of these neurons to chemical activators. Responses of isolated nodose and jugular ganglion neurons innervating the rat lungs were determined by measuring the transient increase in intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]). Our results showed the following. 1) A pretreatment with TNF[alpha] (50 ng/ml) for ~24 h increased significantly the peak [DELTA][[[Ca.sup.2+]].sub.i] evoked by capsaicin (Cap) in these neurons. A pretreatment with the same concentration of TNF[alpha] for a longer duration (~48 h) did not further increase the response, but pretreatment for a shorter duration (1 h) or with a lower concentration (25 ng/ml, 24 h) failed to enhance the Cap sensitivity. 2) The same TNF[alpha] pretreatment also induced similar but less pronounced and less uniform increases in the responses to acid (pH 6.5-5.5), 2-aminoethoxydiphenyl borate (2-APB), a common activator of TRPV1, V2, and V3 channels, and allyl isothiocyanate (AITC), a selective activator of TRPA1 channel. 3) In sharp contrast, the responses to ATP, ACh, and KC1 were not affected by TNF[alpha]. 4) The TNF[alpha]-induced hypersensitivity to Cap was not prevented by pretreatment with indomethacin (30 [micro]M). 5) The immunoreactivity to both TNF receptor types 1 and 2 were detected in rat vagal pulmonary sensory neurons. In conclusion, prolonged treatment with TNF[alpha] induces a pronounced potentiating effect on the responses of isolated pulmonary sensory neurons to TRPV1 activators. This action of TNF[alpha] may contribute in part to the airway hyperresponsiveness induced by this cytokine. intracellular calcium; pulmonary afferent; transient receptor potential vanilloid type 1; airway inflammation; asthma doi: 10.1152/ajplung.00111.2010.
- Published
- 2010
26. Aerobic conditioning and allergic pulmonary inflammation in mice. II. Effects on lung vascular and parenchymal inflammation and remodeling
- Author
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Vieira, Rodolfo P., de Andrade, Vanessa F., Duarte, Anna Cecilia S., dos Santos, Angela B.G., Mauad, Thais, Martins, Milton A., Dolhnikoff, Marisa, and Carvalho, Celso R.F.
- Subjects
Aerobic exercises -- Physiological aspects ,Asthma -- Physiological aspects ,Asthma -- Models ,Cytokines -- Properties ,Biological sciences - Abstract
Recent evidence suggests that asthma leads to inflammation and remodeling not only in the airways but also in pulmonary vessels and parenchyma. In addition, some studies demonstrated that aerobic training decreases chronic allergic inflammation in the airways; however, its effects on the pulmonary vessels and parenchyma have not been previously evaluated. Our objective was to test the hypothesis that aerobic conditioning reduces inflammation and remodeling in pulmonary vessels and parenchyma in a model of chronic allergic lung inflammation. Balb/c mice were sensitized at days 0, 14, 28, and 42 and challenged with ovalbumin (OVA) from day 21 to day 50. Aerobic training started on day 21 and continued until day 50. Pulmonary vessel and parenchyma inflammation and remodeling were evaluated by quantitative analysis of eosinophils and mononuclear cells and by collagen and elastin contents and smooth muscle thickness. Immunohistochemistry was performed to quantify the density of positive cells to interleukin (IL)-2, IL-4, IL-5, interferon-[gamma], IL-10, monocyte chemotatic protein (MCP)- l, nuclear factor (NF)-[kappa]B p65, and insulin-like growth factor (IGF)-I. OVA exposure induced pulmonary blood vessels and parenchyma inflammation as well as increased expression of IL-4, IL-5, MCP-1, NF-[kappa]B p65, and IGF-I by inflammatory cells were reduced by aerobic conditioning. OVA exposure also induced an increase in smooth muscle thickness and elastic and collagen contents in pulmonary vessels, which were reduced by aerobic conditioning. Aerobic conditioning increased the expression of IL-10 in sensitized mice. We conclude that aerobic conditioning decreases pulmonary vascular and parenchymal inflammation and remodeling in this experimental model of chronic allergic lung inflammation in mice. asthma; aerobic training; cytokines; pulmonary inflammation; pulmonary remodeling
- Published
- 2008
27. Effects of chronic L-NAME treatment lung tissue mechanics, eosinophilic and extracellular matrix responses induced by chronic pulmonary inflammation
- Author
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Angeli, Patricia, Prado, Carla M., Xisto, Debora G., Silva, Pedro L., Passaro, Caroline P., Nakazato, Hugo D., Leick- Maldonado, Edna A., Martins, Milton A., Rocco, Patricia R.M., and Tiberio, Iolanda F.L.C.
