Estrogen‐dependent gene regulation: Molecular basis of TIMP ‐1 as a sex‐specific biomarker for acute lung injury
Year: 2024
Type: article
Abstract: Increased circulating tissue inhibitor of metalloproteinases‐1 (TIMP‐1) levels have been observed in patients with acute lung injury (ALI). However, the sex‐specific regulation of TIMP‐1 and the underlying molecular mechanisms have not been well elucidated. In this study, we found that plasma TIMP‐1 levels were significantly higher in COVID‐19 and H1N1 patients compared with those in healthy subjects (n = 25). TIMP‐1 concentrations were significantly different between males and females in each disease group. Among female but not male patients, TIMP‐1 levels significantly correlated with the PaO2/FiO2 ratio and hospital length of stay. Using the mouse model of ALI induced by the H1N1 virus, we found that TIMP‐1 is strikingly induced in PDGFRα‐positive cells in the murine lungs. Moreover, female mice showed a higher Timp‐1 expression in the lungs on day 3 postinfection. Mechanistically, we observed that estrogen can upregulate TIMP‐1 expression in lung fibroblasts, not epithelial cells. In addition, overexpression of estrogen receptor α (ERα) increased the TIMP‐1 promoter activity. In summary, TIMP‐1 is an estrogen‐responsive gene, and its promoter activity is regulated by ERα. Circulating TIMP‐1 may serve as a sex‐specific marker, reflecting the severity and worst outcomes in female patients with SARS‐CoV2‐ and IAV‐related ALI.
Source: Physiological Reports
DOI: 10.14814/phy2.70047
Institutions: University of Georgia, Charlie Norwood VA Medical Center, University of Ha'il, Instituto Nacional de Enfermedades Respiratorias, Tecnológico de Monterrey, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Brigham and Women's Hospital, Harvard University, Augusta University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,950
Awards: G1470409319, G1671183399, G1673709085, G1795591630, G1959396309, G196810821, MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections, G3040072699, Mechanistic Insights of TIMP-1 in Influenza Virus Infection, G6485404418, G7212831060, G7415795898, G7435382582, The Function and Potential Application of Extracellular Vesicle Derived Clara Cell Protein 16 in Gram-negative Bacterial Pneumonia, G9000046174, G9000206136, G9000228648, Emory Specialized Center of Research Excellence (SCORE) on Sex Differences
OpenAlex ID: W4402530834