Ribonuclease (RNase) Prolongs Survival of Grafts in Experimental Heart Transplantation.
Cell damage, tissue and vascular injury are associated with the exposure and release of intracellular components such as RNA, which promote inflammatory reactions and thrombosis. Based on the counteracting anti-inflammatory and cardioprotective functions of ribonuclease A (RNase A) in this context, its role in an experimental model of heart transplantation in rats was studied.



Inbred BN/OrlRj rat cardiac allografts were heterotopically transplanted into inbred LEW/OrlRj rats. Recipients were intravenously treated every other day with saline or bovine pancreatic RNase A (50 μg/kg). Toxic side effects were not found (macroscopically and histologically). Heart tissue flow cytometry and quantitative morphological analyses of explanted hearts at postoperative day 1 or postoperative day 4 showed reduced leukocyte infiltration, edema, and thrombus formation in RNase A-treated rats. In allogeneic mixed lymphocyte reactions, RNase A decreased the proliferation of effector T cells. RNase A treatment of rats resulted in prolonged median graft survival up to 10.5 days (interquartile range 1.8) compared to 6.5 days (interquartile range 1.0) in saline treatment (P=0.001). Treatment of rats with a new generated (recombinant) human pancreatic RNase 1 prolonged median graft survival similarly, unlike treatment with (recombinant) inactive human RNase 1 (each 50 μg/kg IV every other day, 11.0 days, interquartile range 0.3, versus 8.0 days, interquartile range 0.5, P=0.007).



Upon heart transplantation, RNase administration appears to present a promising and safe drug to counteract ischemia/reperfusion injury and graft rejection. Furthermore, RNase treatment may be considered in situations of critical reperfusion after percutaneous coronary interventions or in cardiac surgery using the heart-lung machine.
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany.
Eike
E
Kleinert
Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Germany Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Germany.
Martin C
MC
Langenmayer
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany.
Bruno
B
Reichart
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany Department of Cardiac Surgery, Ludwig-Maximilians-Universität München, Germany.
Jana
J
Kindermann
Institute of Biochemistry, Medical School, Justus-Liebig-Universität, Giessen, Germany.
Barbara
B
Griemert
Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Germany.
Andreas
A
Blutke
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany Department of Vascular and Endovascular Surgery, University Hospital Frankfurt, Frankfurt am Main, Germany.
Kerstin
K
Troidl
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany Department of Anaesthesiology, Ludwig-Maximilians-Universität München, Germany.
Tanja
T
Mayr
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany.
Tobias
T
Grantzow
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Fatih
F
Noyan
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany Department of Anaesthesiology, Ludwig-Maximilians-Universität München, Germany.
Jan-Michael
JM
Abicht
Institute of Biochemistry, Medical School, Justus-Liebig-Universität, Giessen, Germany.
Silvia
S
Fischer
Institute of Biochemistry, Medical School, Justus-Liebig-Universität, Giessen, Germany.
Klaus T
KT
Preissner
Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Germany.
Ruediger
R
Wanke
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany elisabeth.deindl@med.uni-muenchen.de.
Elisabeth
E
Deindl
Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Germany Department of Cardiac Surgery, Ludwig-Maximilians-Universität München, Germany.
Sonja
S
Guethoff
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D004487:Edema / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012259:Ribonuclease, Pancreatic / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects; D013927:Thrombosis / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
D012259:Ribonuclease, Pancreatic
edema; extracellular RNA; ischemia/reperfusion injury; ribonuclease; transplantation