title: Hypertonic resuscitation of hemorrhagic shock prevents alveolar macrophage activation by preventing systemic oxidative stress due to gut ischemia/reperfusion.
abstract: BACKGROUND
  The gut is a target organ of shock/resuscitation (S/R); however, it also contributes to distant inflammation through the generation of oxidants. S/R with antioxidants such as N-acetylcysteine (NAC) prevents lipopolysaccharide (LPS)-induced cytokine production and NF-kappaB activation in rat alveolar macrophages. Therefore, we hypothesized that hypertonic saline (HTS) might exerts its protective effect by preventing gut ischemia/reperfusion injury, thus decreasing oxidative stress and distant priming in alveolar macrophages.
  
  
  METHODS
  A two-hit rat model of shock resuscitation was used. Plasma levels of 8-iso-prostaglandin, a marker of lipid peroxidation, was quantified by eicosanoid immunoassay with acetylcholinesterase kit. Gut histology with hematoxylin and eosin staining was performed 1 to 6 hours after resuscitation. Alternatively, alveolar macrophages from bronchoalveolar lavage (BAL) at end resuscitation were incubated in vitro with LPS (0.01 mug/mL), and NF-kappaB translocation was observed by immunofluorescent staining with anti-p65 antibody.
  
  
  RESULTS
  HTS resuscitation prevented leukosequestration in the alveolar space, and it abrogated the progressive rise in blood 8-iso-prostaglandin production observed with Ringer's lactate (RL) resuscitation. Inhibition of oxidant stress with NAC corresponded with the ability of HTS to prevent S/R-induced edema, villus flattening, and mucosal sloughing in the mid-ileum. LPS-induced NF-kappaB translocation in alveolar macrophages after RL was 42% compared to 20% after HTS. Similar attenuation was observed with NAC resuscitation (16%).
  
  
  CONCLUSIONS
  HTS resuscitation prevents systemic oxidative stress by reducing gut ischemia/reperfusion injury and consequently attenuates distant alveolar macrophage priming, thereby reducing LPS-induced NF-kappaB nuclear translocation in alveolar macrophages and organ injury. This represents a novel mechanism whereby HTS exerts its immunomodulatory effects.
authors.affiliation: Department of Surgery, University of Toronto, University Health Network, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
authors.forename: K A
authors.initials: KA
authors.lastname: Powers
authors.forename: J
authors.initials: J
authors.lastname: Zurawska
authors.forename: K
authors.initials: K
authors.lastname: Szaszi
authors.forename: R G
authors.initials: RG
authors.lastname: Khadaroo
authors.forename: A
authors.initials: A
authors.lastname: Kapus
authors.forename: O D
authors.initials: OD
authors.lastname: Rotstein
mesh_terms: D000818:Animals; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D012151:Resuscitation / Q000379:methods*; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D012771:Shock, Hemorrhagic / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*
chemical_list: D016328:NF-kappa B; D016877:Oxidants; D012462:Saline Solution, Hypertonic