Lipid mediators as agonists for the resolution of acute lung inflammation and injury

Abstract

Resolution of acute lung inflammation and injury is an active process; it is not merely the absence of proinflammatory signals. Restoration of homeostasis is coordinated by specific mediators and cellular events. In response to injury and inflammatory stimuli, infiltrating leukocytes and tissue-resident cells interact to generate lipoxins (LXs), which are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, LXs display potent antiinflammatory actions. LXA(4) interacts with a G protein-coupled receptor, termed ALX, that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to presqualene monophosphate (PSMP) upon cell activation. PSDP, but not PSMP, directly inhibits phospholipase D, phosphoinositol-3 kinase, and superoxide anion generation. LXs block PSDP turnover in neutrophil membranes to prevent proinflammatory responses. Hence, LX and polyisoprenyl phosphate signaling provide a counter-regulatory circuit to promote resolution of acute lung inflammation. LXA(4) and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.

Figure 1.

Polyisoprenyl phosphate remodeling. PMN activation by G-protein–coupled (LTB₄, formyl-methionyl-leucyl-phenylalanine) and growth factor (granulocyte monocyte colony-stimulating factor) receptors can trigger PSDP remodeling to PSMP.

Figure 2.

Polyisoprenyl phosphate remodeling in PMN: a rapid signaling pathway engaged during LX–ALX interactions. LXA₄ and 15-epi-LXA₄ are produced during inflammation as “stop signals” for agonist-triggered PMN responses. Interactions with ALX block agonist-induced PSDP turnover to PSMP. PSDP inhibits PLD and PI3K to reduce prophlogistic cellular responses.

Figure 3.

Resolution of acute lung inflammation by LXs. Acid aspiration is a common cause of ALI. During host responses to injury, LXs are generated locally to block PMN transmigration and activation, decrease edema and leakage of plasma proteins into the airways, promote restitution of injured airway epithelium, and block cytokine and chemokine release.