- Subjects
Asthma -- Models ,Asthma -- Development and progression ,Asthma -- Physiological aspects ,Oxidative stress -- Observations ,Biomechanics -- Research ,Extracellular matrix -- Properties ,Respiratory physiology -- Research ,Biological sciences - Abstract
The importance of lung tissue in asthma pathophysiology has been recently recognized. Although nitric oxide mediates smooth muscle tonus control in airways, its effects on lung tissue responsiveness have not been investigated previously. We hypothesized that chronic nitric oxide synthase (NOS) inhibition by [N.sup.w]-nitro-L-arginine methyl ester (L-NAME) may modulate lung tissue mechanics and eosinophil and extracellular matrix remodeling in guinea pigs with chronic pulmonary inflammation. Animals were submitted to seven saline or ovalbumin exposures with increasing doses (1 ~ 5 mg/ml for 4 wk) and treated or not with L-NAME in drinking water. After the seventh inhalation (72 h), animals were anesthetized and exsanguinated, and oscillatory mechanics of lung tissue strips were performed in baseline condition and after ovalbumin challenge (0.1%). Using morphometry, we assessed the density of eosinophils, neuronal NOS (nNOS)- and inducible NOS (iNOS)-positive distal lung cells, smooth muscle cells, as well as collagen and elastic fibers in lung tissue. Ovalbumin-exposed animals had an increase in baseline and maximal tissue resistance and elastance, eosinophil density, nNOS- and iNOS-positive cells, the amount of collagen and elastic fibers, and isoprostane-8-[PGF.sub.2[alpha]] expression in the alveolar septa compared with controls (P < 0.05). L-NAME treatment in ovalbumin-exposed animals attenuated lung tissue mechanical responses (P < 0.01), nNOS- and iNOS-positive ceils, elastic fiber content (P < 0.001), and isoprostane-8-[PGF.sub.2[alpha]] in the alveolar septa (P < 0.001). However, this treatment did not affect the total number of eosinophils and collagen deposition. These data suggest that NO contributes to distal lung parenchyma constriction and to elastic fiber deposition in this model. One possibility may be related to the effects of NO activating the oxidative stress pathway. experimental models of asthma; lung parenchyma constriction; elastic fibers; oxidative stress; [N.sup.w]-nitro-L-arginine methyl ester
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- 2008
28. Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model
- Author
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Nishiuma, Teruaki, Nishimura, Yoshihiro, Okada, Taro, Kuramoto, Emi, Kotani, Yoshikazu, Jahangeer, Saleem, and Nakamura, Shun-ichi
- Subjects
Asthma -- Development and progression ,Asthma -- Physiological aspects ,Sphingosine -- Health aspects ,Airway (Medicine) -- Properties ,Biological sciences - Abstract
Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N,N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma. bronchial asthma; eotaxin; sphingosine 1-phosphate; bronchial hyperresponsiveness
- Published
- 2008
29. GSK-3/[beta]-catenin signaling axis in airway smooth muscle: role in mitogenic signaling
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Nunes, Raquel O., Schmidt, Martina, Dueck, Gordon, Baarsma, Hoeke, Halayko, Andrew J., Kerstjens, Huib A.M., Meurs, Herman, and Gosens, Reinoud
- Subjects
Airway (Medicine) -- Properties ,Asthma -- Development and progression ,Asthma -- Physiological aspects ,Cell proliferation -- Evaluation ,Growth factors -- Properties ,Cell physiology -- Research ,Biological sciences - Abstract
[beta]-Catenin plays a dual role in cellular signaling by stabilizing cadherin-mediated cell-cell contact and by regulating gene transcription associated with cell cycle progression. Nonetheless, its presence and function in airway smooth muscle have not been determined. We hypothesized a central role for [beta]-catenin in mitogenic signaling in airway smooth muscle in response to growth factor stimulation. Immunocytochemical and biochemical analysis revealed that human airway smooth muscle cells indeed express abundant [beta]-catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with PDGF or FBS induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator in its unphosphorylated form that promotes [beta]-catenin degradation. GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared with quiescent airway smooth muscle cells with a mature phenotype. Parallel with the increase in GSK-3 phosphorylation, growth factor treatment induced an increased expression and nuclear presence of [beta]-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([[sup.3]H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of [beta]-catenin strongly reduced retinoblastoma protein phosphorylation, [[sup.3]H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/[beta]-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling. airway remodeling; asthma; proliferation; growth factor
- Published
- 2008
30. Prolonged heterologous [beta]2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction
- Author
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Hu, Aihua, Nino, Gustavo, Grunstein, Judith S., Fatma, Sumbul, and Grunstein, Michael M.
- Subjects
Phosphodiesterases -- Properties ,Asthma -- Physiological aspects ,Cyclic adenylic acid -- Properties ,G proteins -- Properties ,Physiological research ,Biological sciences - Abstract
[beta]2-Adrenergic receptor ([beta]2AR) agonists acutely relieve bronchoconstriction via cAMP-mediated relaxation of airway smooth muscle (ASM). Airway constrictor responsiveness may be significantly heightened, however, following protracted exposure to these agents, presumably reflecting the effects of [beta]2AR desensitization in ASM accompanying prolonged cAMP signaling. Because cAMP phosphodiesterase (PDE) activity can significantly modulate ASM contractility, we investigated the mechanism regulating PDE expression and its potential role in mediating changes in agonist-induced constrictor and relaxation responsiveness in ASM following its heterologous [beta]2AR desensitization by prolonged exposure to cAMP-elevating agents. Isolated rabbit ASM tissues and cultured human ASM cells treated for 24 h with the receptor- or nonreceptor-coupled cAMP-stimulating agent, prostaglandin [E.sub.2] (PGE2) or forskolin, respectively, exhibited constrictor hyperresponsiveness to acetylcholine and impaired [beta]2AR-mediated relaxation and cAMP accumulation. These proasthmatic-like changes in ASM function were associated with upregulated PDE4 activity, reflective of increased transcription of the PDE4D5 isoform, and were prevented by pretreatment of the ASM with a PDE4 inhibitor. Extended studies using gene silencing and pharmacological approaches to inhibit specific intracellular signaling molecules demonstrated that the mechanism underlying PGE2-induced transcriptional upregulation of PDE4D5 involves PKA-dependent activation of [G.sub.i] protein signaling via the [beta][gamma]-subunits, the latter eliciting downstream activation of ERK1/2 and its consequent induction of PDE4D5 transcription. Collectively, these findings identify that [beta]2AR desensitization in ASM following prolonged exposure to cAMP-elevating agents is associated with proasthmatic-like changes in ASM responsiveness that are mediated by upregulated PDE4 expression induced by activated cross talk between the PKA and ERK1/2 signaling pathways. asthma; cAMP signaling; G proteins; phosphodiesterase-4D5
- Published
- 2008
31. Blood and Sputum Eosinophil Levels in Asthma and Their Relationship to Sinus Computed Tomographic Findings
- Author
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Mehta, Vinay, Campeau, Norbert G., Kita, Hirohito, and Hagan, John B.
