Induction of heme oxygenase-1 improves the survival of pancreas grafts by prevention of pancreatitis after transplantation.
BACKGROUND
Ischemia/reperfusion (I/R) injury after pancreas transplantation might result in graft pancreatitis. The role of heme oxygenase-1 (HO-1) in pancreas transplantation and prevention of graft pancreatitis is unknown.


METHODS
We studied the impact of HO-1 induction with cobalt protoporphyrin (CoPP) in experimental pancreas transplantation with moderate (6 hr) and prolonged (20 hr) cold ischemic time (CIT). Donor animals received CoPP 5 mg/kg intraperitoneal at 48 hr or intraperitoneal saline injections in the corresponding control groups before procurement. Harvested grafts were perfused with HTK solution and stored at 4 degrees C.


RESULTS
After prolonged CIT, graft survival was 100% with CoPP pretreatment in contrast to only 37.5% without pretreatment. CoPP-pretreated grafts demonstrated an unimpaired endocrine graft function at moderate and prolonged CIT. Serum lipase activity as a sign of exocrine preservation was significantly lower. In addition, morphological architecture was well preserved. CoPP pretreatment markedly increased HO-1 gene expression in donor pancreas (130-fold increase) by means of quantitative reverse transcriptase -polymerase chain reaction. Immunohistochemical examinations showed that the increase of HO-1 on the protein level was related to HO-1-positive donor macrophages in the pancreas grafts. HO-1 overexpression was accompanied by significant decrease of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-2, IL-6, interferon-y, and by significant increase of the anti-inflammatory cytokine IL-10 and less expression of adhesion molecules such as e- and p-selectins.


CONCLUSIONS
HO-1 is highly inducible in the allograft rat pancreas and associated with a survival benefit and good graft function after transplantation. This study contributes to the beneficial potentials of HO-1 for the prevention of graft pancreatitis.
Becker
Thomas
T
Department of General, Visceral, and Transplant Surgery, Hannover Medical School, Hannover, Germany. becker.thomas@mh-hannover.de
Zu Vilsendorf
Andreas Meyer
AM
Terbish
Taivankhuu
T
Klempnauer
Jürgen
J
Jörns
Anne
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D004790:Enzyme Induction; D006085:Graft Survival / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008665:Metalloporphyrins / Q000032:analysis; D016035:Pancreas Transplantation / Q000473:pathology / Q000502:physiology*; D010195:Pancreatitis / Q000517:prevention & control*; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001786:Blood Glucose; D017931:DNA Primers; D008665:Metalloporphyrins; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1