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Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation.

ABSTRACT: Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation.

SUBMITTER: Lang JD

PROVIDER: S-EPMC1950460 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation.

Lang John D JD Teng Xinjun X Chumley Phillip P Crawford Jack H JH Isbell T Scott TS Chacko Balu K BK Liu Yuliang Y Jhala Nirag N Crowe D Ralph DR Smith Alvin B AB Cross Richard C RC Frenette Luc L Kelley Eric E EE Wilhite Diana W DW Hall Cheryl R CR Page Grier P GP Fallon Michael B MB Bynon J Steven JS Eckhoff Devin E DE Patel Rakesh P RP

The Journal of clinical investigation 20070901 9

Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in ...[more]

PMID: 17717604

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Project description:Currently, the only fertility preservation option of prepubertal patients is ovarian tissue cryopreservation followed by autotransplantation (OTCTP). Once in remission and patients desire to conceive, autotransplantation of frozen/thawed tissue is performed. A major issue of this technique is follicular loss directly after transplantation, mainly due to follicle activation. Our previous research showed that adding rapamycin to the freezing medium counteracted follicle proliferation and activation induced by OTCTP in heterotopic autotransplantation of ovaries in mice. Our current study aimed to test the potential of this approach to improve fertility restoration in mice. Forty 4-week-old female C57BL/6 mice underwent unilateral oophorectomy followed by slow-freezing of ovaries with or without rapamycin. After chemically disabling the remaining ovary, orthotopic autotransplantation was performed. After recovery, estrous cycle analysis was conducted using daily vaginal smears. The mice were mated with males for 4 months, and pregnancy outcomes were recorded. After mating, half the females were super-ovulated for oocyte quantification and ovarian analysis, while the others had their ovaries collected for analysis of remaining primordial follicles using immunohistochemistry. Female mice whose ovaries were cryopreserved with rapamycin prior to chemically disabling the remaining ovary and orthotopic autotransplantation, gave birth to more pups (102 rapamycin, 48 control). The live birth rate was also higher (P = 0.0025) when ovaries were cryopreserved in rapamycin compared to control medium. Additionally, more mice in the rapamycin group gave birth (13 rapamycin, 8 control) with a higher average litter size (P = 0.0837). More mice had primordial follicles left at the end of the experiment in the rapamycin group (P = 0.0397). Superovulation showed a similar number of oocytes collected (P = 0.4462). While rapamycin did not influence cyst formation after autotransplantation, mice that developed ovarian cysts gave birth to fewer pups per dam (P = 0.0119) with a lower live birth rate compared to mice without ovarian cysts (P = 0.0032). The use of rapamycin improved fertility restoration in mice. Using rapamycin during OTCTP in humans could potentially resolve the massive follicular loss directly after grafting, and thus eventually lead to better opportunities for women to become pregnant.

Dataset Information

Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation.

Publications

Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation.

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