- Subjects
Asthma -- Physiological aspects ,Paranasal sinuses -- Medical examination - Abstract
OBJECTIVE: To investigate the relationship among blood and sputum eosinophil levels, sinus mucosal thickening, and osteitis in patients with asthma. PATIENTS AND METHODS: We conducted an observational study of 201 [...]
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- 2008
32. Adenosine-mediated alteration of vascular reactivity and inflammation in a murine model of asthma
- Author
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Ponnoth, Dovenia S., Nadeem, Ahmed, and Mustafa, S. Jamal
- Subjects
Asthma -- Physiological aspects ,Muridae -- Diseases ,Muridae -- Physiological aspects ,Adenosine -- Properties ,Inflammation -- Medical examination ,Cardiovascular system -- Research ,Biological sciences - Abstract
Chronic respiratory disorders such as asthma are believed to be associated with adverse cardiovascular events. We hypothesize that asthmatic inflammation translates into systemic inflammation and alters vascular responses where adenosine (AD) plays an important role. Therefore, this study investigated the effects of aerosolized AD, used to elevate lung AD levels, on vascular reactivity and inflammation in our allergic mouse model of asthma. Balb/c mice were divided into four groups: control (Con), Con + aerosolized AD (Con + AD), allergen sensitized and challenged (Sen), and Sen + aerosolized AD (Sen + AD). The animals were sensitized with ragweed (200 p[micro]g ip) on days 1 and 6, followed by 1% ragweed aerosol challenges from days 11 to 13. On day 14, the Con + AD and Sen + AD groups received a single AD aerosol challenge (6 mg/ml) for 2 min, followed by the collection of the aorta and plasma on day 15. Organ bath experiments showed concentration-dependent aortic relaxations to AD in the Con and Con + AD groups, which were impaired in the Sen and Sen + AD groups. Real-time PCR data showed changes in aortic AD receptors (ARs), with the expression of [A.sub.1]ARs upregulated, whereas the expression of [A.sub.2]ARs and endothelial nitric oxide synthase genes were downregulated, resulting in an impairment of vasorelaxation in the Sen and Sen + AD groups. The [A.sub.1]AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) reversed the impairment in vasorelaxation observed in the Sen and Sen + AD groups, whereas the [A.sub.2]BAR antagonist alloxazine inhibited vasorelaxation in all groups. Allergen challenge caused systemic inflammation in allergic mice, with AD aerosol further enhancing it as determined by the inflammatory cytokines profile in plasma. In conclusion, asthmatic mice showed altered vascular reactivity and systemic inflammation, with AD aerosol further exacerbating these effects. allergen; systemic inflammation
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- 2008
33. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1
- Author
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Simeone-Penney, Marina C., Severgnini, Mariano, Rozo, Lilliana, Takahashi, Satoe, Cochran, Brent H., and Simon, Amy R.
- Subjects
Cell proliferation -- Research ,Cell proliferation -- Physiological aspects ,Smooth muscle -- Research ,Smooth muscle -- Physiological aspects ,Airway (Medicine) -- Research ,Airway (Medicine) -- Physiological aspects ,Platelet-derived growth factor -- Research ,Platelet-derived growth factor -- Physiological aspects ,Asthma -- Research ,Asthma -- Physiological aspects ,Biological sciences - Abstract
The signal transducers and activators of transcription (STAT) family of transcription factors regulates a variety of biological functions including cellular proliferation, transformation, apoptosis, and differentiation. We have previously determined that PDGF activates the STAT pathway in human airway smooth muscle cells (HASMC) and that the Jak and Src kinases are required for both PDGF-induced STAT activation and HASMC proliferation. As increased airway smooth muscle (ASM) volume is associated with airflow obstruction and disease severity in patients with asthma, it is important to elucidate the cellular and molecular pathways that regulate ASM accumulation. In this paper, we investigated the requirement of STAT3 for PDGFinduced HASMC proliferation. We demonstrate that knockdown of STAT3 expression in HASMC resulted in a significant decrease in mitogen-induced cellular proliferation. Additionally, PDGF-induced activation of STAT3 required the small GTP-binding protein Rac1, and Rac1 was also required for PDGF-induced HASMC proliferation. Furthermore, PDGF treatment induced STAT3 and Rac1 to physically associate and translocate to the nucleus, identifying one mechanism by which STAT3 is regulated in response to PDGF in HASMC. Finally, we determined that STAT3 expression is required for PDGF-mediated regulation of cell cycle targets cyclin D3 and p27. These data define a novel mitogenic signaling pathway in airway smooth muscle cells leading from PDGF to Rac1 and STAT3 and subsequent cell cycle gene regulation. Thus, targeting STAT3 may prove to be a novel therapeutic approach for patients with severe asthma and significant airway wall remodeling, as manifested by ASM accumulation. asthma; airway remodeling; human airway smooth muscle cells
- Published
- 2008
34. Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model
- Author
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Tomei, Alice A., Choe, Melanie M., and Swartz, Melody A.
