Caspase- (8/3) Activation and Organ Inflammation in a Rat Model of Resuscitated Hemorrhagic Shock: A Role for Uric Acid

Background Multiple organ failure can develop after hemorrhagic shock (HS). Uric acid (UA) is released from dying cells and can be pro-inflammatory. We hypothesized that UA could be an alternative mediator of organ apoptosis and inflammation after HS. Methods ventilated male Wistar rats were used for the HS model. Two durations of shock (5 vs 60 min) were compared, and shams were instrumented only; animals were resuscitated and observed for 24h/72h. Caspases-(8/3), myeloperoxidase (MPO), TNF-α were measured in lungs and kidneys. Plasma UA and cytokine (IL-1β, IL-18, TNF-α) were measured. A second set of animals were randomized to vehicle vs Rasburicase intraperitoneally (i.p) intervention (to degrade UA) during resuscitation. Another group received exogenous UA i.p without HS. Measures mentioned above, in addition to organs UA, were done at 24h. In vitro, caspases-(8/3) activity was tested in epithelial cells exposed to UA. Results HS increased organ (kidney and lung) TNF-α, MPO and caspases activity in various patterns, while caspase-8 remained elevated over time. HS led to increased plasma UA at 2h, which remained high until 72h; TNF-α and IL-18 were elevated at 24h. The exogenous UA administration in sham animals reproduced the activation of caspase-8 and MPO in organs, and TNF-α in the lung. The increased plasma and organ UA levels, plasma and lung TNF-α, as well as organ caspase-(8/3) and MPO, observed at 24h after HS, were prevented by the administration of Rasburicase during resuscitation. In vitro, soluble UA induced caspases-(3/8) activity in epithelial cells. Conclusion UA is persistently high after HS and leads to the activation of caspases-8 and organ inflammation; these can be prevented by an intervention to degrade UA. Therefore, UA is an important biomarker and mediator, that could be considered a therapeutic target during HS resuscitation in human. Study type basic science Level of Evidence N/A Corresponding author: Emmanuel Charbonney, Hôpital du Sacré-Coeur de Montréal, 5400 boul. Gouin Ouest, Montréal (Québec) Canada H4J 1C5. Telephone: +1-514-338-2222 Extension 2207. Fax: +1-514-338-2694. E-mail: emmanuel.charbonney@umontreal.ca Submitted on behalf of the Canadian Critical Care Translational Biology Group (CCCTBG) Conflicts of Interest and Source of Funding E. Charbonney received financial support for his program of research from Sanofi Genzyme Canada. The other authors have no conflict of interest to report. The research was funded locally by the Centre de Recherche Hôpital du Sacré-Cœur de Montréal Meeting presentation Part of the data have been presented at 4th Annual Meeting of the Canadian Critical Care Forum, October 25-28, 2015 in Toronto, Canada. © 2018 Lippincott Williams & Wilkins, Inc.

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