Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing.
Lipid mediators derived from 5-lipoxygenase (5-LO) metabolism can activate both pro- and anti-inflammatory pathways, but their role in wound healing remains largely unexplored. In this study we show that 5-LO knockout (5-LO(-/-)) mice exhibited faster wound healing than wild-type (WT) animals, and exhibited upregulation of heme oxygenase-1 (HO-1). Furthermore, HO-1 inhibition in 5-LO(-/-) mice abolished the beneficial effect observed. Despite the fact that 5-LO(-/-) mice exhibited faster healing, in in vitro assays both migration and proliferation of human dermal fibroblasts (HDFs) were inhibited by the 5-LO pharmacologic inhibitor AA861. No changes were observed in the expression of fibronectin, transforming growth factor (I and III), and α-smooth muscle actin (α-SMA). Interestingly, AA861 treatment significantly decreased ROS formation by stimulated fibroblasts. Similar to 5-LO(-/-) mice, induction of HO-1, but not superoxide dismutase-2 (SOD-2), was also observed in response to 5-LO (AA861) or 5-LO activating protein (MK886) inhibitors. HO-1 induction was independent of nuclear factor (erythroid derived-2) like2 (Nrf-2), cyclooxygenase 2 (COX-2) products, or lipoxin action. Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution.
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Ariane R
AR
Brogliato
Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA; Department of Surgery, University of South Florida, Tampa, Florida, USA.
Andrea N
AN
Moor
Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA.
Shannon L
SL
Kesl
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Rafael F
RF
Guilherme
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Janaína L
JL
Georgii
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Marc
M
Peters-Golden
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Claudio
C
Canetti
Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA; Department of Surgery, University of South Florida, Tampa, Florida, USA.
Lisa J
LJ
Gould
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: cbenjamim@icb.ufrj.br.
Claudia F
CF
Benjamim
D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D001094:Arachidonate 5-Lipoxygenase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C583212:ALOX5 protein, human