- Subjects
Asthma -- Physiological aspects ,Asthma -- Complications and side effects ,Virus diseases -- Development and progression ,Airway (Medicine) -- Properties ,Residual stresses -- Influence ,Biomechanics -- Research ,Biological sciences - Abstract
Asthmatic patients are more susceptible to viral infection, and we asked whether dynamic strain on the airway wall (such as that associated with bronchoconstriction) would influence the rate of viral infection of the epithelial and subepithelial cells. To address this, we characterized the barrier function of a three-dimensional culture model of the bronchial airway wall mucosa, modified the culture conditions for optimization of ciliogenesis, and compared epithelial and subepithelial green fluorescent protein (GFP) transduction by a pWpts-GFP lentivirus, pseudotyped with VSV-G, under static vs. dynamic conditions. The model consisted of human lung fibroblasts, bronchial epithelial cells, and a type I collagen matrix, and after 21 days of culture at air liquid interface, it exhibited a pseudostratified epithelium comprised of basal cells, mucus-secreting cells, and ciliated columnar cells with beating cilia. Microparticle tracking revealed partial coordination of mucociliary transport among groups of cells. Slow dynamic compression of the airway wall model (15% strain at 0.1 Hz over 3 days) substantially enhanced GFP transduction of epithelial cells and underlying fibroblasts. Fibroblast-only controls showed a similar degree of transduction enhancement when undergoing dynamic strain, suggesting enhanced transport through the matrix. Tight junction loss in the epithelium after mechanical stress was observed by immunostaining. We conclude that dynamic compressive strain such as that associated with bronchoconstriction may promote transepithelial transport and enhance viral transgene delivery to epithelial and subepithelial cells. This finding has significance for asthma pathophysiology as well as for designing delivery strategies of viral gene therapies to the airways. mechanical stress; three-dimensional model; asthma; bronchoconstriction; ciliogenesis; human
- Published
- 2008
35. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation
- Author
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Wallrapp, Antonia, Riesenfeld, Samantha J., Burkett, Patrick R., Abdulnour, Raja-Elie E., Nyman, Jackson, Dionne, Danielle, Hofree, Matan, Cuoco, Michael S., Rodman, Christopher, Farouq, Daneyal, Haas, Brian J., Tickle, Timothy L., Trombetta, John J., Baral, Pankaj, Klose, Christoph S.N., Mahlakiv, Tanel, Artis, David, Rozenblatt-Rosen, Orit, Chiu, Isaac M., Levy, Bruce D., Kowalczyk, Monika S., Regev, Aviv, and Kuchroo, Vijay K.
- Subjects
Inflammation -- Physiological aspects ,Neuropeptides -- Physiological aspects ,Lung diseases -- Physiological aspects ,Asthma -- Physiological aspects ,Allergy -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMUNMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces., Author(s): Antonia Wallrapp [1]; Samantha J. Riesenfeld [2]; Patrick R. Burkett (corresponding author) [1, 3]; Raja-Elie E. Abdulnour [3]; Jackson Nyman [2]; Danielle Dionne [2]; Matan Hofree [2]; Michael S. [...]
- Published
- 2017
- Full Text
- View/download PDF
36. Effect of PEEP on induced constriction is enhanced in decorin-deficient mice
- Author
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Salerno, Francesco G., Pinelli, Valentina, Pini, Laura, Tuma, Bodil, Iozzo, Renato V., and Ludwig, Mara S.
