Tranilast Reduces Intestinal Ischemia Reperfusion Injury in Rats Through the Upregulation of Heme-Oxygenase (HO)-1

Intestinal ischemia reperfusion injury (IRI) is a harmful process that occurs during intestinal infarction and intestinal transplantation (ITx). It is characterized by severe inflammation which disrupts the mucosal barrier, causing bacterial translocation and sepsis. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) (TL) is a synthetic compound with powerful anti-inflammatory properties. We investigated the effect of pretreatment with TL in a validated rat model of intestinal IRI (60 minutes of ischemia) in 3 experiments. TL (650 mg/kg) was administered by oral gavage 24 and 2 hours before the onset of ischemia. Experiment 1 examined 7-day survival in 3 study groups (sham, vehicle+IRI and TL+IRI, n=10/group). In Experiment 2, the effects on the intestinal wall integrity and inflammation were studied after 60 minutes of reperfusion using 3 groups (sham, IRI and TL+IRI, n=6/group). The following end-points were studied: L-lactate, intestinal fatty acid-binding protein (I-FABP), histology, intestinal permeability, endotoxin translocation, pro- and anti-inflammatory cytokines and heme oxygenase-1 (HO-1) levels. Experiment 3 examined the role of HO-1 upregulation in TL pretreatment, by blocking its expression using Zinc protoporphyrin (ZnPP) at 20 mg/kg vs. placebo (n=6/group). Intestinal IRI resulted in severe damage of the intestinal wall and a 10% 7-day survival. These alterations led to endotoxin translocation and upregulation of pro-inflammatory cytokines. TL pretreatment improved survival up to 50%, significantly reduced inflammation and protected the intestinal barrier. The HO-1 inhibitor ZnPP, abolished the protective effect of TL. TL pretreatment improves survival by protecting the intestinal barrier function, decreasing inflammation and endotoxin translocation, through upregulation of HO-1.