Heme oxygenase-1 accelerates cutaneous wound healing in mice

1 stycznia 2010

Heme oxygenase-1, an anti-inflammatory, cytoprotective and pro-angiogenic enzyme, is strongly induced in injured tissues. We aimed to clarify its role in cutaneous wound healing. Pharmacological or genetic inhibition of HO-1 in keratinocytes and fibroblasts leads to impaired migration of cells and delayed time of wound closure in the scratch assay. In the wild type mice wounding induced HO-1, with the highest stimulation on the 2nd and 3rd days. Inhibition of HO-1 activity by SnPPIX significantly retarded wound closure. This was associated with increased production of proinflammatory mediators, including IL-1b, IL-2, IL-6, KC, or IFNg. Healing of wounds was also significantly delayed in 3 months old HO-1 KO mice.

This was even stronger in 6 months old animals in which HO-1 deficiency could result in complete inhibition of reepithelialization. Lack of HO-1 was associated with reduced production of SDF-1 and significantly impaired vascularization, especially in unhealing wounds. Next, we created the transgenic animals bearing HO-1 gene driven by keratin-14 promoter. Importantly, increased level of HO-1 in keratinocytes is sufficient to improve significantly the neovascularization and reepithelialization of wounds. Finally, induction of HO-1 in wounds was relatively weak and delayed in diabetic (db/db) mice, in which also the angiogenesis and wound closure was significantly impaired. Importantly, wound healing was accelerated by local overexpression of HO-1 with adenoviral vectors. 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.

A. Grochot-Przeczek1, R. Lach1, J. Mis1, K. Skrzypek1, M. Kozakowska1, H. Was1, P. Sroczynska1, M. Gozdecka1, J. Walczynski1, A. Zagórska1, J. Kotlinowski1, K. Kurowski2, C. Kieda3, Y. Herault5, A. Józkowicz1*, J. Dulak1*. * equal contribution 1 Department of Medical Biotechnology, Jagiellonian University, Kraków, Poland,2 ADAMED, Pieńków, Poland, 3 Centre for Molecular Biophysics,4 Centre for Transgenic Animals, CNRS, Orleans, France.