- Subjects
Proteoglycans -- Influence ,Mice -- Physiological aspects ,Asthma -- Physiological aspects ,Airway (Medicine) -- Properties ,Biological sciences - Abstract
Decorin (Dcn), a small leucinerich proteoglycan, is present in the extracellular matrix of the airways and lung tissues, contributes to lung mechanical properties, and its deposition is altered in asthma. The effect of Dcn deficiency on airway parenchymal interdependence was examined during induced bronchoconstriction. Studies were performed in C57B1/6 mice in which the Den gene was disrupted by targeted deletion ([Dcn.sup.-/-]) and in wild-type controls ([Dcn.sup.+/+]). Mice were mechanically ventilated, and respiratory system impedance was measured during in vivo ventilation at positive end-expiratory pressure (PEEP) = 2 and 10 cm[H.sub.2]O, before and after aerosol delivery of methacholine (MCh). Length vs. tension curves in isolated tracheal rings were measured in vitro. Dcn distribution in +/+ mice airways was characterized by immunofluorescence; differences in collagen structure in [Dcn.sup.+/+] and [Dcn.sup.-1-] mouse lungs was examined by electron microscopy. MCh caused similar increases in airway resistance (Raw) and tissue elastance (H) in [Dcn.sup.+/+] and [Dcn.sup.-/-] mice. During MCh-induced constriction, increasing PEEP caused a decrease in Raw that was greater in [Dcn.sup.-/-] mice and a decrease in H in [Dcn.sup.-/-] mice only. Tracheal ring compliance was greater in [Dcn.sup.-/-] mice. Imaging studies showed that Den was deposited primarily in the airway adventitial layer in [Dcn.sup.-/-] mice; in [Dcn.sup.-/-] mice, collagen had an irregular appearance, especially in the lung periphery. These results show that lack of Dcn alters the normal interaction between airways and lung parenchyma; in asthma, changes in Dcn could potentially contribute to abnormal airway physiology. airway responsiveness; asthma; proteoglycan; collagen
- Published
- 2007
37. Heterogeneity of transcription factor expression and regulation in human airway epithelial and smooth muscle cells
- Author
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Panebra, Alfredo, Schwarb, Mary Rose, Glinka, Clare B., and Liggett, Stephen B.
- Subjects
DNA binding proteins -- Properties ,Asthma -- Physiological aspects ,Inflammation -- Observations ,Epithelial cells -- Physiological aspects ,Smooth muscle -- Physiological aspects ,Biological sciences - Abstract
Transcription factors represent a major mechanism by which cells establish basal and conditional expression of proteins, the latter potentially being adaptive or maladaptive in disease. The complement of transcription factors in two major structural cells of the lung relevant to asthma, airway epithelial and smooth muscle cells, is not known. A plate-based platform using nuclear extracts from these cells was used to assess potential expression by binding to oligonucleotide consensus sequences representing >300 transcription factors. Four conditions were studied: basal, [beta]-agonist exposure, culture under proasthmatic conditions (IL-13, IL-4, TGF-[beta], and leukotriene [D.sub.4]), and the dual setting of [beta]-agonist with proasthmatic culture. Airway epithelial cells expressed 70 transcription factors, whereas airway smooth muscle expressed 110. High levels of multiple transcription factors not previously recognized as being expressed in these cells were identified. Moreover, expression/binding patterns under these conditions revealed extreme discordance in the direction and magnitude of change between the cell types. Singular (one cell type displayed regulation) and antithetic (both cell types underwent expression changes but in opposite directions) regulation dominated these patterns, with concomitant regulation in both cell types being rare ( transcription; [beta]-agonist; asthma; inflammation
- Published
- 2007
38. Resistin-like molecule-[beta] is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung
- Author
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Mishra, Anil, Wang, Meiqin, Schlotman, James, Nikolaidis, Nikolaos M., DeBrosse, Charles W., Karow, Margaret L., and Rothenberg, Marc E.
- Subjects
Mice -- Diseases ,Cytokines -- Influence ,Inflammation -- Observations ,Asthma -- Physiological aspects ,Pulmonary fibrosis -- Physiological aspects ,Biological sciences - Abstract
Resistin-like molecule (RELM)-[beta] is a cysteine-rich cytokine implicated in insulin resistance and asthmatic responses, but its function remains an enigma. We now report that RELM-[beta] has a role in promoting airway inflammation and lung remodeling in the mouse lung. RELM-[beta] is strongly induced by diverse allergens and T helper type 2 (Th2) cytokines by an IL-13- and STAT6-dependent mechanism. To understand the in vivo role of RELM-[beta], we delivered recombinant routine RELM-[beta] intratracheally to halve mice. RELM-[beta] induced dose-dependent leukocyte accumulation (most prominently involving macrophages) and goblet cell hyperplasia. The most prominent effect induced by RELM-[beta] was increased perivascular and peribronchial collagen deposition. Mice genetically deficient in RELM-[beta] had reduced accumulation of collagen and goblet cell hyperplasia in an experimental model of allergic airway inflammation. In vitro experiments demonstrated that RELM-[beta] had fibroblast motogenic activity. These results identify RELM-[beta] as a Th2-associated cytokine with potent inflammatory and remodeling activity. lymphocytes; asthma; fibrosis
- Published
- 2007
39. Human Th2 cells selectively express the orexigenic peptide, pro-melanin-concentrating hormone
- Author
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Sandig, Hilary, McDonald, Joanne, Gilmour, Jane, Arno, Matthew, Lee, Tak H., and Cousins, David J.
