Abstract
Heme oxygenase-1 (HO-1), a cytoprotective, pro-angiogenic and anti-inflammatory enzyme, is strongly induced in injured tissues. Our aim was to clarify its role in cutaneous wound healing. In wild type mice, maximal expression of HO-1 in the skin was observed on the 2nd and 3rd days after wounding. Inhibition of HO-1 by tin protoporphyrin-IX resulted in retardation of wound closure. Healing was also delayed in HO-1 deficient mice, where lack of HO-1 could lead to complete suppression of reepithelialization and to formation of extensive skin lesions, accompanied by impaired neovascularization. Experiments performed in transgenic mice bearing HO-1 under control of keratin 14 promoter showed that increased level of HO-1 in keratinocytes is enough to improve the neovascularization and hasten the closure of wounds. Importantly, induction of HO-1 in wounded skin was relatively weak and delayed in diabetic (db/db) mice, in which also angiogenesis and wound closure were impaired. In such animals local delivery of HO-1 transgene using adenoviral vectors accelerated the wound healing and increased the vascularization. In summary, induction of HO-1 is necessary for efficient wound closure and neovascularization. Impaired wound healing in diabetic mice may be associated with delayed HO-1 upregulation and can be improved by HO-1 gene transfer.
Highlights
The repair of wound is a complex process engaging activity of various cell types, tightly orchestrated by specific cytokines
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme playing a role in regulation of angiogenesis and in modulation of immune response [11,12,13,14,15,16,17,23,24]
Our study demonstrates that: i) pharmacological or genetic inhibition of HO1 impairs healing of cutaneous wounds in mice; ii) induction of HO-1 in response to injury is impaired in diabetic mice, in which wound healing is delayed; iii) this delay may be partially reversed by HO-1 overexpression, the effect associated with increased vascularization of the wounded tissue
Summary
The repair of wound is a complex process engaging activity of various cell types, tightly orchestrated by specific cytokines. Chronic nonhealing wounds, leading very often to ulceration, necrosis and amputation, are one of the severe consequences of diabetes, which result in significant morbidity. In this case, the new avenues for therapeutic approaches of deep skin injuries are urgently needed. Skin wound healing occurs in three overlapping phases: inflammation, granulation tissue formation and remodeling [2]. During the final phase of wound healing the granulation tissue is replaced with an acellular scar, when myofibroblastic and vascular cells in the wound undergo apoptosis [3]
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