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Constitutional Smpd1 (Smpd1\u2212\/\u2212 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 \u00d7 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 \u03bcg), 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\u20139 d), Smpd1fl\/fl lungs had increased cell proliferation with reduced accumulation of autophagosome-tagging p62\/SQSTM1. These results indicate that before developing lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and may stimulate repair after inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of Niemann-Pick disease and the role of distinct sphingolipid metabolites in lung injury and repair.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0380oc","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T12:32:28Z","timestamp":1738931548000},"page":"275-287","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":8,"title":["Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice"],"prefix":"10.1093","volume":"73","author":[{"given":"Joanna M.","family":"Poczobutt","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4471-3963","authenticated-orcid":false,"given":"Nicholas","family":"Egersdorf","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-1485","authenticated-orcid":false,"given":"Max S.","family":"Hiltabidle","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8127-6539","authenticated-orcid":false,"given":"Koichi","family":"Nishino","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4850-8320","authenticated-orcid":false,"given":"Matthew J.","family":"Justice","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2038-8733","authenticated-orcid":false,"given":"Tanner","family":"Rivera","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Dubois","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Borowiec","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9408-3596","authenticated-orcid":false,"given":"S. Ali","family":"Mousavi-Aghdas","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6887-7545","authenticated-orcid":false,"given":"Katrina","family":"Kopf","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0503-7411","authenticated-orcid":false,"given":"Fabienne","family":"Gally","sequence":"additional","affiliation":[{"name":"Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado; and"},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, 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