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T cells -- Genetic aspects ,Cytokines -- Genetic aspects ,Cytokines -- Physiological aspects ,Neuropeptides -- Physiological aspects ,Cell differentiation -- Evaluation ,Asthma -- Physiological aspects ,Obesity -- Physiological aspects ,Science and technology - Abstract
Th1 and Th2 cells represent the two main functional subsets of [CD4.sup.+] T helper cell, and are defined by their cytokine expression. Human Th1 cells express IFN[gamma], whilst Th2 cells express IL-4, IL-5, and IL-13. Th1 and Th2 cells have distinct immunological functions, and can drive different immunopathologies. Here, we show that in vitro-differentiated human Th2 cells highly selectively express the gene for pro-melanin-concentrating hormone (PMCH), using real-time RT-PCR, enzyme immunoassay, and Western blot analysis. PMCH encodes the prohormone, promelanin-concentrating hormone (PMCH), which is proteolytically processed to produce several peptides, including the orexigenic hormone melanin-concentrating hormone (MCH). PMCH expression by Th2 cells was activation responsive and increased throughout the 28-day differentiation in parallel with the expression of the Th2 cytokine genes. MCH immunoreactivity was detected in the differentiated Th2 but not Th1 cell culture supernatants after activation, and contained the entire PMCH protein, in addition to several smaller peptides. Human Th1 and Th2 cells were isolated by their expression of IFN[gamma] and CRTH2, respectively, and the ex vivo Th2 cells expressed PMCH upon activation, in contrast to the Th1 cells. Because Th2 cells are central to the pathogenesis of allergic diseases including asthma, expression of PMCH by activated Th2 cells in vivo may directly link allergic inflammation to energy homeostasis and may contribute to the association between asthma and obesity. appetite regulation | asthma | T cell differentiation | Th1/Th2 cells
- Published
- 2007
40. Dendritic cells in allergic airway inflammation
- Author
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Bharadwaj, Arpita S., Bewtra, Againdra K., and Agrawal, Devendra K.
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Dendritic cells -- Physiological aspects ,Asthma -- Physiological aspects ,Biological sciences ,Physiological aspects - Abstract
Abstract: Dendritic cells (DCs) are primary antigen-presenting cells involved in interactions with T cells leading to the proliferation of [T.sub.H]1 or [T.sub.H]2 cell types. In asthma, predominance of [T.sub.H]2 cells [...]
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- 2007
41. Crosstalk between [G.sub.i] and [G.sub.q]/[G.sub.s] pathways in airway smooth muscle regulates bronchial contractility and relaxation
- Author
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McGraw, Dennis W., Elwing, Jean M., Fogel, Kevin M., Wang, Wayne C.H., Glinka, Clare B., Mihlbachler, Kathryn A., Rothenberg, Marc E., and Liggett, Stephen B.
- Subjects
Asthma -- Diagnosis ,Asthma -- Care and treatment ,Asthma -- Physiological aspects - Abstract
Receptor-mediated airway smooth muscle (ASM) contraction via [G.sub.[alpha]q], and relaxation via [G.sub.[alpha]s], underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM [G.sub.[alpha]i] expression, considered the [...]
- Published
- 2007
42. Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease
- Author
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Allen, Irving C., Pace, Amy J., Jania, Leigh A., Ledford, Julie G., Latour, Anne M., Snouwaert, John N., Bernier, Virginie, Stocco, Rino, Therien, Alex G., and Koller, Beverly H.
- Subjects
Asthma -- Physiological aspects ,Asthma -- Genetic aspects ,Disease susceptibility -- Genetic aspects ,G proteins -- Research ,Biological sciences - Abstract
A genetic contribution to asthma susceptibility is well recognized, and linkage studies have identified a large number of genes associated with asthma pathogenesis. Recently, a locus encoding a seven-transmembrane protein was shown to be associated with asthma in founder populations. The expression of the protein GPRA (G protein-coupled receptor for asthma susceptibility) in human airway epithelia and smooth muscle, and its increased expression in a mouse model of asthma, suggested that a gain-of-function mutation in this gene increased the disease risk. However, we report here that the development of allergic lung disease in GPRA-deficient mice is unaltered. A possible explanation for this finding became apparent upon reexamination of the expression of this gene. In contrast to initial studies, our analyses failed to detect expression of GPRA in human lung tissue or in mice with allergic lung disease. We identify a single parameter that distinguishes GPRA-deficient and wild-type mice. Whereas the change in airway resistance in response to methacholine was identical in control and GPRA-deficient mice, the mutant animals showed an attenuated response to thromboxane, a cholinergic receptor-dependent bronchoconstricting agent. Together, our studies fail to support a direct contribution of GPRA to asthma pathogenesis. However, our data suggest that GPRA may contribute to the asthmatic phenotype by altering the activity of other pathways, such as neurally mediated mechanisms, that contribute to disease. This interpretation is supported by high levels of GPRA expression in the brain and its recent identification as the neuropeptide S receptor. neuropeptide S; G protein-coupled receptor; allergic lung disease; anaphylaxis
- Published
- 2006
43. Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP
- Author
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Szema, Anthony M., Hamidi, Sayyed A., Lyubsky, Sergey, Dickman, Kathleen G., Mathew, Suni, Abdel-Razek, Tarek, Chen, John J., Waschek, James A., and Said, Sami I.
