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.
Highlights
Cutaneous wound repair occurs in temporally coordinated and overlapping phases: inflammation, granulation tissue formation and remodelling [1]
Because of the described intricate involvement of both haem oxygenase (HO)-1 and HO-2 in wound healing and regulation of inflammatory responses, this study focused on exploring the possible role of HO-2 in cutaneous wound healing using a full-thickness excisional wound model and HO-2 KO mice
We investigated the degree of vascularization in the wound areas of HO-2 KO and WT mice by semi-quantitative scoring of wound sections stained for collagen IV, a basement membrane protein found in the walls of blood vessels [30]
Summary
Cutaneous wound repair occurs in temporally coordinated and overlapping phases: inflammation, granulation tissue formation and remodelling [1]. The timely progression of the different phases is coordinated by cytokines and growth factors, and each phase is. Haem oxygenases (HO) are enzymes that degrade haem into biliverdin, carbon monoxide and iron. Biliverdin is converted into the antioxidant bilirubin by biliverdin reductase. HO-1 is highly inducible by a wide range of stresses, including inflammatory and oxidative stress, whereas HO-2 is mainly constitutively expressed [5, 6]. The HO system is important in the resolution of inflammation [7, 8].
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