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The matrikine PGP is a mediator of pathological epithelial remodeling in asthma. Extracellular matrix extends its influence in asthma: The interplay between immune cells and smooth muscle cells in asthma pathogenesis and response to treatment is under increasing scrutiny. Patel et al. focused on how leukotrienes can modulate immune inflammation and airway hypersensitivity. Mice lacking leukotriene A4 hydrolase had exaggerated epithelial remodeling but dampened immune responses in a house dust mite model of asthma. This was due to release of Pro-Gly-Pro (PGP), a component of the extracellular matrix, which was also elevated in the sputum from severe asthmatics in two clinical cohorts. Their results showcase how the extracellular matrix is a dynamic player in disease and reveal a mediator to be targeted in asthma therapy. 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. [ABSTRACT FROM AUTHOR]