Wound healing activity of carbon monoxide liberated from CO-releasing molecule (CO-RM)

Abstract

Wound microenvironment presents widespread oxidant stress, inflammation, and onslaught of apoptosis. Carbon monoxide (CO) exerts pleiotropic cellular effects by modulating intracellular signaling pathways which translate into cellular protection against oxidative stress, inflammation, and apoptosis. CO-releasing molecules (CO-RMs) deliver CO in a controlled manner without altering carboxyhemoglobin levels. This study observed a potential therapeutic value of CO in the wound healing by using tricarbonyldichlororuthenium (II) dimer (CO-releasing molecule (CO-RM)-2), as one of the novel CO-releasing agent. The effect of CO-RM-2 treatment was studied on wound contraction, glucosamine, hydroxyproline levels, and mRNA of cytokines/adhesion molecule in rats using a full-thickness cutaneous wound model and angiogenesis in chick chorioallantoic membrane (CAM) model. CO-RM-2 treatment increased cellular proliferation and collagen synthesis as evidenced by the increase in wound contraction and hydroxyproline and glucosamine contents. The mRNA expression of cytokines endorsed fast healing, as was indicated by the inhibition of pro-inflammatory adhesion molecules such as ICAM-1 and cytokine TNF-α and upregulation of anti-inflammatory cytokine IL-10. An ELISA assay of IL-10 and TNF-α cytokines revealed pro-healing modulation in excision wound by CO-RM-2 treatment. CO-RM significantly promoted the angiogenesis as compared to the iCO-RM group in vitro in CAM model demonstrating pro-angiogenic effects of CO-RM-2 in wound healing process. These results indicate that CO-RM-2 may have a potential application in the management of recalcitrant/obstinate wounds wherein, active wound healing is desired. This study also opens up a new area of research for the synthesis of novel CO-releasing molecules to be used for such purposes.