Inhibition of neutrophil apoptosis via sphingolipid signaling in acute lung injury.

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 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.

• Authors: Wei-Chieh Lin, Chiou-Feng Lin, Chia-Ling Chen, Chang-Wen Chen, Yee-Shin Lin
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 1 Pg. 45-53 (Oct 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21724966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Lipopolysaccharides
• Sphingolipids
• p38 Mitogen-Activated Protein Kinases
• Sphingomyelin Phosphodiesterase
• Caspases

Topics

• Acute Lung Injury (chemically induced, pathology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Bronchoscopy
• Caspases (metabolism)
• Ceramides (metabolism)
• Fiber Optic Technology
• Flow Cytometry
• Humans
• Immunohistochemistry
• Lipopolysaccharides (toxicity)
• Lung (pathology)
• Mice
• Mice, Inbred C3H
• Neutrophils (drug effects)
• Phosphorylation
• Respiratory Distress Syndrome (pathology)
• Signal Transduction (physiology)
• Sphingolipids (metabolism, physiology)
• Sphingomyelin Phosphodiesterase (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)