Involvement of ceramide in cell death responses in the pulmonary circulation

Abstract

Ceramides are signaling sphingolipids involved in cellular homeostasis but also in pathological processes such as unwanted apoptosis, growth arrest, oxidative stress, or senescence. Several enzymatic pathways are responsible for the synthesis of ceramides, which can be activated in response to exogenous stimuli such as cytokines, radiation, or oxidative stress. Endothelial cells are particularly rich in acid sphingomyelinases, which can be rapidly activated to produce ceramides, both intracellular and at the plasma membrane. In addition, neutral sphingomyelinases, the de novo pathway and the ceramide recycling pathway, may generate excessive ceramides involved in endothelial cell responses. When up-regulated, ceramides trigger signaling pathways that culminate in endothelial cell death, which in murine lungs has been linked to the development of emphysema-like disease. Furthermore, ceramides may be released paracellularly where they are believed to exert paracrine activities. Such effects, along with ceramides released by inflammatory mediators, may contribute to lung inflammation and pulmonary edema, because ceramide-challenged pulmonary endothelial cells exhibit decreased barrier function, independent of apoptosis. Reestablishing the sphingolipid homeostasis, either by modulating ceramide synthesis or by opposing its biological effects through augmentation of the prosurvival sphingosine-1 phosphate, may alleviate acute or chronic pulmonary conditions characterized by vascular endothelial cell death or dysfunction.

Figure 1.

Schematic of ceramide-centered sphingolipid metabolism and subcellular localization of specific metabolic pathways. CerK = ceramide kinase; cytoplasm = cytopl; ER = endoplasmic reticulum; GCS = glucosylceramide synthase; ceramide-Gly = glucosylceramides; lys = lysosome; PM = plasma membrane; SPhK = sphingosine kinases; SPP = S1P phosphatase.

Figure 2.

Cartoon of proposed amplification loops triggered by disruptions of ceramide and S1P homeostasis leading to emphysema development. They include self-amplification of ceramide synthesis by ceramides produced paracellularly via soluble acid SMase; positive feedback between oxidative stress and apoptosis triggered by excess ceramides; and induction of structural lung endothelial and epithelial cells apoptosis (EC), with concomitant inhibition of their apoptotic body removal via a direct effect on alveolar macrophages (AM). This in turn may lead to spillage of intracellular contents and decreased antiinflammatory signaling by macrophages, contributing to lung inflammation. VEGF = vascular endothelial growth factor.