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Suppression of the mitochondrial permeability transition (MPT) with NIM811 mitigates storage/reperfusion injury and improves graft survival after rat liver transplantation (LT)
Author(s) -
Theruvath Tom P,
Ramshesh Venkat K,
Zhong Zhi,
Lemasters John J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.730.6
Subject(s) - propidium iodide , mitochondrial permeability transition pore , transplantation , chemistry , membrane potential , apoptosis , programmed cell death , andrology , medicine , biochemistry
We examined whether N‐methyl‐4‐isoleucine cyclosporin (NIM811) prevents mitochondrial dysfunction via the MPT and improves graft function after rat LT. METHODS. LT was performed after 18 h cold storage and vehicle or NIM811 treatment of explants and recipients. Serum ALT, necrosis, and apoptosis at 6 h after LT and 30‐day survival were assessed. At 4 h after LT, recipients were infused with membrane potential‐indicating rhodamine 123 (Rh123) and cell death‐indicating propidium iodide (PI), and fluorescence was then assessed by intravital multiphoton microscopy. RESULTS. After LT with vehicle and NIM811, ALT increased to 5242 U/L and 2159 U/L, respectively (p<0.01). Necrosis and TUNEL also decreased from 21% and 21 cells/field, respectively, after vehicle to 9% and 5 cells/field after NIM811, (p<0.05). Long‐term graft survival increased from 27% after vehicle treatment to 70% after NIM811 (p<0.05). After vehicle, 4.3 hepatocytes/HPF contained depolarized mitochondria not retaining Rh123 without PI labeling, whereas nonviable hepatocytes with depolarized mitochondria were 3.3 cells/HPF. After NIM811, viable hepatocytes with depolarized mitochondria decreased to 0.7 cells/HPF (p<0.05), and nonviable hepatocytes decreased to 0.4 cells/HPF (p<0.05). In CONCLUSION, NIM811 attenuated graft injury and prolonged survival by blocking the MPT and preventing mitochondrial depolarization.