A Critical Role for LTA4H in Limiting Chronic Pulmonary Neutrophilic Inflammation

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Science  02 Sep 2010:
DOI: 10.1126/science.1190594


Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme which generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H also possesses aminopeptidase activity with unknown substrate and physiological significance. We identified the neutrophil chemoattractant, Pro-Gly-Pro (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 that inhibit LTA4H to prevent LTB4 generation may not reduce neutrophil recruitment because of elevated PGP.