An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness.

Abstract

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.

• Authors: Dhiren F Patel, Teresa Peiró, Amelia Shoemark, Samia Akthar, Simone A Walker, Aleksander M Grabiec, Patricia L Jackson, Tracy Hussell, Amit Gaggar, Xin Xu, Jennifer L Trevor, Jindong Li, Chad Steele, Gael Tavernier, J Edwin Blalock, Robert M Niven, Lisa G Gregory, Angela Simpson, Clare M Lloyd, Robert J Snelgrove
• Journal: Science translational medicine (Sci Transl Med) Vol. 10 Issue 455 (08 22 2018) ISSN: 1946-6242 [Electronic] United States
• PMID: 30135247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Inflammation Mediators
• Oligopeptides
• prolyl-glycyl-proline
• Proline
• Epoxide Hydrolases
• leukotriene A4 hydrolase

Topics

• Airway Remodeling
• Airway Resistance
• Animals
• Asthma (complications, immunology, pathology, physiopathology)
• Bronchi (pathology)
• Cell Count
• Disease Models, Animal
• Epithelial Cells (metabolism)
• Epoxide Hydrolases (deficiency, metabolism)
• Extracellular Matrix (metabolism)
• Humans
• Hypersensitivity (complications, immunology, pathology, physiopathology)
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• Mice, Inbred C57BL
• Mucus (metabolism)
• Neutrophils (metabolism)
• Oligopeptides (metabolism)
• Proline (analogs & derivatives, metabolism)
• Pyroglyphidae (physiology)
• Respiratory Hypersensitivity (immunology, parasitology, pathology, physiopathology)
• Sputum (metabolism)
• T-Lymphocytes, Helper-Inducer (immunology)