An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness
| Autor: | Clare M. Lloyd, Angela Simpson, Tracy Hussell, Xin Xu, J. Edwin Blalock, Robert Niven, Lisa G. Gregory, Dhiren F. Patel, Samia Akthar, Chad Steele, Aleksander M. Grabiec, Simone A. Walker, Teresa Peiró, Jindong Li, Amit Gaggar, Amelia Shoemark, Robert J. Snelgrove, G Tavernier, Patricia L. Jackson, Jennifer Trevor |
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| Přispěvatelé: | Wellcome Trust, Asthma UK, Medical Research Council (MRC) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Neutrophils Leukotriene B4 Cell Count Research & Experimental Medicine Extracellular matrix chemistry.chemical_compound 0302 clinical medicine Airway resistance LEUKOTRIENE A(4) HYDROLASE Medicine INDUCED SPUTUM 11 Medical and Health Sciences Epoxide Hydrolases Pyroglyphidae INHIBITOR T-Lymphocytes Helper-Inducer General Medicine respiratory system Phenotype Extracellular Matrix 3. Good health CHEMOATTRACTANT Medicine Research & Experimental Airway Remodeling Inflammation Mediators medicine.symptom Life Sciences & Biomedicine Oligopeptides Proline Bronchi Inflammation OBSTRUCTIVE PULMONARY-DISEASE Article Proinflammatory cytokine Leukotriene-A4 hydrolase 03 medical and health sciences NEUTROPHILIC INFLAMMATION Hypersensitivity Respiratory Hypersensitivity PROLINE-GLYCINE-PROLINE Animals Humans Science & Technology B-4 business.industry Airway Resistance Sputum Epithelial Cells Chemotaxis Cell Biology 06 Biological Sciences Asthma respiratory tract diseases Mice Inbred C57BL Disease Models Animal Mucus 030104 developmental biology 030228 respiratory system chemistry Immunology business LUNG SEVERE ASTHMA |
| Zdroj: | Science Translational Medicine. 10 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4H exacerbated AHR, despite the absence of LTB4. This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling. Thus, we demonstrate a disconnect between airway inflammation and AHR and the ability of a matrikine to promote an epithelial remodeling phenotype that negatively affects lung function. Subsequently, we show that substantial quantities of PGP are detectable in the sputum of moderate-severe asthmatics in two distinct cohorts of patients. These studies have implications for our understanding of remodeling phenotypes in asthma and may rationalize the failure of LTA4H inhibitors in the clinic. |
| Databáze: | OpenAIRE |
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