Alcohol increases lung ACE2 expression and exacerbates SARS-CoV-2 Spike protein subunit 1-induced acute lung injury in K18-hACE2 transgenic mice.

Abstract

During the SARS-CoV-2 pandemic alcohol consumption increased markedly. Nearly 1 in 4 adults reported drinking more alcohol to cope with stress. Chronic alcohol abuse is now recognized as a factor complicating the course of acute respiratory distress syndrome (ARDS). and increasing mortality. To investigate the mechanisms behind this interaction, we developed a combined ARDS and chronic alcohol abuse mouse model by intratracheally instilling the S1 subunit of SARS-CoV-2 Spike protein (S1SP) in K18-hACE2 transgenic mice that express the human ACE2 receptor for SARS-CoV-2 and are kept on an ethanol diet. 72 hours after S1SP instillation, mice on ethanol diet exhibited a strong decline in body weight, a dramatic increase in white blood cell content of bronchoalveolar lavage fluid, and an augmented “cytokine storm”, compared to S1SP treated mice on control diet. Histologic examination of lung tissue demonstrated abnormal recruitment of immune cells in the alveolar space, abnormal parenchymal architecture, and worsening of the Ashcroft score in S1SP- and alcohol-treated animals. Along with the activation of pro-inflammatory biomarkers (NF-κB, STAT3, NLRP3 inflammasome), lung tissue homogenates from mice on alcohol diet, demonstrated overexpression of ACE2 compared to mice on control diet. This model could be useful for the development of therapeutic approaches against alcohol-exacerbated COVID-19.