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 A4 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).

• Authors: 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 I Rennard, Patricia L Jackson, J Edwin Blalock
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 190 Issue 1 Pg. 51-61 (Jul 01 2014) ISSN: 1535-4970 [Electronic] United States
• PMID: 24874071 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proline
• Epoxide Hydrolases
• Glycine
• leukotriene A4 hydrolase

Topics

• Aged
• Animals
• Bronchoalveolar Lavage Fluid (chemistry, immunology)
• Cohort Studies
• Disease Models, Animal
• Emphysema (etiology, immunology)
• Epoxide Hydrolases (immunology)
• Female
• Glycine (metabolism)
• Humans
• Inflammation (complications, physiopathology)
• Lung (immunology)
• Male
• Mice
• Middle Aged
• Myocardium (immunology)
• Neutrophils (immunology)
• Proline (metabolism)
• Pulmonary Disease, Chronic Obstructive (etiology, immunology, physiopathology)
• Smoking (adverse effects, immunology)