title: 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.
authors.affiliation: Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Biochimica e Fisiologia Veterinaria, Università degli Studi di Milano, Milan, Italy. silvia.mazzola@unimi.it
authors.forename: S
authors.initials: S
authors.lastname: Mazzola
authors.forename: M
authors.initials: M
authors.lastname: Forni
authors.forename: M
authors.initials: M
authors.lastname: Albertini
authors.forename: M L
authors.initials: ML
authors.lastname: Bacci
authors.forename: A
authors.initials: A
authors.lastname: Zannoni
authors.forename: F
authors.initials: F
authors.lastname: Gentilini
authors.forename: M
authors.initials: M
authors.lastname: Lavitrano
authors.forename: F H
authors.initials: FH
authors.lastname: Bach
authors.forename: L E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: M G
authors.initials: MG
authors.lastname: Clement
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001777:Blood Coagulation; D002248:Carbon Monoxide / Q000378:metabolism*; D002263:Carboxyhemoglobin / Q000378:metabolism; D004195:Disease Models, Animal; D006418:Heme / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D012120:Respiration Disorders / Q000517:prevention & control*; D012772:Shock, Septic / Q000517:prevention & control*; D013552:Swine; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D006418:Heme; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D010100:Oxygen