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Science 330 (6000): 90-94

Copyright © 2010 by the American Association for the Advancement of Science

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 Blalock1,5

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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