Sphingolipids in Lung Growth and Repair

Sphingolipids comprise a class of bioactive lipids that are involved in a variety of pathophysiologic processes, including cell death and survival. Ceramide and sphingosine-1-phosphate (S1P) form the center of sphingolipid metabolism and determine proapoptotic and antiapoptotic balance. Findings in animal models suggest a possible pathophysiologic role of ceramide and S1P in COPD, cystic fibrosis, and asthma. Sphingolipid research is now focusing on the role of ceramides during lung inflammation and its regulation by sphingomyelinases. Recently, sphingolipids have been shown to play a role in the pathogenesis of bronchopulmonary dysplasia (BPD). Ceramide upregulation was linked with vascular endothelial growth factor suppression and decreased surfactant protein B levels, pathways important for the development of BPD. In a murine model of BPD, intervention with an S1P analog had a favorable effect on histologic abnormalities and ceramide levels. Ceramides and S1P also regulate endothelial permeability through cortical actin cytoskeletal rearrangement, which is relevant for the pathogenesis of ARDS. On the basis of these observations, the feasibility of pharmacologic intervention in the sphingolipid pathway to influence disease development and progression is presently explored, with promising early results. The prospect of new strategies to prevent and repair lung disease by interfering with sphingolipid metabolism is exciting and could potentially reduce morbidity and mortality in patients with severe lung disorders. Sphingolipids comprise a class of bioactive lipids that are involved in a variety of pathophysiologic processes, including cell death and survival. Ceramide and sphingosine-1-phosphate (S1P) form the center of sphingolipid metabolism and determine proapoptotic and antiapoptotic balance. Findings in animal models suggest a possible pathophysiologic role of ceramide and S1P in COPD, cystic fibrosis, and asthma. Sphingolipid research is now focusing on the role of ceramides during lung inflammation and its regulation by sphingomyelinases. Recently, sphingolipids have been shown to play a role in the pathogenesis of bronchopulmonary dysplasia (BPD). Ceramide upregulation was linked with vascular endothelial growth factor suppression and decreased surfactant protein B levels, pathways important for the development of BPD. In a murine model of BPD, intervention with an S1P analog had a favorable effect on histologic abnormalities and ceramide levels. Ceramides and S1P also regulate endothelial permeability through cortical actin cytoskeletal rearrangement, which is relevant for the pathogenesis of ARDS. On the basis of these observations, the feasibility of pharmacologic intervention in the sphingolipid pathway to influence disease development and progression is presently explored, with promising early results. The prospect of new strategies to prevent and repair lung disease by interfering with sphingolipid metabolism is exciting and could potentially reduce morbidity and mortality in patients with severe lung disorders.