Work

Ethanol‐induced Nrf2 suppression in the lung is mediated by AP ‐1‐driven expression of mi R ‐144

Year: 2025

Type: article

Abstract: BACKGROUND: Alcohol use disorders (AUD) increase susceptibility to lung diseases. Ethanol suppresses nuclear factor erythroid 2-related factor 2 (Nrf2), impairing pulmonary antioxidant and immune defenses. We showed that HIV-mediated Nrf2 suppression in the lung is driven by miR-144. We hypothesized that ethanol similarly suppresses Nrf2 by inducing miR-144 in the lung. METHODS: miR-144 expression was quantified in lungs from rats chronically fed an ethanol-containing diet and in rat alveolar epithelial cells (AEC), alveolar macrophages (AMs), and lung fibroblasts (PLF) treated with ethanol. The levels of the AP-1 subunits c-Fos and c-Jun, both total and phosphorylated, were quantified by western immunoblotting in rat PLF. The link between ethanol-induced AP-1 activation and miR-144 expression on Nrf2 and Nrf2-regulated antioxidants was then assessed using c-Fos silencing RNA and AP-1 inhibitors. The impact of manipulating miR-144 expression and/or activity on the expression of Nrf2 and two key Nrf2-dependent antioxidants in ethanol-treated PLF was evaluated. RESULTS: miR-144 expression was increased in the lungs of chronic ethanol-fed rats, and ethanol exposure increased miR-144 expression in AEC and PLF, with a trend toward increased expression in AM. Ethanol induced both total and phosphorylated c-Fos protein and total c-Jun protein in PLF. Inhibiting AP-1 with c-Fos silencing RNA or AP-1 inhibitors blocked ethanol-induced miR-144 expression in PLF. Furthermore, RNA silencing of c-Fos or inhibiting miR-144 restored the expression of Nrf2 and the Nrf2-dependent antioxidants GCLC and NQO-1 in ethanol-treated PLF. In contrast, direct overexpression of miR-144 suppressed Nrf2, GCLC, and NQO-1, thereby reproducing the pathophysiological effects of ethanol. CONCLUSIONS: Ethanol induces miR-144 expression in the lung, mediated by AP-1 activation. These steps can be implicated in the ethanol-mediated inhibition of Nrf2 and the downstream suppression of Nrf2-dependent antioxidant and immune defenses. These results suggest that miR-144 could be a novel therapeutic target to mitigate susceptibility to acute inflammatory lung diseases in individuals with AUD.

Source: Alcoholism Clinical and Experimental Research

DOI: 10.1111/acer.70088

Authors: Viranuj Sueblinvong, Xian Fan, Justin Guo, Hui Tao, David M. Guidot

Institution: Emory University

Language: English

Topic: Genomics, phytochemicals, and oxidative stress

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,110