Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. Academic Article Article uri icon

Overview

MeSH

  • Animals
  • Apoptosis
  • Bronchoalveolar Lavage Fluid
  • Cells, Cultured
  • Chemotaxis, Leukocyte
  • Cytokines
  • Enzyme Induction
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hepatocytes
  • Lipopolysaccharides
  • Macrophage Activation
  • Macrophages, Alveolar
  • Male
  • Multiple Organ Failure
  • NF-kappa B
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Organ Specificity
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha

MeSH Major

  • Carbon Monoxide
  • Liver
  • Lung
  • Nitric Oxide Synthase
  • Shock, Septic

abstract

  • Carbon monoxide (CO) has recently emerged as having potent cytoprotective properties; the mechanisms underlying these effects, however, are just beginning to be elucidated. In a rat model of lipopolysaccharide (LPS)-induced multiorgan failure, we demonstrate that exposure to a low concentration of CO for only 1 h imparts a potent defense against lethal endotoxemia and effectively abrogates the inflammatory response. Exposure to CO leads to long-term survival of >80% of animals vs. 20% in controls. In the lung, CO suppressed LPS-induced lung alveolitis and associated edema formation, while in the liver, it reduced expression of serum alanine aminotransferase, a marker of liver injury. This protection appears to be based in part on different mechanisms in the lung and liver in that CO had reciprocal effects on LPS-induced expression of iNOS and NO production, important mediators in the response to LPS. CO prevented the up-regulation of iNOS and NO in the lung while augmenting expression of iNOS and NO in the liver. Studies of primary lung macrophages and hepatocytes in vitro revealed a similar effect; CO inhibited LPS-induced cytokine production in lung macrophages while reducing LPS-induced iNOS expression and nitrite accumulation and protected hepatocytes from apoptosis while augmenting iNOS expression. Although it is unclear to which extent these changes in iNOS contribute to the cytoprotection conferred by CO, it is fascinating that in each organ CO influences iNOS in a manner known to be protective in that organ: NO is therapeutic in the liver while it is damaging in the lung.

publication date

  • May 2004

has subject area

  • Animals
  • Apoptosis
  • Bronchoalveolar Lavage Fluid
  • Carbon Monoxide
  • Cells, Cultured
  • Chemotaxis, Leukocyte
  • Cytokines
  • Enzyme Induction
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hepatocytes
  • Lipopolysaccharides
  • Liver
  • Lung
  • Macrophage Activation
  • Macrophages, Alveolar
  • Male
  • Multiple Organ Failure
  • NF-kappa B
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Organ Specificity
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Septic
  • Tumor Necrosis Factor-alpha

Research

keywords

  • Comparative Study
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1096/fj.03-0643fje

PubMed ID

  • 15001560

Additional Document Info

start page

  • 854

end page

  • 856

volume

  • 18

number

  • 7