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However, the sex\u2010specific regulation of TIMP\u20101 and the underlying molecular mechanisms have not been well elucidated. In this study, we found that plasma TIMP\u20101 levels were significantly higher in COVID\u201019 and H1N1 patients compared with those in healthy subjects (<jats:italic>n<\/jats:italic>\u2009=\u200925). TIMP\u20101 concentrations were significantly different between males and females in each disease group. Among female but not male patients, TIMP\u20101 levels significantly correlated with the PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio and hospital length of stay. Using the mouse model of ALI induced by the H1N1 virus, we found that TIMP\u20101 is strikingly induced in PDGFR\u03b1\u2010positive cells in the murine lungs. Moreover, female mice showed a higher Timp\u20101 expression in the lungs on day 3 postinfection. Mechanistically, we observed that estrogen can upregulate TIMP\u20101 expression in lung fibroblasts, not epithelial cells. In addition, overexpression of estrogen receptor \u03b1 (ER\u03b1) increased the <jats:italic>TIMP\u20101<\/jats:italic> promoter activity. In summary, TIMP\u20101 is an estrogen\u2010responsive gene, and its promoter activity is regulated by ER\u03b1. Circulating TIMP\u20101 may serve as a sex\u2010specific marker, reflecting the severity and worst outcomes in female patients with SARS\u2010CoV2\u2010 and IAV\u2010related ALI.<\/jats:p>","DOI":"10.14814\/phy2.70047","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T03:40:20Z","timestamp":1726198820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Estrogen\u2010dependent gene regulation: Molecular basis of\u00a0<scp>TIMP<\/scp>\u20101 as a sex\u2010specific biomarker for acute lung injury"],"prefix":"10.14814","volume":"12","author":[{"given":"Sultan","family":"Almuntashiri","sequence":"first","affiliation":[{"name":"Clinical and Experimental Therapeutics, College of Pharmacy University of Georgia and Charlie Norwood VA Medical Center  Augusta Georgia USA"},{"name":"Department of Clinical Pharmacy, College of Pharmacy University of Hail  Hail Saudi 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