{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T10:03:31Z","timestamp":1790330611898,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["DA040619"],"award-info":[{"award-number":["DA040619"]}]},{"name":"National Institute of Health","award":["AA030841"],"award-info":[{"award-number":["AA030841"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic alcohol and nicotine exposure can increase susceptibility to lung injury and promote the release of extracellular ATP (eATP). Elevated eATP activates the purinergic P2X7 receptor (P2X7R), a membrane ion channel that amplifies inflammatory signaling and promotes extracellular vesicle (EV) release. These EVs may serve as mediators of lung to systemic communications. Proteomic analysis of lung epithelial cell-derived EVs revealed enrichment of urokinase-type plasminogen activator (uPA), a key enzyme involved in extracellular matrix remodeling. Treatment of hPAEpiCs with ETH, acetaldehyde (ALD), and e-cigarette vapor, with or without nicotine, induced NLRP3 inflammasome activation, IL-1\u03b2 secretion, and increased incorporation of uPA into EVs. Exposure of human brain microvascular endothelial cells (hBMVECs) to these EVs enhanced plasmin conversion and activated MMP-9 and TGF-\u03b21, resulting in reduced transendothelial electrical resistance (TEER), indicating blood\u2013brain barrier (BBB) dysfunction. Pharmacological inhibition of P2X7R using \u2018A804598\u2019 significantly reduced EV-associated uPA release and attenuated endothelial injury. In vivo, chronic ETH vapor exposure increased expression of uPA, uPAR, MMP-2, and MMP-9 while decreasing SERPIN1 and TIMP1 in murine brain microvessels, changes associated with BBB disruption and IgG leakage into brain parenchyma. P2X7R inhibition normalized these effects. Collectively, these findings identify EV-associated uPA as a mediator of lung-to-brain signaling and BBB injury following ETH and e-cigarette exposure.<\/jats:p>","DOI":"10.3390\/cells15191750","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:23:01Z","timestamp":1790328181000},"page":"1750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alcohol and E-Cigarettes Activate P2X7R in Lung Epithelial Cells, Stimulating Release of Plasminogen Activator in Extracellular Vesicles, Injuring Blood-Brain Barrier"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5343-8167","authenticated-orcid":false,"given":"Naveen","family":"Mekala","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5840-6458","authenticated-orcid":false,"given":"Namdev","family":"Togre","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Sunil","family":"Kurian","sequence":"additional","affiliation":[{"name":"Scripps Clinic and Biorepository, Scripps Center for Organ and Cell Transplantation Research, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-1955","authenticated-orcid":false,"given":"Slava","family":"Rom","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9592-2785","authenticated-orcid":false,"given":"Uma","family":"Sriram","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Yuri","family":"Persidsky","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230233","DOI":"10.1183\/16000617.0233-2023","article-title":"The association between alcohol consumption and pulmonary function: A scoping review","volume":"33","author":"Nielsen","year":"2024","journal-title":"Eur. 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