Inhibition of IL-18 reduces myeloperoxidase activity and prevents edema in intestine following alcohol and burn injury

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Abstract
Previous studies have shown that alcohol (EtOH) ingestion before burn injury impaired intestinal barrier and immune function. This study determined whether EtOH and burn injury up-regulate interleukin (IL)-18 and whether IL-18 up-regulation following EtOH and burn injury is a cause for neutrophilrecruitment and increased intestinal edema. Rats (250 g) were gavaged with EtOH to achieve a blood EtOH level in the range of 100 mg/dL prior to burn or sham injury (25% total body surface area). A group of rats was treated with Ac-YVAD-CHO (5 mg/kg), an inhibitor of caspase-1 (an enzyme that converts pro-IL-18, an inactive form of IL-18, to mature IL-18), at the time of injury. One day after injury, rats were killed. IL-18 production was determined in circulation and in the supernatants harvested from spleen, mesenteric lymph nodes, and Peyer's patch cell cultures as well as in intestinal tissue homogenates. Neutrophil accumulation in intestine was determined by measuring myeloperoxidase (MPO) activity. We found a significant increase in IL-18 levels in the lymphoid cell supernatants and intestinal tissue homogenates obtained from EtOH and burn-injured rats compared with the rats receiving burn or sham injury. This was accompanied by an increase in intestinal MPO and edema. No demonstrable change in intestinal morphology was observed in any group. Treatment of rats with caspase-1 inhibitor significantly attenuated the increase in IL-18 levels and intestinal MPO activity in EtOH and burn-injured rats. Inhibition of IL-18 also prevented an increase in intestinal tissue water content. As MPO is considered an index of neutrophil infiltration, results presented in this manuscript collectively suggest that IL-18 up-regulation is likely to contribute to the increased neutrophil infiltration and edema in intestinal tissue observed following EtOH and burn injury.
Funding Information
  • NIH (AA12901)
  • Department of Surgery
  • University of Alabama at Birmingham