An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness

Academic Article

Abstract

  • It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A hydrolase (LTA H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B (LTB ) and degradation of pro-neutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA H exacerbated AHR, despite the absence of LTB . 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 LTA H inhibitors in the clinic. 4 4 4 4 4 4 4 4
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Patel DF; Peiró T; Shoemark A; Akthar S; Walker SA; Grabiec AM; Jackson PL; Hussell T; Gaggar A; Xu X
  • Volume

  • 10
  • Issue

  • 455