A Critical Role for LTA₄H in Limiting Chronic Pulmonary Neutrophilic Inflammation

Robert J. Snelgrove,^1,2,* Patricia L. Jackson,¹ Matthew T. Hardison,¹ Brett D. Noerager,³ Andrew Kinloch,⁴ Amit Gaggar,^1,5,6 Suresh Shastry,¹ Steven M. Rowe,^1,5,7 Yun M. Shim,⁸ Tracy Hussell,² J. Edwin Blalock^1,5

Abstract: Leukotriene A₄ hydrolase (LTA₄H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B₄ (LTB₄). LTA₄H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (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 inhibiting LTA₄H to prevent LTB₄ generation may not reduce neutrophil recruitment because of elevated levels of PGP.

¹ Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham Lung Health Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
² Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
³ Department of Biology, Chemistry and Mathematics, University of Montevallo, Montevallo, AL 35115, USA.
⁴ Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, UK.
⁵ Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁶ Birmingham VA Medical Center, Birmingham, AL 35294, USA.
⁷ Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁸ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.

^* To whom correspondence should be addressed. E-mail: rjs198{at}imperial.ac.uk

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