title: A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation.
abstract: Leukotriene A(4) hydrolase (LTA(4)H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B(4) (LTB(4)). LTA(4)H 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 LTA(4)H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA(4)H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA(4)H to prevent LTB(4) generation may not reduce neutrophil recruitment because of elevated levels of PGP.
authors.affiliation: 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. rjs198@imperial.ac.uk
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Snelgrove
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Hardison
authors.forename: Brett D
authors.initials: BD
authors.lastname: Noerager
authors.forename: Andrew
authors.initials: A
authors.lastname: Kinloch
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: Suresh
authors.initials: S
authors.lastname: Shastry
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: Yun M
authors.initials: YM
authors.lastname: Shim
authors.forename: Tracy
authors.initials: T
authors.lastname: Hussell
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
mesh_terms: D000107:Acetylation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011008:Pneumococcal Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012906:Smoke; D014026:Nicotiana
chemical_list: D019743:Chemokines, CXC; D009842:Oligopeptides; D012906:Smoke; C113164:prolyl-glycyl-proline; D007975:Leukotriene B4; D011392:Proline; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
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