title: Inhalation of carbon monoxide following resuscitation ameliorates hemorrhagic shock-induced lung injury.
abstract: Even after successful resuscitation, hemorrhagic shock frequently causes pulmonary inflammation that induces acute lung injury (ALI). We previously demonstrated that when CO is inhaled at a low concentration both prior to and following hemorrhagic shock and resuscitation (HSR) it ameliorates HSR-induced ALI in rats due to its anti-inflammatory effects. In the present study, we administered CO to the same model of ALI only after resuscitation and examined whether it exerted a therapeutic effect without adverse events on HSR-induced ALI, since treatment of animals with CO prior to HSR did not prevent lung injury. HSR were induced by bleeding animals to achieve a mean arterial pressure of 30 mmHg for 1 h followed by resuscitation with the removed blood. HSR resulted in the upregulation of inflammatory gene expression and increased the rate of apoptotic cell death in the lungs. This was determined from an observed increase in the number of cells positive for transferase-mediated dUTP-fluorescein isothiocyanate (FITC), nick-end labeling staining and activated caspase-3. HSR also resulted in prominent histopathological damage, including congestion, edema, cellular infiltration and hemorrhage. By contrast, CO inhalation for 3 h following resuscitation significantly ameliorated these inflammatory events, demonstrated by reduced histological damage, inflammatory mediators and apoptotic cell death. The protective effects of CO against lung injury were notably associated with an increase in the protein expression level of peroxisome proliferator-activated receptor (PPAR)-γ, an anti-inflammatory transcriptional regulator in the lung. Moreover, CO inhalation did not affect the hemodynamic status or tissue oxygenation during HSR. These findings suggest that inhalation of CO at a low concentration exerts a potent therapeutic effect against HSR-induced ALI and attenuates the inflammatory cascade by increasing PPAR-γ protein expression.
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama 700‑8558, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimatsu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.forename: Emiko
authors.initials: E
authors.lastname: Omori
authors.forename: Kenji
authors.initials: K
authors.lastname: Sato
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Maeda
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Morita
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000378:metabolism*; D002263:Carboxyhemoglobin / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006439:Hemodynamics; D000860:Hypoxia; D018836:Inflammation Mediators; D001239:Inhalation; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020556:Neutrophil Infiltration / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D051381:Rats; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D052247:Nitric Oxide Synthase Type II