- Subjects
Vasoactive intestinal peptides -- Research ,Vasoactive intestinal peptides -- Genetic aspects ,Asthma -- Physiological aspects ,Asthma -- Health aspects ,Biological sciences - Abstract
The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease. vasoactive intestinal peptide; asthma phenotype; knockout mice
- Published
- 2006
44. Perception of Airway Obstruction and Airway Inflammation in Asthma: A Review
- Author
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Rosi, Elisabetta, Stendardi, Loredana, Binazzi, Barbara, and Scano, Giorgio
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Asthma -- Physiological aspects ,Shortness of breath -- Risk factors ,Airway obstruction (Medicine) -- Evaluation ,Inflammation -- Evaluation - Abstract
Byline: Elisabetta Rosi (1), Loredana Stendardi (2), Barbara Binazzi (2), Giorgio Scano (2,3) Keywords: Airway inflammation; Asthma; Dyspnea Abstract: Dyspnea has a multifactorial nature and the exact mechanism that causes breathlessness in asthma is not fully understood. There is compelling evidence that factors other than merely mechanical ones take part in the pathophysiology of breathlessness. Some recent reports attribute airway inflammation, which may contribute to the unexplained variability in the perception of dyspnea associated with bronchoconstriction. Eosinophil airway inflammation has been proposed as a determinant of breathlessness via mechanisms affecting either the mechanical pathways that control breathlessness or the afferent nerves involved in perception of dyspnea. In this review, data on the interrelation between inflammation and dyspnea sensation and the impact of treatment on dyspnea sensation are discussed. We conclude that regardless of whether mechanical or chemical inflammatory factors are involved, much variability in dyspnea scores remains unexplained. Author Affiliation: (1) Section of Respiratory Medicine, Department of Medical-Surgical Specialty, University of Florence, Florence, Firenze, Italy (2) Department of Internal Medicine, Section of Immunology and Respiratory Medicine, University of Florence, Viale Morgagni 85, 50134, Firenze, Italy (3) Department of Respiratory Medicine, Fondazione Don C. Gnocchi (IRCCS), via Imprunetana, 124-50023, Pozzolatico, Firenze, Italy Article History: Registration Date: 01/01/2005 Accepted Date: 01/03/2006
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- 2006
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45. Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle
- Author
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Gosens, Reinoud, Stelmack, Gerald L., Dueck, Gordon, MeNeill, Karol D., Yamasaki, Akira, Gerthoffer, William T., Unruh, Helmut, Gounni, Abdelilah Soussi, Zaagsma, Johan, and Halayko, Andrew J
- Subjects
Asthma -- Physiological aspects ,Asthma -- Health aspects ,Smooth muscle -- Research ,Biological sciences - Abstract
Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperresponsiveness. Increased muscle mass is due, in part, to increased ASM proliferation, although the precise molecular mechanisms for this response are not completely clear. Caveolae, which are abundant in smooth muscle cells, are membrane microdomains where receptors and signaling effectors can be sequestered. We hypothesized that caveolae and caveolin-1 play an important regulatory role in ASM proliferation. Therefore, we investigated their role in p42/p44 MAPK signaling and proliferation using human ASM cell lines. Disruption of caveolae using methyl-[beta]-cyclodextrin and small interfering (si)RNA-knockdown of caveolin-1 caused spontaneous p42/p44 MAPK activation; additionally, caveolin-1 siRNA induced ASM proliferation in mitogen deficient conditions, suggesting a key role for caveolae and caveolin-1 in maintaining quiescence. Moreover, caveolin-1 accumulates twofold in myocytes induced to a contractile phenotype compared with proliferating ASM cells. Caveolin-1 siRNA failed to increase PDGF-induced p42/p44 MAPK activation and cell proliferation, however, indicating that PDGF stimulation actively reversed the antimitogenic control by caveolin-1. Notably, the PDGF induced loss of antimitogenic control by caveolin-1 coincided with a marked increase in caveolin-1 phosphorylation. Furthermore, the strong association of PDGF receptor-[beta] with caveolin-1 that exists in quiescent cells was rapidly and markedly reduced with agonist addition. This suggests a dynamic relationship in which mitogen stimulation actively reverses caveolin-1 suppression of p42/p44 MAPK signal transduction. As such, caveolae and caveolin-1 coordinate PDGF receptor signaling, leading to myocyte proliferation, and inhibit constitutive activity of p42/p44 MAPK to sustain cell quiescence. airway remodeling; hyperplasia; airway smooth muscle phenotype; platelet-derived growth factor receptor-[beta]; asthma doi:10.1152/ajplung.00013.2006.
- Published
- 2006
46. Detection of allergen-induced airway hyperresponsiveness in isolated mouse lungs
- Author
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Witzenrath, Martin, Ahrens, Birgit, Kube, Stefanie M., Braun, Armin, Hoymann, Heinz G., Hocke, Andreas C., Rosseau, Simone, Suttorp, Norbert, Hamelmann, Eckard, and Schutte, Hartwig
- Subjects
Asthma -- Health aspects ,Asthma -- Physiological aspects ,Allergens -- Health aspects ,Biological sciences - Abstract
Airway hyperresponsiveness (AHR) is a hallmark of bronchial asthma. Important features of this exaggerated response to bronchoconstrictive stimuli have mostly been investigated in vivo in intact animals or in vitro in isolated tracheal or bronchial tissues. Both approaches have important advantages but also certain limitations. Therefore, the aim of our study was to develop an ex vivo model of isolated lungs from sensitized mice for the investigation of airway responsiveness (AR). BALB/c mice were sensitized by intraperitoneal ovalbumin (Ova) and subsequently challenged by Ova inhalation. In vivo AR was measured in unrestrained animals by whole body plethysmography after stimulation with aerosolized methacholine (MCh) with determination of enhanced pause ([P.sub.enh]). Twenty-four hours after each [P.sub.enh] measurement, airway resistance was continuously registered in isolated, perfused, and ventilated lungs on stimulation with inhaled or intravascular MCh or nebulized Ova. In a subset of experiments, in vivo AR was additionally measured in orotracheally intubated, spontaneously breathing mice 24 h after [P.sub.enh] measurement, and lungs were isolated further 24 h later. Isolated lungs of allergen-sensitized and -challenged mice showed increased AR after MCh inhalation or infusion as well as after specific provocation with aerosolized allergen. AR was increased on days 2 and 5 after Ova challenge and had returned to baseline on day 9. AHR in isolated lungs after aerosolized or intravascular MCh strongly correlated with in vivo AR. Pretreatment of isolated lungs with the [[beta].sub.2]-agonist fenoterol diminished AR. In conclusion, this model provides new opportunities to investigate mechanisms of AHR as well as pharmacological interventions on an intact organ level. airway inflammation; sensitized mice; airway resistance; ovalbumin; asthma doi:10.1152/ajplung.00011.2004
- Published
- 2006
47. Asthma: pathology and pathophysiology
- Author
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Barrios, Roberto J., Kheradmand, Farrah, Batts, LaKeisha, and Corry, David B.
