Carbon monoxide pretreatment prevents respiratory derangement and ameliorates hyperacute endotoxic shock in pigs

Abstract

Endotoxic shock, one of the most prominent causes of mortality in intensive care units, is characterized by pulmonary hypertension, systemic hypotension, heart failure, widespread endothelial activation/injury, and clotting culminating in disseminated intravascular coagulation and multi-organ system failure. In the last few years, studies in rodents have shown that administration of low concentrations of carbon monoxide (CO) exerts potent therapeutic effects in a variety of diseases/disorders. In this study, we have administered CO (one our pretreatment at 250 ppm) in a clinically relevant, well-characterized model of LPS-induced acute lung injury in pigs. Pretreatment only with inhaled CO significantly ameliorated several of the acute pathological changes induced by endotoxic shock. In terms of lung physiology, CO pretreatment corrected the LPS-induced changes in resistance and compliance and improved the derangement in pulmonary gas exchange. In terms of coagulation and inflammation, CO reduced the development of disseminated intravascular coagulation and completely suppressed serum levels of the proinflammatory IL-1beta in response to LPS, while augmenting the anti-inflammatory cytokine IL-10. Moreover, the effects of CO blunted the deterioration of kidney and liver function, suggesting a beneficial effect in terms of end organ damage associated with endotoxic shock. Lastly, CO pretreatment prevents LPS-induced ICAM expression on lung endothelium and inhibits leukocyte marginalization on lung parenchyma.

Carbon monoxide in biological systems: an experimental and clinical study

“…The body could perhaps cope with the inflammation itself without the effect of CO. Our study was designed to test for possible anti-inflammatory effects of CO in an endotoxin-induced systemic inflammatory situation. There has been one study before ours that performed a similar intervention in pigs though without definitively answering this question (Mazzola et al, 2005). However, the conclusions in that study can be questioned.…”

“…The uptake of CO decreased throughout the experiments as a result of the severe inflammatory situation, resulting in a need to increase the CO delivery. The constant CO levels was achieved which is a strength in this study, compared to other studies were the CO level in blood have decreased throughout the experiments (Mayr et al, 2005;Mazzola et al, 2005) or never been measured (Otterbein et al, 2000). The level of CO chosen (5 % COHb) in this study was determined to be a clinically relevant dose since higher doses may induce toxic symptoms.…”

“…In that study, higher levels of TNF-alpha in the CO pre-treated group were observed compared with the control group (Mazzola et al, 2005). The authors of that porcine study (Mazzola et al, 2005), based on only four animals, concluded that even though the TNF-alpha levels were higher in the CO treated group, CO ameliorated several of the acute pathological changes. In the study by Mazzola and co-workers, IL-1beta was suppressed in the CO-infused group but not in the control group.…”

“…In toxicological articles, negative effects of CO have been described at levels from 2 % COHb (Aronow, 1981). In physiological articles, positive effects are shown at levels of 10 % COHb (Mazzola et al, 2005).…”

Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II–Induced Cardiac Hypertrophy

“…With this model, we examined the effects of low-dose exogenous CO administration. Different from conventional CO exposure conditions at 250 to 1000 ppm 3,10,17,18 that clinically induce CO intoxication, we used a lower and shorter-time CO exposing condition at 60 ppm for 2 hours daily. This clinically applicable CO treatment significantly attenuated Ang II-induced hypertension and cardiac and aortic hypertrophic responses accompanied with reduced ROS accumulation in these tissues.…”