Topical application of sustained released-carbon monoxide promotes cutaneous wound healing in diabetic mice

Clinical incidences of pressure ulcers in the elderly and intractable skin ulcers in diabetic patients are increasing because of the aging population and an increase in the number of diabetic patients worldwide. Although various agents are used to treat pressure and skin ulcers, these ulcers are often refractory and deteriorate the patients' quality of life. Therefore, a novel therapeutic agent with a novel mechanism of action is required. Carbon monoxide (CO) contributes to many physiological and pathophysiological processes, including anti-inflammatory activity; therefore, it can be a therapeutic gaseous molecule. Recent studies have revealed that CO accelerates wound healing in gastrointestinal tract injuries. However, it remains unclear whether CO promotes cutaneous wound healing. Therefore, we aimed to evaluate the therapeutic effects of topical application of a CO-containing solution and elucidate the underlying mechanism. A full-thickness skin wound generated on the back of diabetic mice was treated topically with CO or vehicle. Sustained release of CO was achieved using polyacrylic acid (PAA) as a thickener. The administration of CO-containing PAA aqueous solution resulted in a significant acceleration in wound recovery without elevating serum CO levels in association with increased angiogenesis and supported by elevated expression of vascular endothelial growth factor mRNA in the wound granulomatous tissues. These data suggest that CO might represent a novel therapeutic agent for the treatment of cutaneous wounds.