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Asthma -- Research ,Asthma -- Physiological aspects ,Asthma -- Diagnosis ,Pathology -- Evaluation ,Bronchoscopy -- Usage - Published
- 2006
48. Interactions between leukotriene (C sub 4) and interleukin 13 signaling pathways in a mouse model of airway disease
- Author
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Chavez, Jaime, Young, Hays W.J., Corry, David B., and Lieberman, Michael W.
- Subjects
Leukotrienes -- Analysis ,Leukotrienes -- Physiological aspects ,Interleukin-13 -- Analysis ,Interleukin-13 -- Physiological aspects ,Mice -- Usage ,Mice -- Physiological aspects ,Asthma -- Research ,Asthma -- Physiological aspects ,Leukotrienes -- Synthesis - Published
- 2006
49. Exposure to TARC alters [[beta].sub.2]-adrenergic receptor signaling in human peripheral blood T lymphocytes
- Author
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Heijink, Irene H., Vellenga, Edo, Oostendorp, Jaap, de Monchy, Jan G.R., Postma, Dirkje S., and Kauffman, Henk F.
- Subjects
T cells -- Research ,Antigen receptors, T cell -- Research ,Chemokines -- Research ,Asthma -- Physiological aspects ,T cells -- Receptors ,Biological sciences - Abstract
The [[beta].sub.2]-adrenergic receptor ([[beta].sub.2]-AR) negatively regulates T cell activity through the activation of the [G.sub.8]/adenylyl cyclase/cAMP pathway. [[beta].sub.2]-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of [[beta].sub.2]-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and [beta]-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the [[beta].sub.2]-AR as well as its association with GRK2 and [beta]-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs [[beta].sub.2]-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to [beta]-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous [beta]-agonists promotes T cell-mediated inflammation in asthma. cAMP-responsive element binding protein phosphorylation; Src kinases; G protein-coupled receptor kinase 2; [beta]-arrestin; thymus and activation-regulated chemokine
- Published
- 2005
50. Effect of 1,1-dimethylphenyl 1,4-piperazinium on mouse tracheal smooth muscle responsiveness
- Author
-
Dorion, G., Israel-Assayag, E., Beaulieu, M.J., and Cormier, Y.
- Subjects
Asthma -- Research ,Asthma -- Physiological aspects ,Smooth muscle -- Research ,Smooth muscle -- Physiological aspects ,Trachea -- Research ,Trachea -- Physiological aspects ,Mice -- Research ,Mice -- Physiological aspects ,Biological sciences - Abstract
Bronchial hyperresponsiveness is one of the main features of asthma. A nicotinic receptor agonist, 1,l-dimethylphenyl 1,4-piperazinium (DMPP), has been shown to have an inhibitory effect on airway response to methacholine in an in vivo model of asthma. The aims of this study were to 1) verity whether nicotinic acetylcholine receptors (nAChR) were present on mouse tracheal smooth muscle, 2) verify whether bronchoprotection observed in mice was due to a direct effect on airway smooth muscle, and 3) compare the effects of nicotinic agonists to that of salbutamol. [[alpha].sub.3-], [[alpha].sub.4-], and [[alpha].sub.7-]nAChR subunits were detected by immunofluorescence on tracheal tissues from normal BALB/c mice. The effect of DMPP on tracheal responsiveness was verified by an isometric method. Tracheas were isolated from normal mice, placed in organ baths, and contracted with a single dose of methacholine. Cumulative doses of DMPP or salbutamol were added to the baths. Results show that mouse tracheal smooth muscle is positive for [[alpha].sub.4-] and [[alpha].sub.7-]nAChR subunits and that the epithelium is positive for [[alpha]3.sub.-], [[alpha].sub.4-], and [[alpha].sub.7-] subunits. DMPP induced a greater dose-dependent relaxation of tracheal smooth muscles precontracted with methacholine than with salbutamol. These results suggest that the smooth muscle-relaxing effect of DMPP could have some interest in the treatment of obstructive pulmonary diseases. airway responsiveness; salbutamol; nicotinic agonists
- Published
- 2005
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