Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing.
In the immune-privileged cornea, epithelial wounds heal rapidly with almost no scarring and, unlike in most other tissues, acute inflammation in the absence of infection is beneficial to healing. Molecular mechanisms, which account for this striking property, remain to be clearly defined, but they likely include autacoids that control leukocyte activation. Two prominent enzymes, 12/15-lipoxygenase (LOX), which generates antiinflammatory lipid autacoids, and heme-oxygenase (HO), which generates antioxidants and carbon monoxide, are highly expressed in human and mouse corneas. LXA4, an endogenous 12/15-LOX product, proved to be a potent inhibitor of exacerbated inflammation and significantly increased re-epithelialization in corneal wounds. In vivo deletion of 12/15-LOX correlated with exacerbated inflammation and impaired wound healing in 12/15-LOX(-/-) mice, a phenotype that was rescued by treatment with LXA4. More importantly, 12/15-LOX(-/-) mice demonstrated impaired induction of HO-1 in both acute and exacerbated inflammation. Topical LXA4 restored HO-1 expression in 12/15-LOX(-/-) mice and amplified HO-1 gene expression in human corneal epithelial cells. HO-2(-/-) mice, which fail to induce HO-1, also demonstrated exacerbated inflammation in response to injury, a phenotype that, notably, correlated with a 50% reduction in endogenous LXA4 formation. Collectively, results demonstrate a critical role for LXA4 in inflammatory/reparative responses and provide the first evidence that 12/15-LOX and HO systems function in concert to control inflammation.
Biteman
Benjamin
B
Department of Pharmacology, New York Medical College, Basic Science Bldg., Valhalla, NY 10595, USA.
Hassan
Iram R
IR
Walker
Everald
E
Leedom
Alexander J
AJ
Dunn
Michael
M
Seta
Francesca
F
Laniado-Schwartzman
Michal
M
Gronert
Karsten
K
D000287:Administration, Topical; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012898:Autacoids / Q000494:pharmacology; D002478:Cells, Cultured; D019573:Epithelium, Corneal / Q000166:cytology / Q000293:injuries* / Q000378:metabolism; D005131:Eye Injuries / Q000188:drug therapy; D025461:Feedback, Physiological; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007634:Keratitis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D044045:Lipoxins / Q000008:administration & dosage / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D012898:Autacoids; D008070:Lipopolysaccharides; D044045:Lipoxins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C040527:lipoxin A4; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2