A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation.
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.
Snelgrove
Robert J
RJ
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
Jackson
Patricia L
PL
Hardison
Matthew T
MT
Noerager
Brett D
BD
Kinloch
Andrew
A
Gaggar
Amit
A
Shastry
Suresh
S
Rowe
Steven M
SM
Shim
Yun M
YM
Hussell
Tracy
T
Blalock
J Edwin
JE
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
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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