Bioactive Sphingolipids in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

A better understanding of the pathogenesis of distinct chronic obstructive pulmonary disease (COPD) phenotypes will improve diagnostic and therapeutic options for this common disease. We present evidence that sphingolipids such as ceramides are involved in the emphysema pathogenesis. Whereas distinct ceramide species cause cell death by apoptosis and necroptosis, cell adaptation leads to accumulation of other sphingolipid metabolites that extend cell survival by triggering autophagy. Cigarette smoke-released sphingolipids have been involved in both the initiation and persistence of lung injury via intracellular signaling and paracrine effects mediated via exosomes and plasma membrane-bound microparticles. Strategies to control sphingolipid metabolite production may promote cellular repair and maintenance to treat COPD.

The role of oxidised self-lipids and alveolar macrophage CD1b expression in COPD

“…Our data showing increased sphingomyelin in the smoke-oxidised lipid, alongside the known role of Saposin-C in the CD1b pathway indicates a role for the sphingolipid pathway in COPD. This notion is in accordance with our and others data on a shift of sphingolipid pathway towards favouring inflammation in COPD/response to cigarette smoke, including ceramide overproduction, an upregulation of a range of sphingosine-1-phosphate (S1P) signalling-related genes including sphingosine kinases, but downregulation of their enzyme activity and subcellular redistribution in macrophages 62 , 63 . We also showed that a change in sphingosine pathway was likely involved in reduced efferocytosis and bacterial phagocytosis seen in COPD patients and macrophages exposed to cigarette smoke 39 , 40 .…”

Enhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model

“…Depending on the subcellular compartmentalization of S1P generation and the cell types involved, S1P signalling leads to diverse effects, including those offsetting the effects of ceramides [7,25]. Given that ceramides are increased in muco-obstructive diseases [9][10][11][12] and that they can directly activate the NLRP3 inflammasome [13], a decrease in S1P signaling may have a role in amplification of the proinflammatory response.…”

“…S1P signalling is part of the 'sphingolipid rheostat' regulatory system in which S1P and ceramides and sphingosine usually induce effects opposing to each other [7]. Increase in ceramides is a common feature and potential cause of the increased cell death, inflammation and susceptibility to infections in the airway of muco-obstructive diseases including CF, COPD and cigarette smoke-induced inflammation [9][10][11][12]. Relevant to a mechanistic relationship between inflammasome pathways and sphingolipid signalling, intracellular ceramides have been shown to be directly sensed by the NLRP3 inflammasome [13].…”

Alveolar lipids in pulmonary disease. A review

“…Sphingolipids are essential constituents of plasma membranes and regulate important cellular functions, including apoptosis and proliferation. The balance of intracellular sphingomyelin and ceramide is crucial in inflammatory conditions, and the roles of ceramides and sphingolipids in chronic lung disease have been reviewed recently [169,170]. S1P is synthesized by phosphorylation of sphingosine by sphingosine kinase 1 (SPK-1) and Sphingosine Kinase 2 (SPK-2).…”