Heme oxygenase-2 is a critical determinant for execution of an acute inflammatory and reparative response.
Heme oxygenase (HO) represents an intrinsic anti-inflammatory system based on its ability to regulate leukocyte function and inhibit expression of proinflammatory cytokines. This anti-inflammatory function is linked to the inducible isoform HO-1; the role of the constitutive isoform HO-2 is unknown. The current study was undertaken to investigate the role of HO-2 in the regulation of the acute inflammatory and reparative response by using HO-2-null mice and well-established animal models of epithelial injury and antigen-induced peritonitis. Here we show that in vivo deletion of HO-2 disables execution of the acute inflammatory and reparative response after epithelial injury and leads to an exaggerated inflammatory response in antigen-induced peritonitis. HO-2 deletion was associated with impaired HO-1 induction, indicating that HO-2 is critical for HO-1 expression and that the subsequent failure to up-regulate the HO system may contribute to unresolved inflammation and the development of chronic inflammatory conditions. Indeed, supplementation with the HO bioactive product, biliverdin, rescued the acute inflammatory and reparative response in HO-2-null mice. Thus, HO-2 sets in place a basal tone of anti-inflammatory signals that may be a prerequisite for the ordered execution of an inflammatory and reparative response.
Seta
Francesca
F
Department of Pharmacology, New York Medical College, Grassland Reservation, Valhalla, NY 10595, USA.
Bellner
Lars
L
Rezzani
Rita
R
Regan
Raymond F
RF
Dunn
Michael W
MW
Abraham
Nader G
NG
Gronert
Karsten
K
Laniado-Schwartzman
Michal
M
D000818:Animals; D001664:Biliverdine / Q000494:pharmacology; D003315:Cornea / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D018836:Inflammation Mediators; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D001664:Biliverdine