{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:05Z","timestamp":1787027825710,"version":"build-2736575974"},"reference-count":27,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,13]],"date-time":"2021-06-13T00:00:00Z","timestamp":1623542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["UO1ES030674"],"award-info":[{"award-number":["UO1ES030674"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Exposure to hydrochloric acid (HCl) leads acutely to asthma-like symptoms, acute respiratory distress syndrome (ARDS), including compromised alveolo-capillary barrier, and respiratory failure. To better understand the direct effects of HCl on pulmonary endothelial function, we studied the characteristics of HCl-induced endothelial barrier dysfunction in primary cultures of human lung microvascular endothelial cells (HLMVEC), defined the involved molecular pathways, and tested the potentially beneficial effects of Heat Shock Protein 90 (HSP90) inhibitors. HCl impaired barrier function in a time- and concentration-dependent manner and was associated with activation of Protein Kinase B (AKT), Ras homolog family member A (RhoA) and myosin light chain 2 (MLC2), as well as loss of plasmalemmal VE-cadherin, rearrangement of cortical actin, and appearance of inter-endothelial gaps. Pre-treatment or post-treatment of HLMVEC with AUY-922, a third-generation HSP90 inhibitor, prevented and restored HCl-induced endothelial barrier dysfunction. AUY-922 increased the expression of HSP70 and inhibited the activation (phosphorylation) of extracellular-signal regulated kinase (ERK) and AKT. AUY-922 also prevented the HCl-induced activation of RhoA and MLC2 and the internalization of plasmalemmal VE-cadherin. We conclude that, by increasing the expression of cytoprotective proteins, interfering with actomyosin contractility, and enhancing the expression of junction proteins, inhibition of HSP90 may represent a useful approach for the management of HCl-induced endothelial dysfunction and acute lung injury.<\/jats:p>","DOI":"10.3390\/cells10061489","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:30:25Z","timestamp":1623666625000},"page":"1489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-3876","authenticated-orcid":false,"given":"Ruben M. L.","family":"Colunga Biancatelli","sequence":"first","affiliation":[{"name":"Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1705-027X","authenticated-orcid":false,"given":"Pavel","family":"Solopov","sequence":"additional","affiliation":[{"name":"Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy","family":"Gregory","sequence":"additional","affiliation":[{"name":"Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Catravas","sequence":"additional","affiliation":[{"name":"Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA"},{"name":"School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA 23508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,13]]},"reference":[{"key":"ref_1","unstructured":"National Research Council (US), S.o.R.-E.T. (1998). Acute Toxicity of Hydrogen Chloride, Appendix D, National Academies Press (US)."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bingham, E., Cohrssen, B., and Powell, C.H. (2001). Patty\u2019s Toxicology, John Wiley & Sons. [5th ed.].","DOI":"10.1002\/0471125474"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1378\/chest.94.3.476","article-title":"Increases in airway responsiveness following acute exposure to respiratory irritants. Reactive airway dysfunction syndrome or occupational asthma?","volume":"94","author":"Boulet","year":"1988","journal-title":"Chest"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1136\/oem.58.6.399","article-title":"Short term respiratory effects of acute exposure to chlorine due to a swimming pool accident","volume":"58","author":"Agabiti","year":"2001","journal-title":"Occup. Environ. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1378\/chest.98.4.928","article-title":"Reactive airway dysfunction syndrome in three police officers following a roadside chemical spill","volume":"98","author":"Promisloff","year":"1990","journal-title":"Chest"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/08958378.2019.1624895","article-title":"Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis","volume":"31","author":"Marinova","year":"2019","journal-title":"Inhal. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Solopov, P., Colunga Biancatelli, R.M., Dimitropoulou, C., and Catravas, J.D. (2021). Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115909"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/bja\/46.2.127","article-title":"A comparison of the pulmonary response to the endotracheal instillation of 0.1 N hydrochloric acid and Hartmann\u2019s solution in the rabbit","volume":"46","author":"Davidson","year":"1974","journal-title":"Br. J. Anaesth."