A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation

Academic Article

Abstract

  • Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H 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 LTA4H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA4H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil recruitment because of elevated levels of PGP.
  • Digital Object Identifier (doi)

    Author List

  • 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