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

Author:

Almuntashiri Sultan12,Dutta Saugata1,Zhu Yin1,Gamare Siddhika1,Ramírez Gustavo3,Irineo‐Moreno Valeria34ORCID,Camarena Angel3,Regino Nora34,Campero Paloma3,Hernández‐Cardenas Carmen M.5ORCID,Rodriguez‐ Reyna Tatiana S.6,Zuñiga Joaquin34,Owen Caroline A.7,Wang Xiaoyun1,Zhang Duo18ORCID

Affiliation:

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

Abstract

AbstractIncreased 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.

Funder

Foundation for the National Institutes of Health

National Heart, Lung, and Blood Institute

Publisher

Wiley

Reference59 articles.

1. TIMP‐1 promotes the immune response in influenza‐induced acute lung injury;Allen J. R.;Lung,2018

2. TIMP‐1 and its potential diagnostic and prognostic value in pulmonary diseases;Almuntashiri S.;Chinese Medical Journal Pulmonary and Critical Care Medicine,2023

3. Plasma TIMP‐1 as a sex‐specific biomarker for acute lung injury;Almuntashiri S.;Biology of Sex Differences,2022

4. Polymorphic X‐chromosome inactivation of the human TIMP1 gene;Anderson C. L.;American Journal of Human Genetics,1999

5. Differential expression of estrogen receptor variants in response to inflammation signals in human airway smooth muscle;Aravamudan B.;Journal of Cellular Physiology,2017

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3