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000362980","article-title":"Differential Regulation of Lung Endothelial Permeability in vitro and in situ","volume":"34","author":"Uhlig","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1165\/rcmb.2012-0496OC","article-title":"Heat shock protein 90 inhibitors prevent LPS-induced endothelial barrier dysfunction by disrupting RhoA signaling","volume":"50","author":"Joshi","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1165\/rcmb.2007-0324OC","article-title":"Heat shock protein 90 inhibitors protect and restore pulmonary endothelial barrier function","volume":"39","author":"Antonov","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Colunga Biancatelli, R.M., Solopov, P., Gregory, B., and Catravas, J.D. (2020). HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF). Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155286"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/01902148.2020.1764148","article-title":"Post-treatment with a heat shock protein 90 inhibitor prevents chronic lung injury and pulmonary fibrosis, following acute exposure of mice to HCl","volume":"46","author":"Marinova","year":"2020","journal-title":"Exp. Lung Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1501941","DOI":"10.1183\/13993003.01941-2015","article-title":"Amplified canonical transforming growth factor-\u03b2 signalling viaheat shock protein 90 in pulmonary fibrosis","volume":"49","author":"Sibinska","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/s41416-019-0688-y","article-title":"TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-na\u00efve and imatinib-resistant gastrointestinal stromal tumours","volume":"122","author":"Saito","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bohush, A., Bieganowski, P., and Filipek, A. (2019). Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases. Int J. Mol. Sci, 20.","DOI":"10.3390\/ijms20204976"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"43996","DOI":"10.1038\/srep43996","article-title":"Hsp90 dependence of a kinase is determined by its conformational landscape","volume":"7","author":"Luo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112063","DOI":"10.1016\/j.ejmech.2020.112063","article-title":"Natural heat shock protein 90 inhibitors in cancer and inflammation","volume":"189","author":"Costa","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.vph.2009.12.009","article-title":"Harvesting, identification and barrier function of human lung microvascular endothelial cells","volume":"52","author":"Catravas","year":"2010","journal-title":"Vasc. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Barabutis, N., Marinova, M., Solopov, P., Uddin, M.A., Croston, G.E., Reinheimer, T.M., and Catravas, J.D. (2020). Protective mechanism of the selective vasopressin V1A receptor agonist selepressin against endothelial barrier dysfunction. J. Pharmacol. Exp. Ther.","DOI":"10.1124\/jpet.120.000146"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fnmol.2011.00051","article-title":"PI3K\/AKT\/mTOR Pathway in Angiogenesis","volume":"4","author":"Karar","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1161\/01.CIR.0000129768.35536.FA","article-title":"AKT participates in endothelial dysfunction in hypertension","volume":"109","author":"Iaccarino","year":"2004","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1111\/gtc.12438","article-title":"ERK activation in endothelial cells is a novel marker during neovasculogenesis","volume":"21","author":"Terai","year":"2016","journal-title":"Genes Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1006\/jmcc.2000.1250","article-title":"Cytoprotective mechanism of heat shock protein 70 against hypoxia\/reoxygenation injury","volume":"32","author":"Kawana","year":"2000","journal-title":"J. Mol. Cell Cardiol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1165\/rcmb.2013-0214OC","article-title":"Novel mechanism of attenuation of LPS-induced NF-\u03baB activation by the heat shock protein 90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, in human lung microvascular endothelial cells","volume":"50","author":"Thangjam","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"L964","DOI":"10.1152\/ajplung.00054.2016","article-title":"Hsp90 inhibition suppresses NF-\u03baB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells","volume":"310","author":"Thangjam","year":"2016","journal-title":"Am. J. Physiol. -Lung Cell. Mol. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Solopov, P., Biancatelli, R.M., Marinova, M., Dimitropoulou, C., and Catravas, J.D. (2020). The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134740"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/6\/1489\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:55Z","timestamp":1760163235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/6\/1489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,13]]},"references-count":27,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["cells10061489"],"URL":"https:\/\/doi.org\/10.3390\/cells10061489","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,13]]}}}