Role of Ceramide in SARS-CoV-2 Spike Protein-amplified Acute Lung Injury

作者：S. Mousavi Aghdas, Katrina W. Kopf, Aastha Singh, Monica J. Justice, Joanna M. Poczobutt, Max S. Hiltabidle, T. Rivera, B. Dubois, Evgeny Berdyshev, Richard Kolesnick, Irina Petrache · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2025 · DOI：10.1164/ajrccm.2025.211.abstracts.a2453 · 被引用次数：1 · 研究领域：Sphingolipid Metabolism and Signaling、Phagocytosis and Immune Regulation

Abstract Rationale: Despite effective antiviral therapies, the development of acute respiratory distress syndrome (ARDS) following SARS-CoV-2 infection (COVID-ARDS) remains a significant clinical challenge. We have shown marked elevations of injurious ceramide species in COVID-ARDS lungs and plasma, indicating a potential role for ceramides in its pathogenesis. We posit that increased ceramides are the result of the stress-induced activation of acid sphingomyelinase (ASM) on endothelial cells. ASM can be activated by oxidative stress, inflammatory cytokines, and in the context of COVID-ARDS, by the activation of the angiotensin receptor 1 from excess circulating angiotensin 2 (Ang2). We hypothesized that inhibition of ASM decreases ceramide levels and alleviates lung injury in a mouse model induced by aspiration pneumonia amplified by SARS-CoV Spike (S1) protein. Methods: Following the model described by Kuba et al. (Nat Med, 2005), wild type C57BL/6 mice (n=5/group; females) received HCl (pH 1.5; 1.5 uL/g; intratracheal) and SARS-CoV-2 S1 (490 ug/kg thrice; intraperitoneal). ASM was inhibited by amitriptyline or endothelial-specific conditional Smpd1 knockout mice. Mice underwent tracheal cannulation and mechanical ventilation (Scireq Flexivent) under general anesthesia and neuromuscular blockade with pulmonary function tests measured at 30-minute intervals. We evaluated capillary permeability via albumin, IgM (ELISA), and lung parenchymal inflammation on H/E-stained lung se...