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.

Plasma methemoglobin as a potential biomarker of anemic stress in humans

“…25 In addition, direct exposure to inhaled NO can have significant impact on the systemic circulation and remote tissue perfusion via the action of stable NO metabolites. 38 Inhaled NO can also cause elevated MetHb levels in specific clinical settings. 39 Despite the rarity of clinically significant increases in MetHb, two of the largest series of case reports have shown a high incidence of anemia in 84% and 94% of cases.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…For example, the oral administration of S-nitroso-N-acetylcysteine prevented the onset of NAFLD in response to a methionine-choline deficient diet [110,111]; however, it is unclear whether the benefit was due to NO or Nacetylcysteine exposure. Recently, inhaled NO administration was shown to accelerate the restoration of liver function in transplantation patients presumably through increased circulating levels of nitrite [112], a newly recognized vascular endocrine transporter of NO [113] that protects against heart and liver ischemia-reperfusion injury [114]. In models of chronic alcohol consumption eNOS activity is decreased in liver through increased expression of the inhibitory protein caveolin-1 and/or decreased eNOS phosphorylation [115,116].…”

Ischemic preconditioning of the liver: A few perspectives from the bench to bedside translation

“…The merits of this composite endpoint were discussed in the Severity of Ischemia and RP Injury section, subsection Liver Transplantation. Remote preconditioning via limb ischemia 81,82 (1) Applicable to DCD donors; (2) Inexpensive Hypertonic saline dextran 83,84 (1) Volume enhancement, especially in donors and applicable to DCD donors; (2) Inexpensive Anesthetic preconditioning (volatile anesthetics, nitric oxide) 3,4,85 (1) May not be feasible in all donor hospitals; (2) Nitric oxide is expensive Pharmacologic preconditioning (nitrites, adenosine, interleukin-10) 2,6,7 (1) More expensive; (2) Potential side effects of agents NOTE: In contradistinction to ischemic preconditioning, all listed modalities are applicable in both liver donors and recipients. They share avoidance of direct organ ischemia and, when used in deceased donors, have the potential to benefit recipients of many organs.…”