@article {Linjpet.111.181560, author = {Wei-Chieh Lin and Chiou-Feng Lin and Chia-Ling Chen and Chang-Wen Chen and Yee-Shin Lin}, title = {Inhibition of Neutrophil Apoptosis via Sphingolipid Signaling in Acute Lung Injury}, elocation-id = {jpet.111.181560}, year = {2011}, doi = {10.1124/jpet.111.181560}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils into the alveolar space. The inhibition of alveolar neutrophil apoptosis has been implicated in the pathogenesis of ALI. Although sphingolipids may regulate cell apoptosis, the role of sphingolipids in activated neutrophils during ALI is not clear. In this study, we test the hypothesis that sphingolipids would attenuate neutrophil apoptosis which contributes to the development of ALI. Lipopolysaccharide (LPS)-stimulated human neutrophils, with or without inhibitor treatment, were analyzed for apoptosis. We found that the inhibitory effect of LPS on neutrophil apoptosis was blocked by treatment with neutral sphingomyelinase (nSMase) inhibitor sphingolactone-24 (Sph-24), sphingosine kinase inhibitor (SKI)-II, and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, but not by acidic sphingomyelinase inhibitor chlorpromazine. LPS-activated phosphorylation of p38 MAPK was attenuated by treatment with Sph-24 and SKI-II. Furthermore, mice with LPS-induced lung injury were treated with nSMase inhibitor Sph-24 to evaluate its impact on lung injury and survival. The severity of LPS-induced ALI was reduced and the survival rate was increased in mice treated with Sph-24 as compared with those given LPS alone. Intracellular levels of sphingolipids in alveolar neutrophils from patients with acute respiratory distress syndrome (ARDS) were also measured. We found that intracellular levels of ceramide and phospho-p38MAPK were elevated in alveolar neutrophils from ARDS patients. Our results demonstrate that activation of the nSMase/S1P pathway to induce p38 MAPK phosphorylation results in inhibition of neutrophil apoptosis, which may contribute to the development of ALI.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2011/07/01/jpet.111.181560}, eprint = {https://jpet.aspetjournals.org/content/early/2011/07/01/jpet.111.181560.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }