A novel CCR5/CXCR3 antagonist protects intestinal ischemia/reperfusion injury

Chemokines and chemokine receptors have been demonstrated to be critical regulators in a variety of physiologic and pathologic immune responses. In particular, CCR5 and CXCR3 have been reported to play important roles in the alloimmune response. In this study, we investigated the therapeutic efficacy of a novel small-molecule compound, TAK779, an antagonist targeting both CCR5 and CXCR3 in intestinal ischemia/reperfusion (I/R) injury. We utilized an established murine intestinal I/R injury model. TAK779 treatment significantly improved mouse survival after 60 minutes of intestinal ischemia. We then examined the local intestinal expression of several cytokines and chemokines at 2 hours after reperfusion using real-time PCR. TAK779 treatment downregulated the expression of several cytokines, including TNF-alpha, IFN-gamma, and IL-4, suggesting that the beneficial effect of TAK779 was associated with inhibition of local immune activation. We further examined the systemic response after TAK779 treatment. Lung tissue damage was significantly prevented by the treatment, as determined by lung wet-to-dry weight ratios at 4 hours after intestinal I/R injury. In addition, we observed that CCR5 expression in the lung was significantly downregulated by the treatment, suggesting that TAK779 inhibited the infiltration of CCR5-positive cells into the remote organ. Our data suggest the critical role of CCR5 and CXCR3 in intestinal I/R injury and therapeutic efficacy of a novel small compound, TAK779, for protection against the intestinal I/R injury.