Estrogen‐dependent gene regulation: Molecular basis of <scp>TIMP</scp>‐1 as a sex‐specific biomarker for acute lung injury
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 PaO<sub>2</sub>/FiO<sub>2</sub> 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.
Authors
- Sultan Almuntashiri (ORCID: https://orcid.org/0000-0003-4353-6043)
- Caroline Ann Owen (ORCID: https://orcid.org/0000-0003-4377-3591)
- Joaquı́n Zúñiga (ORCID: https://orcid.org/0000-0002-7143-0281)
- Gustavo Ramírez-Martínez
- Tatiana Sofia Rodrı́guez-Reyna (ORCID: https://orcid.org/0000-0002-5799-5016)
- Carmen Margarita Hernández‐Cardenas (ORCID: https://orcid.org/0000-0002-0311-2978)
- Yin Zhu (ORCID: https://orcid.org/0000-0003-1683-4205)
- Nora E. Regino-Zamarripa (ORCID: https://orcid.org/0000-0002-5311-9633)
- Saugata Dutta (ORCID: https://orcid.org/0000-0003-4377-5706)
- Duo Zhang (ORCID: https://orcid.org/0000-0003-0361-4174)
- Valeria Irineo‐Moreno (ORCID: https://orcid.org/0009-0005-9997-9742)
- Paloma Campero
- Xiaoyun Wang (ORCID: https://orcid.org/0000-0002-9900-740X)
- Siddhika Gamare
- Ángel Camarena
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Georgia (US)
- Augusta University (US)
- Charlie Norwood VA Medical Center (US)
- University of Ha'il (SA)
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX)
- Instituto Nacional de Enfermedades Respiratorias (MX)
- Tecnológico de Monterrey (MX)
Publication Details
- Journal
- Physiological Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.14814/phy2.70047
- Citations
- 3
- Primary Topic
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Type
- article
- Field-Weighted Citation Impact
- 1.26
Funders
- Foundation for the National Institutes of Health
- National Institutes of Health
- National Heart, Lung, and Blood Institute