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However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PE-containing exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0108oc","type":"journal-article","created":{"date-parts":[[2015,7,29]],"date-time":"2015-07-29T16:27:26Z","timestamp":1438187246000},"page":"359-369","source":"Crossref","is-referenced-by-count":59,"title":["Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes"],"prefix":"10.1093","volume":"54","author":[{"given":"Tomasz","family":"Szul","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"},{"name":"Program in Protease and Matrix Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Preston E.","family":"Bratcher","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"},{"name":"Program in Protease and Matrix Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle B.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Departments of Neurology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Kong","sequence":"additional","affiliation":[{"name":"Pediatrics"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabindra","family":"Tirouvanziam","sequence":"additional","affiliation":[{"name":"Program in Protease and Matrix Biology"},{"name":"Department of Pediatrics and Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, Georgia; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Ingersoll","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, Georgia; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Sztul","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil","family":"Rangarajan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Edwin","family":"Blalock","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"},{"name":"Program in Protease and Matrix Biology"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center"},{"name":"University of Alabama at Birmingham Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"},{"name":"Program in Protease and Matrix Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Gaggar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine"},{"name":"Program in Protease and Matrix Biology"},{"name":"Gregory Fleming James Cystic Fibrosis Research 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