Inhibition of neutrophil apoptosis via sphingolipid signaling in acute lung injury

Wei-Chieh Lin, Chiou Feng Lin, Chia-Ling Chen, Chang-Wen Chen, Yee-Shin Lin

研究成果: 雜誌貢獻文章同行評審

43 引文 斯高帕斯(Scopus)


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 that 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 the neutral sphingomyelinase (nSMase) inhibitor sphingolactone-24 (Sph-24), sphingosine kinase inhibitor II, and p38 mitogen-activated protein kinase (MAPK) inhibitor 4-[4-(4-fluorophenyl)-2-(4- methylsulfinylphenyl)- 1H-imidazol-5-yl]pyridine (SB203580) but not by the acidic sphingomyelinase inhibitor chlorpromazine. LPS-activated phosphorylation of p38 MAPK also was attenuated by treatment with Sph-24 and sphingosine kinase inhibitor II. Furthermore, mice with LPS-induced lung injury were treated with the 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 compared with that in those given LPS alone. Intracellular levels of sphingolipids in alveolar neutrophils from patients with acute respiratory distress syndrome also were measured. We found that intracellular levels of ceramide and phospho-p38 MAPK were elevated in alveolar neutrophils from acute respiratory distress syndrome patients. Our results demonstrate that activation of the nSMase/ sphingosine-1-phosphate pathway to induce p38 MAPK phosphorylation results in inhibition of neutrophil apoptosis, which may contribute to the development of ALI.
頁(從 - 到)45-53
期刊Journal of Pharmacology and Experimental Therapeutics
出版狀態已發佈 - 10月 2011

ASJC Scopus subject areas

  • 藥理
  • 分子醫學


深入研究「Inhibition of neutrophil apoptosis via sphingolipid signaling in acute lung injury」主題。共同形成了獨特的指紋。