An Aberrant Leukotriene A₄ Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

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: We investigated changes to the leukotriene A 4 hydrolase (LTA 4 H)-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 LTA 4 H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA 4 H aminopeptidase activity were detected by mass spectroscopy, LTA 4 H 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 LTA 4 H 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 LTA 4 H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA 4 H 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 LTA 4 H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Leukotriene A4 Hydrolase: The Janus Enzyme Shows Its Ugly Side in Smokers

“…This finding supports growing evidence that any severe illness is associated with physical or emotional difficulties after hospital discharge (7), as well as the fact that survivors of severe sepsis are known to be at higher risk of death after hospitalization (8).…”

“…51-61) extends these latter studies in a cigarette smoke-induced emphysema model and translates them into two human smoking/COPD cohorts (8). Cigarette smoke-exposed mice displayed elevated BAL fluid concentrations of PGP and a profound loss of LTA 4 H peptidase activity, while maintaining LTA 4 H hydrolase activity and LTB 4 production.…”

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…COX8A is a cytochrome c oxidase subunit, which is involved in apoptosis (Liu et al 1996). Inhibition of LTA4H is associated with chronic inflammation (Snelgrove et al 2010;Wells et al 2014), and mutations in this gene may reflect de-differentiation of the tumor, although the recurrent nature of the mutations rather suggests a gain-of-function mutation.…”

A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease

“…In contrast, proline-glycine-proline (PGP) and its acetylated form (AcPGP) are tripeptide collagen fragments generated from extracellular matrix breakdown that act as potent neutrophil chemoattractants, and are detected in sputum of patients with COPD (16)(17)(18)(19). AcPGP and PGP are generated through a multistep proteolytic pathway with prolyl endopeptidase serving as the critical rate-limiting enzyme (19).…”