Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice

作者：Joanna M. Poczobutt, N.W. Egersdorf, Max S. Hiltabidle, Koichi Nishino, Matthew J. Justice, T. Rivera, B. Dubois, Alexander Borowiec, Seyed Ali Mousavi‐Aghdas, Katrina W. Kopf, Fabienne Gally, Jennifer L. Matsuda, Evgeny Berdyshev, Irina Petrache · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2025 · DOI：10.1165/rcmb.2024-0380oc · 被引用次数：6 · 研究领域：Sphingolipid Metabolism and Signaling、Autophagy in Disease and Therapy、Erythrocyte Function and Pathophysiology

Abstract Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick disease that, in type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 (Smpd1−/− mouse) deletion causes lung inflammation with foamy dysfunctional macrophages but is protective against acute lung injury. It is unknown whether these manifestations are a result of progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, CAGG-CreERTM × Smpd1fl/fl, induced by tamoxifen (5 wk), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief postdevelopmental ASM insufficiency affects lung sphingolipids and pathology, including after LPS-induced injury. Compared with control animals, Smpd1fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios and increased de novo sphingolipid synthesis and sphingosine-1-phosphate concentrations. At 3 days after LPS instillation (20 μg), control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1fl/fl mice showed more exuberant inflammation, but had significantly reduced apoptosis, particularly in endothelial cells. During repair phase (6–9 d), Smpd1fl/fl lungs had increased cell proliferation with reduced accumulation of autophagosome-tagging p62/SQSTM1. These results indicate that befor...