The role of sphingolipids in respiratory disease

Abstract

Sphingolipids form a broad class of lipids with diverse functions ranging from membrane constituents to intracellular second messengers and extracellular mediators. They can be rapidly generated or converted into each other and they play pivotal roles in various cellular processes, many of which are broadly associated with inflammation and apoptosis. Among the numerous sphingolipids, ceramide and sphingosine-1-phosphate (S1P) have received the greatest attention. Ceramide is a hydrophobic molecule that is increased in the lungs of patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD). Ceramide is the eponym for ceramide-rich membrane platforms. that need to form as a prerequisite to the uptake of several microorganisms including Pseudomonas aeruginosa, and as a prerequisite to many signaling processes including apoptosis and increased vascular permeability. Accordingly, abnormal amounts of enzymes involved in the synthesis of ceramide, such as neutral or acid sphingomyelinase, are found in emphysematic smokers and in patients with severe sepsis, and are considered as novel pharmacological targets. S1P acts as an extracellular mediator that opposes several actions of ceramide and acts by binding to G-protein coupled S1P receptors (S1P(1)-S1P(5)). Of particular interest are S1P(1) receptors that enhance vascular barrier functions and are antiapoptotic. Therefore, S1P(1)-receptor ligands are suggested as novel drugs for COPD and acute lung injury. S1P is a potent chemotaxin for many leukocytes, it organizes lymphocyte trafficking and is involved in several key symptoms of asthma such as airway hyperresponsiveness and pulmonary eosinophil sequestration. S1P is formed by sphingosine kinases that have been identified as possible drug targets for the treatment of asthma. Based on these findings, several new drugs have recently been developed to specifically target sphingomyelinases, sphingosine kinases and S1P receptors for the treatment of COPD, cystic fibrosis, asthma and acute lung injury.

Differential Regulation of Lung Endothelial Permeability <b><i>in Vitro</i></b> and <b><i>in Situ</i></b>

“…The recruited caveolin-1 engages TRPC6 channels that become disinhibited in part by the dramatic decrease in endothelial NO levels through the silencing of eNOS by its interaction with caveolin-1 [31,32]. We have recently reviewed this mechanism in detail [11,33]. …”

Plasma Sphingolipids Associated with Chronic Obstructive Pulmonary Disease Phenotypes

“…Sphingolipids have been implicated in several lung diseases, including COPD (3,8,9). The majority of sphingolipid lung research has focused on ceramides, the central intermediate metabolites in the sphingolipid metabolism and key proapoptotic signaling molecules, and on sphingosine-1-phosphate (S1P), a downstream metabolite of ceramide and key prosurvival and immune regulator.…”

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

“…Since their initial description, sphingoid bases have been found to be critical structural components of biological membranes and highly essential bioactive lipids that regulate diverse signaling pathways. The aberrant regulation of the sphingoid bases is known to contribute to a variety of pathologies that underlie cancer, inflammation, injury, edema, and infections (5)(6)(7)(8)(9). Of the several hundred sphingoid bases described to date, at least six, namely, sphingomyelin (SM), sphingosine (Sph), Sph-1-phosphate (S1P), ceramide, ceramide 1-phosphate (Cer1P), and sphingosylphosphorylcholine (lyso-SM), are considered key signaling and regulatory bioactive lipids (10).…”

“…Among the various organs, the lung has been intensely investigated to understand better the role of S1P, its receptors, and its metabolizing enzymes in cellular functions under physiological as well as pathological conditions such as acute and subacute lung injury, pulmonary barrier dysfunction/edema, emphysema, and airway inflammation (5,6,11). In view of the complexity of the sphingolipid metabolism, the interconversion of bioactive sphingolipids, and the varied expressions and differential functions of their multiple G protein-coupled receptors, we perceived the need for a comprehensive review of the literature that addresses the pathways that regulate the metabolism and mechanisms of action for S1P in ALI.…”