Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 36, Issue 2, Pages 201-205Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2006-0269TR
Keywords
acute inflammation; lipid mediators; resolution
Funding
- NHLBI NIH HHS [R01 HL090927, R01 HL068669, HL68669] Funding Source: Medline
- NIAID NIH HHS [AI068084] Funding Source: Medline
- NIDCR NIH HHS [DE016191] Funding Source: Medline
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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. LXA4 and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.
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