Investigating TIMP-1 as a Potential Biomarker and Target in Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS) confers high morbidity and mortality, with a death rate reaching 40%. Several etiology factors lead to ARDS, including trauma, multiple blood transfusion, sepsis, bacterial pneumonia as well as viral pneumonia like influenza A virus (IAV) and corona virus disease (COVID-2019). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs) that regulate adaptive immune responses and located on the X chromosome. This thesis collectively aimed to evaluate the prognostic role of circulating TIMP-1 in aspect of sex difference, investigate if TIMP-1 is a downstream target of the estrogen signaling pathway and the regulation and function of TIMP-1 during lung injury. TIMP-1 was measured from plasma samples of healthy human subjects, patients with acute lung injury caused by IAV infection, COVID-2019 or other etiologies using enzyme-linked immunosorbent assay (ELISA) method. Normal lung fibroblasts IMR-90 and MLg were investigated in response to estrogen treatment to evaluate the TIMP-1 expression. Wild type and Timp-1 deficient mice were employed to study the possibility of TIMP-1 as a novel therapeutic target for lung injury. Our results showed that circulating TIMP-1 appeared to be a promising predictor of severity and mortality outcomes like ventilator-free days (VFDs), ICU-free days and death at 30 and 90-day among females with ARDS. Fibroblasts treated with estrogens confirmed that TIMP-1 is significantly linked to estrogen, and luciferase reporter assay indicated that ERα not ERβ regulates TIMP-1 promoter activity. Lastly, Timp-1 deficiency protects mice from IAV- induced weight loss, mortality, and lung injury.