Original communication| Volume 137, ISSUE 1, P66-74, January 2005

Hypertonic resuscitation of hemorrhagic shock prevents alveolar macrophage activation by preventing systemic oxidative stress due to gut ischemia/reperfusion


      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-κB 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.


      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 μg/mL), and NF-κB translocation was observed by immunofluorescent staining with anti-p65 antibody.


      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-κB translocation in alveolar macrophages after RL was 42% compared to 20% after HTS. Similar attenuation was observed with NAC resuscitation (16%).


      HTS resuscitation prevents systemic oxidative stress by reducing gut ischemia/reperfusion injury and consequently attenuates distant alveolar macrophage priming, thereby reducing LPS-induced NF-κB nuclear translocation in alveolar macrophages and organ injury. This represents a novel mechanism whereby HTS exerts its immunomodulatory effects.
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