CO and CO-releasing molecules (CO-RMs) in acute gastrointestinal inflammation

Abstract

Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti-inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO-releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post-operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.

Figure 1

Graphical representation of the possible mechanisms of action of CO in POI. Intestinal manipulation induces oxidative stress and an inflammatory cascade, leading to increased expression/activity of iNOS and GI hypomotility via iNOS-derived NO. CO reduces the inflammatory cascade and iNOS expression/activity (Moore et al., ; Nakao et al., ; De Backer et al., 2009). Contributing mechanisms can be inhibition of ROS production (De Backer et al., 2009), suppression of ERK MAPK phosphorylation (De Backer et al., 2009) in a sGC-dependent way (Nakao et al., 2006a) and induction of HO1 (Moore et al., 2003) via enhanced p38 MAPK phosphorylation (De Backer et al., 2009).