An aberrant leukotriene A₄ hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease

Rationale: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated. Objectives:Weinvestigated changes to the leukotrieneA4 hydrolase (LTA₄H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD. Methods: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA₄H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA₄H aminopeptidase activity were detected by mass spectroscopy, LTA₄H amounts were detected by ELISA, and acrolein was detected by Western blot. Measurements and Main Results: Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA₄H aminopeptidase, which ordinarily degrades PGP.We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA₄H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA₄H and inhibits aminopeptidase activity to the same extent as cigarette smoke. Conclusions: These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure.We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA₄H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).