title: 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.
authors.affiliation: Department of Respiratory Disease, Arnaud de Villeneuve Hospital, Montpellier, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnans
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000818:Animals; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D044045:Lipoxins / Q000494:pharmacology*; D011014:Pneumonia / Q000473:pathology* / Q000628:therapy*; D011106:Polyisoprenyl Phosphates / Q000737:chemistry; D044067:Receptors, Lipoxin / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000473:pathology* / Q000628:therapy*
chemical_list: D044045:Lipoxins; D011106:Polyisoprenyl Phosphates; D044067:Receptors, Lipoxin