Anti-inflammatory mechanisms of Carbon monoxide

Carbon monoxide (CO) can suppress the inflammatory response in numerous disease models. In the model of lipopolysaccharide (LPS)-induced inflammation to be studied here, CO modulates activation of p38 mitogen- activated protein kinase (MAPK), enhances production of the anti-inflammatory cytokine IL-10 (both in vivo and in vitro), and suppresses the induction of inducible nitric oxide synthase (iNOS) seen with LPS alone. The p38 MAPK is obligatorily involved in the anti-inflammatory effects of CO as well as in the regulation of iNOS. CO alone leads to a burst of reactive oxygen species (ROS) and the up-regulation of peroxisome proliferator-activated receptor- (PPAR). I have shown that the ROS and PPAR are needed for the anti-inflammatory effects of CO in macrophages and that expression of PPAR is also required for protection in vivo. Based on these and other findings, the main hypothesis for the work proposed herein is that CO, via a mitochondrial-derived rapid and low burst of ROS, activates specific signaling pathways that result in suppression of iNOS and protection from acute endotoxin-precipitated lung injury. Further, that the protective effects of CO involve PPAR and p38 MAPK. I am focusing many of my studies on monocyte-macrophages, which are inarguably one of the two most important cells in inflammation, particularly in the lung.