A Critical Role for LTA ₄ H in Limiting Chronic Pulmonary Neutrophilic Inflammation

Abstract

Leukotriene A4 Hydrolase (LTA4H) is a pro-inflammatory 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.

Impact of cigarette smoke exposure on host–bacterial pathogen interactions

“…It generates LTB 4 and it has aminopeptidase activity, thus inactivating PGP, which contributes to the resolution of the neutrophilic inflammation in acute lung infections once the pathogen is no longer present. Smoke inhibits LTA 4 H aminopeptidase activity and stabilises PGP through acetylation; in this way, neutrophil migration into the lung increases, leading to persistent inflammation [37]. Cigarette smoke exposure also results in a suppression of neutrophil caspase-3-like activity, which ultimately impairs its phagocytic activity [38].…”

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.…”

Efferocytosis and Lung Disease

“…38 The clinical phenotype in a given patient with COPD results from variable involvement of these processes, several of which, especially emphysema, are characterized by apoptosis of lung structural cells. Neutrophils, recruited by IL-8 and by generation of the tripeptide prolineglycine-proline from breakdown of extracellular matrix collagen, 39 are believed to die almost entirely by apoptosis at the site to which they are recruited. Hence, COPD presents a considerable challenge to sustain high levels of efferocytosis within the lungs.…”