Traumatic injury is a significant cause of morbidity and mortality worldwide. Microcirculatory activation and injury from hemorrhage contributes to organ injury. Many adaptive responses occur within the microcirculatory beds to limit injury including up regulation of heme oxygenase (HO) enzymes, the rate limiting enzymes in the breakdown of heme to carbon monoxide (CO), iron, and biliverdin. Here we tested the hypothesis that CO abrogates trauma induced injury and inflammation protecting the microcirculatory beds. Methods. C57Bl/6 mice underwent sham operation or hemorrhagic shock to a mean arterial pressure of 25mmHg for 120 minutes. Mice were resuscitated with Lactated Ringer’s at 2X the volume of maximal shed blood. Mice were randomized to receive CO-releasing molecule (CO-RM) or inactive CO-RM at resuscitation. A cohort of mice was pretreated with tin protoporphyrin-IX (SnPP) to inhibit endogenous CO generation by heme oxygenases (HO). Primary mouse liver sinusoidal endothelial cells were cultured for in vitro experiments. Results. CO-RM protected against hemorrhagic shock/resuscitation (HS/R) organ injury and systemic inflammation and reduced hepatic sinusoidal endothelial injury. Inhibition of HO activity with SnPP exacerbated liver hepatic sinusoidal injury. HS/R in vivo or cytokine stimulation in vitro resulted in increased endothelial expression of adhesion molecules that was associated with decreased leukocyte adhesion in vivo and in vitro. Conclusions. HS/R is associated with endothelial injury. HO enzymes and CO are involved in part in diminishing this injury and may prove useful as a therapeutic adjunct that can be harnessed to protect against endothelial activation and damage.

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