Hyaluronidase ameliorates rejection-induced edema

Hyaluronan, a glucosaminoglycan with unique water-binding capacity, is accumulated in the interstitial edematous tissue in rejecting organs. We here investigated whether the increased tissue content of water and hyaluronan seen during allograft rejection can be prevented by treatment with the hyaluronan-degrading enzyme hyaluronidase. Heterotopic heart transplantations between PVG and Wistar/Kyoto rats were performed. Recipient rats were treated with hyaluronidase prophylactically or therapeutically, either alone or in combination with cyclosporine. Daily intravenous injections of hyaluronidase induced a significant reduction of the cardiac content of both hyaluronan and water, as evaluated on day six after transplantation. Morphological examination revealed grafts with better preserved morphology and fewer infiltrating mononuclear cells, compared to untreated controls. Hyaluronidase therapy, alone or combined with cyclosporine, resulted in prolonged graft survival times. Hyaluronidase infusion for two hours also reduced already established edema five days after transplantation. This study confirms the hypothesis that hyaluronan accumulation plays a critical role in edema formation, and that hyaluronidase therapy can be used to reduce edema after organ transplantation.