An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness

• DOI: 10.1126/scitranslmed.aaq0693
• Publication Date: 2018-08-22T18:06:26Z
• Authors: Dhiren F. Patel; Teresa Peiró; Amelia Shoemark; Samia Akthar; Simone A. Walker; Aleksander M. Gra...; 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
• Keywords: Leukotriene B4; Proinflammatory cytokine; Airway hyperresponsiveness

It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence development and progression chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory anti-inflammatory activities, through generation B4 (LTB4) degradation proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show abrogation LTB4 signaling ameliorated inflammation airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss LTA4H exacerbated AHR, despite absence This AHR was attributable to neutrophil-independent capacity PGP promote pathological epithelial remodeling. Thus, we demonstrate disconnect between ability an remodeling phenotype negatively affects lung function. Subsequently, substantial quantities are detectable sputum moderate-severe asthmatics two distinct cohorts patients. These studies have implications for our understanding phenotypes may rationalize failure inhibitors clinic.