Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation
John D. Lang Jr., Xinjun Teng, Phillip Chumley, Jack H. Crawford, T. Scott Isbell, Balu K. Chacko, Yuliang Liu, Nirag Jhala, D. Ralph Crowe, Alvin B. Smith, Richard C. Cross, Luc Frenette, Eric E. Kelley, Diana W. Wilhite, Cheryl R. Hall, Grier P. Page, Michael B. Fallon, J. Steven Bynon, Devin E. Eckhoff, Rakesh P. Patel
John D. Lang Jr., Xinjun Teng, Phillip Chumley, Jack H. Crawford, T. Scott Isbell, Balu K. Chacko, Yuliang Liu, Nirag Jhala, D. Ralph Crowe, Alvin B. Smith, Richard C. Cross, Luc Frenette, Eric E. Kelley, Diana W. Wilhite, Cheryl R. Hall, Grier P. Page, Michael B. Fallon, J. Steven Bynon, Devin E. Eckhoff, Rakesh P. Patel
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Research Article

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.

Authors

John D. Lang Jr., Xinjun Teng, Phillip Chumley, Jack H. Crawford, T. Scott Isbell, Balu K. Chacko, Yuliang Liu, Nirag Jhala, D. Ralph Crowe, Alvin B. Smith, Richard C. Cross, Luc Frenette, Eric E. Kelley, Diana W. Wilhite, Cheryl R. Hall, Grier P. Page, Michael B. Fallon, J. Steven Bynon, Devin E. Eckhoff, Rakesh P. Patel

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Figure 4

Changes in circulating NOx metabolites.

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Changes in circulating NOx metabolites. Plasma (A, C, E, and G) and rbc ...
Plasma (A, C, E, and G) and rbc (B, D, F, H, and I) of nitrate (A and B), nitrite (C and D), SNO (E and F), XNO (G and H), and HbNO (I) are shown as a function of blood draw in placebo (filled squares) and iNO (filled circles) groups. Plasma NOx levels were normalized to protein. Absolute concentration ranges (minimum to maximal) were: nitrate (μM), placebo 47.9 ± 15.7 to 54.7 ± 19.2, iNO 84.6 ± 32.5 to 140.3 ± 24.5; nitrite (nM), placebo 202 ± 38.4 to 381.3 ± 49.3, iNO 462.2 ± 181.13 to 923.1 ± 240; SNO (nM), placebo –0.16 ± 0.17 to 1.3 ± 0.66, iNO 0.05 ± 0.2 to 2.3 ± 0.66; XNO (nM), placebo, 0.29 ± 0.2 to 3.5 ± 0.58, iNO 1.04 ± 0.35 to 4.7 ± 1.9. rbc NOx levels were normalized to heme. Absolute concentrations (in packed rbc) were: nitrate (μM), placebo 31.7 ± 12.5 to 41.5 ± 19.1, iNO 80.3 ± 48.3 to 196.2 ± 44.3; nitrite (nM), placebo 646.1 ± 80.8 to 1,219.5 ± 131.7, iNO 1,241.4 ± 447.7 to 2,533.3 ± 681.1; SNO (nM), placebo 4.9 ± 2.5 to 6.2 ± 2.2, iNO 29.1 ± 16.3 to 40.7 ± 18.2; XNO (nM), placebo 0.19 ± 0.15 to 1.8 ± 1.2, iNO 7.3 ± 4.9 to 13.4 ± 9.3; HbNO (nM), placebo 93.4 ± 4.4 to 242.8 ± 32.9, iNO- 222.9 ± 53.2 to 764.6 ± 108.1. Differences were assessed by 2-way repeated measures ANOVA and Bonferroni post-test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 for placebo versus iNO at corresponding blood draw. (J) Plasma and rbc A-V gradients at BD3 for indicated NO intermediates. Concentration units for each NOx are as indicated in respective panels showing changes in individual NOx as a function of BD (A–I). *P ≤ 0.001 for placebo versus iNO for plasma nitrite. All values are mean ± SEM; n = 10, and n = 6–7 for HbNO.