Sphingolipids in COPD

Abstract

Sphingolipids are a distinct class of lipid molecules widely found in nature, principally as cell membrane constituents. After initial uncertainty about their function, sphingolipids have been increasingly recognised to be metabolically active entities involved in many biological processes, including the control of inflammation. Their role as mediators of inflammation may have significant implications for a range of lung diseases in which inflammation is a central element of pathogenesis. Chronic obstructive pulmonary disease (COPD), a highly prevalent and morbid condition predominantly affecting cigarette smokers, is a prime example of a respiratory illness with an inflammatory component. Understandably, sphingolipids have received growing attention for their increasingly demonstrated role in the pathophysiology of COPD. The present review aims to be among the first to focus exclusively on the connection between sphingolipids and lung inflammation in COPD, providing the reader with a clinically oriented synopsis of this intriguing association.

FIGURE 1

a) Schematic depiction of the three major pathways capable of producing ceramide with relevant enzymes (italics) and therapeutic inhibition points (arrows) indicated. b) Schematic representation of the three major reactions involving ceramide as substrate. Relevant enzymes are listed in italics, and options for so-called “sphingosine 1-phosphate rescue” are indicated by arrows. −: inhibitory actions; +: promoter actions.

FIGURE 2

Competing sphingolipids with predominantly pro-inflammatory and anti-inflammatory properties, the net balance of which constitutes the “sphingolipid rheostat”.

FIGURE 3

Schematic summary of sphingolipid actions implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) with ceramide as the central mediator. C1P: ceramide 1-phosphate; S1P: sphingosine 1-phosphate; nSMase: neutral sphingomyelinase; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumour necrosis factor-α. +: pro-inflammatory effects of ceramide derivatives; −: anti-inflammatory.