{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:52:52Z","timestamp":1792165972465,"version":"4.4.0"},"reference-count":41,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,22]],"date-time":"2024-12-22T00:00:00Z","timestamp":1734825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["RO1HL167192"],"award-info":[{"award-number":["RO1HL167192"]}]},{"name":"NIH","award":["RO1HL152761"],"award-info":[{"award-number":["RO1HL152761"]}]},{"name":"NIH","award":["RO1HL155051"],"award-info":[{"award-number":["RO1HL155051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tissue acidification resulting from dysregulated cellular bioenergetics accompanies various inflammatory states. GPR68, along with other members of proton-sensing G protein-coupled receptors, responds to extracellular acidification and has been implicated in chronic inflammation-related diseases such as ischemia, cancer, and colitis. The present study examined the role of extracellular acidification on human pulmonary endothelial cell (EC) permeability and inflammatory status per se and investigated potential synergistic effects of acidosis on endothelial dysfunction caused by bacterial lipopolysaccharide (LPS, Klebsiella pneumoniae). Results showed that medium acidification to pH 6.5 caused a delayed increase in EC permeability illustrated by a decrease in transendothelial electrical resistance and loss of continuous VE-cadherin immunostaining at cell junctions. Likewise, acidic pH induced endothelial inflammation reflected by increased mRNA and protein expression of EC adhesion molecules VCAM-1 and ICAM-1, upregulated mRNA transcripts of tumor necrosis factor-\u03b1, IL-6, IL-8, IL-1\u03b2, and CXCL5, and increased secretion of ICAM-1, IL-6, and IL-8 in culture medium monitored by ELISA. Among the GPCRs tested, acidic pH selectively increased mRNA and protein expression of GPR68, and only the GPR68-specific small molecule inhibitor OGM-8345 rescued acidosis-induced endothelial permeability and inflammation. Furthermore, acidic pH exacerbated LPS-induced endothelial permeability and inflammatory response in cultured lung macrovascular as well as microvascular endothelial cells. These effects were suppressed by OGM-8345 in both EC types. Altogether, these results suggest that GPR68 is a critical mediator of acidic pH-induced dysfunction of human pulmonary vascular endothelial cells and mediates the augmenting effect of tissue acidification on LPS-induced endothelial cell injury.<\/jats:p>","DOI":"10.3390\/cells13242125","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T05:58:27Z","timestamp":1734933507000},"page":"2125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["GPR68 Mediates Lung Endothelial Dysfunction Caused by Bacterial Inflammation and Tissue Acidification"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3087-5516","authenticated-orcid":false,"given":"Pratap","family":"Karki","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, UMSOM Lung Biology Program, University of Maryland School of Medicine, 20 Penn Street, HSF-2, Room S143, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, UMSOM Lung Biology Program, University of Maryland School of Medicine, 20 Penn Street, HSF-2, Room S143, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamoltip","family":"Promnares","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, UMSOM Lung Biology Program, University of Maryland School of Medicine, 20 Penn Street, HSF-2, Room S143, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H.","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0424-8252","authenticated-orcid":false,"given":"Charles C.","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0303-5394","authenticated-orcid":false,"given":"Konstantin G.","family":"Birukov","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna A.","family":"Birukova","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, UMSOM Lung Biology Program, University of Maryland School of Medicine, 20 Penn Street, HSF-2, Room S143, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1189\/jlb.69.4.522","article-title":"The effects of extracellular pH on immune function","volume":"69","author":"Lardner","year":"2001","journal-title":"J. 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