Estrogen-dependent gene regulation: Molecular basis of TIMP-1 as a sex-specific biomarker for acute lung injury

  • Physiol Rep. 2024 Sep;12(17):e70047. doi: 10.14814/phy2.70047.
Sultan Almuntashiri  1  2 ,  Saugata Dutta  1 ,  Yin Zhu  1 ,  Siddhika Gamare  1 ,  Gustavo Ramírez  3 ,  Valeria Irineo-Moreno  3  4 ,  Angel Camarena  3 ,  Nora Regino  3  4 ,  Paloma Campero  3 ,  Carmen M Hernández-Cardenas  5 ,  Tatiana S Rodriguez-Reyna  6 ,  Joaquin Zuñiga  3  4 ,  Caroline A Owen  7 ,  Xiaoyun Wang  1 ,  Duo Zhang  1  8
Affiliations
  • 1. Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
  • 2. Department of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail, Saudi Arabia.
  • 3. Laboratory of Immunobiology and Genetics and Intensive Care Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
  • 4. Tecnologico de Monterrey, School of Medicine and Health Sciences, Mexico City, Mexico.
  • 5. Intensive Care Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
  • 6. Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • 7. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
  • 8. Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
PMID: 39267201 DOI: 10.14814/phy2.70047
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.

Keywords
COVID‐19; PDGFRA; fibroblasts; gene regulation; influenza A virus; sex differences.
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