Accelerated Wound Closure in a Diabetic Mouse Model After Exposure to Phenanthrenequinone

Abstract

Reactive oxygen species (ROS) have been shown to be important in wound healing by promoting angiogenesis (also mentioned by Ushio-Fukai and Nakamura). Likewise ROS have been implicated by toxicological studies as a primary mechanism of air pollution-associated morbidity. We sought to determine how exposure to a reactive diesel exhaust chemical (phenanthrenequinone [PQ]), which promotes formation of ROS and is considered an air pollutant, would affect wound healing. Since wound healing is compromised in diabetic (db) individuals, we examined the effects of PQ on wound healing in a db mouse model. db mice consumed PQ-containing chow for a short period (2 weeks) before wounding and through generations. Wound closure rates and wound vascularization were evaluated 10 days after wounding. The effects of PQ on endothelial cell proliferation and ROS generation in vitro were also measured. db mice exposed to short-term PQ and PQ-exposed first-generation db mice demonstrated the highest closure rates, significantly better than control db mice (P < 0.05). Furthermore, a higher concentration of PQ in sera of db mice coincides with the higher rate of closure. PQ was also shown to produce ROS in cell culture and stimulate endothelial cell proliferation at nanomolar concentrations. Second- and third-generation db mice exposed to PQ did not show improved wound healing. This study suggests that the free radical-generating air pollutant PQ enhances wound closure in the db mouse model possibly by stimulating angiogenesis, as suggested by in vitro results. We speculate that PQ may increase oxidation levels systemically and therefore help modulate inflammation at the wound site. Alternatively, antioxidant mechanisms recruited for wound healing may interfere with PQ metabolism and elimination as it accumulates in sera. Generational resistance to improve wound healing in PQ-exposed db mice could also be due to disturbances in metabolism caused by continuous exposure. In either case, these results introduce a new perspective on the effects of air pollution on wound healing.