Short-term TNF-alpha inhibition reduces short-term and long-term inflammatory changes post-ischemia/reperfusion in rat intestinal transplantation.

BACKGROUND

Tumor necrosis factor (TNF)-α inhibition was shown to reduce ischemia/reperfusion injury (IRI) after intestinal transplantation (ITX). We studied the effects of different TNFα inhibitors on acute IRI and long-term inflammatory responses in experimental ITX.

METHODS

Orthotopic ITX was performed in an isogenic ischemia/reperfusion model in Lewis rats. The TNFα inhibition groups received infliximab post-reperfusion; etanercept pre-reperfusion and at postoperative days (POD) 1, 3, 5, and 7; or pentoxifylline pre-reperfusion and at POD 1 to 5. Tissue samples were taken from proximal and distal graft sections and mesenteric lymph nodes at 20 min, 12 hr, 7 day, and 6 months post-reperfusion for histopathology, immunohistology, terminal deoxyribosyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and real-time RT-PCR. Lung sections were stained for the myeloperoxidase assay.

RESULTS

TNFα inhibitors decreased inflammatory changes after IRI in all treatment groups. Infliximab significantly improved 7-day survival and reduced the histological and immunohistochemical signs of IRI, the numbers of graft-infiltrating T cells and ED1 monocytes and macrophages, and pulmonary neutrophil infiltration, and also enhanced the accumulation of cytoprotective markers. Graft injury was more prominent in the distal graft than in the proximal graft in all groups, regardless of TNFα inhibition.

CONCLUSION

Infliximab significantly reduced both acute IRI and, as with other TNFα inhibitors, long-term inflammatory responses after rat ITX. TNFα inhibition may help diminish chronic inflammatory long-term effects and avoid chronic allograft enteropathy.