sCR1sLe(x) ameliorates ischemia/reperfusion injury in experimental lung transplantation

Background: The nonspecific immune response with activation of the compleme nt system and polymorphonuclear leukocytes is important for the mediation o f reperfusion injury after lung transplantation, In this study, we investig ated the combined blockade of the complement system and leukocyte adhesion by a novel drug combining soluble complement receptor type 1 (sCR1, CD35) w ith the selectin ligand sialyl Lewis X (sLe(X), CD15s) synthesized to sCR1s Le(X). Both sCR1 and sCR1Le(X) were supplied by AVANT Immunotherapeutics, I nc, Needham, Massachusetts. Methods: Orthotopic allogeneic single left lung transplantation was perform ed in male rats (Brown Norway to Fischer F334; n = 5 in all groups) after a total ischemic time of 20 hours. Recipients received either no specific tr eatment (control) or administration of sCR1 (10 mg/kg) or sCR1sLe(X) (10 mg /kg) 15 minutes before reperfusion by intracardiac injection, Twenty-four h ours after reperfusion, the native contralateral lung was occluded to asses s gas exchange of the graft only. In additional animals (5 per group), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxid ase activity as a measurement of neutrophil migration into the graft and th iobarbituric acid reactive substances to quantify lipid peroxidation. Results: Graft function as assessed by arterial Po-2 in recipients treated with sCR1sLeX was superior not only to that of controls (383 +/- 53 vs 56 /- 7 mm Hg, P =.000095) but also to that of animals treated with sCR1 (243 +/- 35 mm Hg, P =.031). This improvement was confirmed by significant reduc tion of neutrophil migration (0.33 +/- 0.05 vs control, 1.0 +/- 0.09 Delta OD/mg/min, P =.0000024) and lipid peroxidation (6.2 +/- 0.38 vs control, 10 .6 +/- 0.53 pmol/g, P =.00021). Conclusions: Our data indicate that combined inhibition of complement activ ation and leukocyte adhesion with sCR1sLe(X) reduces reperfusion injury sig nificantly and that both mechanisms are effectively inhibited in this model .