title: Delayed cutaneous wound closure in HO-2 deficient mice despite normal HO-1 expression.
abstract: Impaired wound healing can lead to scarring, and aesthetical and functional problems. The cytoprotective haem oxygenase (HO) enzymes degrade haem into iron, biliverdin and carbon monoxide. HO-1 deficient mice suffer from chronic inflammatory stress and delayed cutaneous wound healing, while corneal wound healing in HO-2 deficient mice is impaired with exorbitant inflammation and absence of HO-1 expression. This study addresses the role of HO-2 in cutaneous excisional wound healing using HO-2 knockout (KO) mice. Here, we show that HO-2 deficiency also delays cutaneous wound closure compared to WT controls. In addition, we detected reduced collagen deposition and vessel density in the wounds of HO-2 KO mice compared to WT controls. Surprisingly, wound closure in HO-2 KO mice was accompanied by an inflammatory response comparable to WT mice. HO-1 induction in HO-2 deficient skin was also similar to WT controls and may explain this protection against exaggerated cutaneous inflammation but not the delayed wound closure. Proliferation and myofibroblast differentiation were similar in both two genotypes. Next, we screened for candidate genes to explain the observed delayed wound closure, and detected delayed gene and protein expression profiles of the chemokine (C-X-C) ligand-11 (CXCL-11) in wounds of HO-2 KO mice. Abnormal regulation of CXCL-11 has been linked to delayed wound healing and disturbed angiogenesis. However, whether aberrant CXCL-11 expression in HO-2 KO mice is caused by or is causing delayed wound healing needs to be further investigated.
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ditte M S
authors.initials: DM
authors.lastname: Lundvig
authors.forename: Alwin
authors.initials: A
authors.lastname: Scharstuhl
authors.forename: Niels A J
authors.initials: NA
authors.lastname: Cremers
authors.forename: Sebastiaan W C
authors.initials: SW
authors.lastname: Pennings
authors.forename: Jeroen
authors.initials: J
authors.lastname: te Paske
authors.forename: René
authors.initials: R
authors.lastname: van Rheden
authors.forename: Coby
authors.initials: C
authors.lastname: van Run-van Breda
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Regan
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.forename: Carine E
authors.initials: CE
authors.lastname: Carels
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Maltha
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000293:injuries / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D054371:Chemokine CXCL11; C515203:Cxcl11 protein, mouse; D018836:Inflammation Mediators; D019394:Ki-67 Antigen; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D051546:Cyclooxygenase 2
keywords: haem oxygenase; skin; wound healing