Heme Oxygenase-1 Accelerates Cutaneous Wound Healing in Mice

• DOI: 10.1371/journal.pone.0005803
• Publication Date: 2009-06-03T21:14:49Z
• Authors: Anna Grochot-Prze...; Radoslaw Lach; Jacek Mis; Klaudia Skrzypek; Malgorzata Gozdecka; Patrycja Sroczynska; Milena Dubiel; Andrzej Rutkowski; Magdalena Kozakowska; Anna Zagorska; Jacek Walczynski; Halina Was; Jerzy Kotlinowski; Justyna Drukala; Krzysztof Kurowski; Claudine Kieda; Yann Herault; Jozef Dulak; Alicja Jozkowicz
• Keywords: [SDV.IMM] Life Sciences [q-bio]/Immunology; Science; Anti-Inflammatory Agents; Angiogenesis Inhibitors; Adenoviridae; Diabetes Mellitus, Experimental; Mice; 03 medical and health sciences; Animals; Humans; Transgenes; Promoter Regions, Genetic; Inflammation; Wound Healing; 0303 health sciences; Q; R; Gene Transfer Techniques; 3. Good health; Mice, Inbred C57BL; [SDV.IMM]Life Sciences [q-bio]/Immunology; Medicine; Keratins; Heme Oxygenase-1; Research Article

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 2(nd) and 3(rd) 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.