Protective effect of heme oxygenase-1 to pancreas islet xenograft

Our work was to study the protective effect of cobalt protoporphyrin (CoPP) on islet xenograft and its mechanism. According to CoPP induction of rat pancreas islet cells in different concentration and time, the optimal CoPP dosage to induce high expression of HO-1 would be determined by examining expression of HO-1 mRNA and protein in graft and islet function. Subsequently, islet cells with untreated, CoPP-induced, and CoPP-induced with zinc protoporphyrin (ZnPP)-blocked were randomly transplanted into murine subrenal capsule, then the survival time among these different treated groups was compared by blood glucose level and pathologic examination and meanwhile the IFN-γ, TNF-α, IL-10, and IL-1β level in serum and their mRNA and protein expression would be examined in grafts. CoPP at 50 mmol/L for 36 h incubation induced the highest HO-1 mRNA and protein expression in islets. CoPP treated islets under low glucose and high glucose stimulation exhibited insulin secretion of 30.52 ± 2.04 μIU/mL and 104.60 ± 5.10 μIU/mL, respectively in comparison to control (20.35 ± 1.79 μIU/mL and 62.39 ± 2.50 μIU/mL, respectively) (P<0.05). CoPP induction could increase higher expression of HO-1 in graft (mRNA: 3.33-fold; protein: 2.85-fold), but ZnPP-blocked would decrease expression of HO-1 (mRNA: 0.72-fold; protein: 0.68-fold). The survival time in induction group (14.63 ± 1.19 d) was significantly longer than untreated group (9.88 ± 2.17 d) and ZnPP-blocked group (9.38 ± 1.60 d). Serum C-peptide in induction group (60.67 ± 9.87 pmol/L) was significantly higher than that in untreated group (35.67 ± 11.72 pmol/L) and blockage group (34.67 ± 12.90 pmol/L) (P<0.05). HbA1C in induction group (2.37% ± 0.21%) was significantly lower than that in untreated group (3.00% ± 0.17%) and blockage group (3.07% ± 0.15%) (P<0.01). The pathologic examination showed that lymphocyte infiltration to the graft in induction group was obviously less serious than other two groups. The Il-10 level in the serum in induction group (72.97 ± 9.74 pg/mL) was significantly higher than untreated group (30.57 ± 3.94 pg/mL) and blocked group (45.55 ± 8.26 pg/mL), and the expression of IL-10 mRNA in graft was in the same condition. The higher expression of HO-1 induced by CoPP in vitro would significantly improve pancreatic function, prolong graft survival time, and reduce lymphocyte infiltration to the graft. The CoPP induction could be inhibited by ZnPP and its mechanism could be related to immune modulation of IL-10.