Carbon liberated from CO-releasing molecules attenuates leukocyte infiltration in the small intestine of thermally injured mice

Abstract

INTRODUCTIONSystemic inflammator y response syndrome (SIRS) and multiple organ failure (MOF) still continue to be leading causes of morbidity and mortality in severe burn patients [1,2] . The intestine is considered to be the critical organ in the development of organ dysfunction in trauma, burns, and intensive care unit patients [3] . Thermal injury is accompanied by complex events that exert deleterious effects on various organs, such as the small intestine, distant from the original burn wound. Following thermal injury, the small intestine is subjected to ischemia, and consequently, especially during burn resuscitation, reperfusion injury occurs [4] . Intestinal ischemia-reperfusion results in organ injury through both tissue hypoxia and reperfusion phenomena mediated by neutrophils [5,6] . A variety of cytokines are released into the microcirculation by neutrophils, endothelial cells and monocytes during phases of hypoxia and reperfusion [7,8] . Although the pathophysiological basis of organ damage remains unclear, there is increasing evidence that leukocyte infiltration into intestinal tissue plays an important role in bacterial or endotoxin translocation and development of SIRS after thermal injury [9][10][11][12] . A lot of evidence indicates that endogenous Carbon (CO), a by-product of inducible heme oxygenase (HO-1) Abstract AIM: To determine whether Carbon (CO) liberated from CO-releasing molecules attenuates leukocyte infiltration in the small intestine of thermally injured mice.METHODS: Thirty-six mice were assigned to four groups. Mice in the sham group (n = 9) were underwent to sham thermal injury; mice in the burn group (n = 9) received 15% total body surface area full-thickness thermal injury; mice in the burn + CORM-2 group (n = 9) were underwent to the same thermal injury with immediate administration of tricarbonyldichlororut henium (Ⅱ) dimer CORM-2 (8 mg/kg, i.v.); and mice in the burn+DMSO group (n = 9) were underwent to the same thermal injury with immediate administration of 160 μL bolus injection of 0.5% DMSO/saline. Histological alterations and granulocyte infiltration of the small intestine were assessed. Polymorphonuclear neutrophil (PMN) accumulation (myeloperoxidase assay) was assessed in mice mid-ileum. Activation of nuclear factor (NF)-κΒ, expression levels of intercellular adhesion molecule-1 (ICAM-1) and inducible heme oxygenase in mid-ileum were assessed. RESULTS:Treatment of thermally injured mice with CORM-2 attenuated PMN accumulation and prevented activation of NF-κΒ in the small intestine. This was accompanied by a decrease in the expression of ICAM-1. In parallel, burn-induced granulocyte infiltration in midileum was markedly decreased in the burn mice treated with CORM-2.

A single dose of carbon monoxide intraperitoneal administration protects rat intestine from injury induced by lipopolysaccharide

“…8 Effects of CO i.p on the expression of the phosphorylated p38 MAPK Fig. 7 Effects of CO i.p on intestinal cells apoptosis inflamed tissues, and correlates significantly with the number of PMNs in tissues (Sun et al 2007). In the present study, we found that intestinal MPO activity was markedly elevated after LPS injection, and significantly decreased after CO i.p.…”

“…In several models of cellular injury with LPS, the effect of CO on the down-regulation of the pro-inflammatory proteins has been observed (Zuckerbraun et al 2005;Dolinay et al 2004). In this context, it is noteworthy that treatment with CO at the conclusion of LPS limited the development of inflammation in the intestine, as evidenced by the reduction of the proinflammatory mediators PAF and ICAM-1 (Liu et al 2007;Sun et al 2007;Moore et al 2003;Moore et al 2005;Morisaki et al 2001Morisaki et al , 2002, as well as by the increase in the expression of a key anti-inflammatory cytokine IL-10 Zuckerbraun et al 2005;Dolinay et al 2004;Goebel et al 2008). …”

Suppression of inflammatory cytokine production and oxidative stress by CO-releasing moleculesliberated CO in the small intestine of thermally-injured mice1

“…The intestine is one of the most sensitive tissues to ischemia and reperfusion induced by thermal injury. Our previous data have indicated that polymorphonuclear neutrophils (PMN) play an important role in ischemic injury, and reperfusion of the intestine is associated with an accumulation of PMN in the intestinal tissue [37] . We also reported that the CORM-released CO exerts a protective effect against the pathological changes caused by thermal injury of the small intestine.…”

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

“…For example, CO-RMs reduce cytokine release in LPS-stimulated macrophages (Sawle et al, 2005) and decrease inflammatory response and oxidative stress in LPS-stimulated endothelial cells (Sun et al, 2008). In vivo, CO-RMs attenuate systemic inflammation and proadhesive vascular endothelial cell properties in septic and thermally injured mice by reducing nuclear factor B activation, protein expression of ICAM-1, and tissue granulocyte infiltration (Sun et al, 2007;Cepinskas et al, 2008). It is interesting that CO-RMs doses that are protective in vivo are well below the threshold needed to raise blood CO hemoglobin levels, implying that at least some of the CO released by CO-RMs escapes the reaction with hemoglobin in the blood and is delivered to tissues.…”