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

J. Michael Wells, Philip J. O'Reilly, Tomasz Szul, Daniel I. Sullivan, Guy Handley, Chris Garrett, Carmel M. McNicholas, Mojtaba Abdul Roda, Bruce E. Miller, Ruth Tal-Singer, Amit Gaggar, Stephen Israel Rennard, Patricia L. Jackson, J. Edwin Blalock

Research output: Contribution to journalArticle

30 Citations (Scopus)

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: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).

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number1
DOIs
StatePublished - Jul 1 2014

Fingerprint

Proline
Glycine
Chronic Obstructive Pulmonary Disease
Hydrolases
Aminopeptidases
Tobacco Products
Smoke
Acrolein
Inflammation
leukotriene A4 hydrolase
Emphysema
Bronchoalveolar Lavage
Disease Progression
Mass Spectrometry
Western Blotting
Smoking
Enzyme-Linked Immunosorbent Assay
Air
Clinical Trials

Keywords

  • Acrolein
  • COPD
  • Inflammation
  • PGP

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease. / Wells, J. Michael; O'Reilly, Philip J.; Szul, Tomasz; Sullivan, Daniel I.; Handley, Guy; Garrett, Chris; McNicholas, Carmel M.; Roda, Mojtaba Abdul; Miller, Bruce E.; Tal-Singer, Ruth; Gaggar, Amit; Rennard, Stephen Israel; Jackson, Patricia L.; Blalock, J. Edwin.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 190, No. 1, 01.07.2014, p. 51-61.

Research output: Contribution to journalArticle

Wells, JM, O'Reilly, PJ, Szul, T, Sullivan, DI, Handley, G, Garrett, C, McNicholas, CM, Roda, MA, Miller, BE, Tal-Singer, R, Gaggar, A, Rennard, SI, Jackson, PL & Blalock, JE 2014, 'An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 1, pp. 51-61. https://doi.org/10.1164/rccm.201401-0145OC
Wells, J. Michael ; O'Reilly, Philip J. ; Szul, Tomasz ; Sullivan, Daniel I. ; Handley, Guy ; Garrett, Chris ; McNicholas, Carmel M. ; Roda, Mojtaba Abdul ; Miller, Bruce E. ; Tal-Singer, Ruth ; Gaggar, Amit ; Rennard, Stephen Israel ; Jackson, Patricia L. ; Blalock, J. Edwin. / An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 190, No. 1. pp. 51-61.
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