A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation.

Academic Article

Abstract

  • Leukotriene A(4) hydrolase (LTA(4)H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B(4) (LTB(4)). LTA(4)H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (PGP) as this physiological substrate. PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA(4)H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA(4)H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA(4)H to prevent LTB(4) generation may not reduce neutrophil recruitment because of elevated levels of PGP.
  • Published In

  • Science  Journal
  • Keywords

  • Acetylation, Animals, Bronchoalveolar Lavage Fluid, Cells, Cultured, Chemokines, CXC, Chemotaxis, Leukocyte, Epoxide Hydrolases, Female, Humans, Inflammation, Leukotriene B4, Lung, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neutrophils, Oligopeptides, Orthomyxoviridae Infections, Pneumococcal Infections, Pneumonia, Proline, Pulmonary Disease, Chronic Obstructive, Smoke, Tobacco
  • Digital Object Identifier (doi)

    Authorlist

  • Snelgrove RJ; Jackson PL; Hardison MT; Noerager BD; Kinloch A; Gaggar A; Shastry S; Rowe SM; Shim YM; Hussell T
  • Start Page

  • 90
  • End Page

  • 94
  • Volume

  • 330
  • Issue

  • 6000