Inhibition of histone deacetylase 6 attenuates intestinal inflammation and apoptosis in a rodent model of hemorrhagic shock

Abstract

BACKGROUND Intestinal inflammation is a mediator of multiorgan failure in trauma. We have previously shown that histone deacetylase (HDAC6) inhibitors, including ACY1083, improve survival and preserve intestinal tight junction integrity in a rodent model of hemorrhagic shock (HS). However, mechanisms leading to this alleviation in intestinal injury remain poorly defined. In this study, we sought to determine whether HDAC6 inhibition by ACY1083 can attenuate intestinal inflammation and apoptosis in rats subjected to HS. METHODS Sprague Dawley rats were subjected to hemorrhage (40% of total blood volume) followed by intravenous injection of either ACY1083 (30 mg/kg) dissolved in cyclodextrin or cyclodextrin only (vehicle group). Three hours after hemorrhage, blood samples were collected, and small bowel was harvested. Histological effects of ACY1083 on small bowel were examined. Myeloperoxidase (MPO) levels were assessed as a marker for neutrophil infiltration. Whole cell lysates were analyzed for acetylated &agr;-tubulin, metalloproteinase (ADAM) 17, TNF-&agr;, IL-6, and cleaved caspase 3 using Western blot. The levels of ADAM17, TNF-&agr;, and IL-6 in serum were also examined using enzyme-linked immunosorbent assay. RESULTS ACY1083 treatment significantly attenuated HS-induced intestinal injury and MPO production. Both systemic and intestinal TNF-&agr; and IL-6 levels were attenuated following ACY1083 administration. Increased acetylation of &agr;-tubulin was observed in rats treated with ACY1083, along with a significantly decreased expression of cleaved caspase 3 following hemorrhage. CONCLUSION Inhibition of HDAC6 with ACY1083 provides intestinal protection by attenuating both the inflammatory and apoptotic responses during HS.