Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Ramshesh, Venkat K.; Theruvath, Tom P.; Chavin, Kenneth D.; Schnellmann, Rick G.; Lemasters, John J.; Zhong, Zhi

doi:10.1016/j.freeradbiomed.2012.05.012

Cited by 19 publications

(27 citation statements)

References 75 publications

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“…Previous studies showed that one inebriating dose of ethanol causes overt steatosis (Zhong et al, 1997;Liu et al, 2012b). Consistent with these previous reports, livers from rats given saline revealed sparse distribution of small red fat droplets within hepatocytes (Fig.…”

Section: Acute Ethanol Treatment Causes Hepatic Steatosissupporting

confidence: 90%

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Suramin Decreases Injury and Improves Regeneration of Ethanol-Induced Steatotic Partial Liver Grafts

Rehman

Shi

et al. 2012

J Pharmacol Exp Ther

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Steatotic grafts are excluded for use in partial liver transplantation (LT) because of the increased risk of primary nonfunction. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, intragastric administration), reduced in size to ∼1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin levels as well as hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/ kg, i.p.) decreased ALT by ∼60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-29-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 hours, and the mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and the mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. Tumor necrosis factor-a (TNF-a) mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and caspase-3 in FPG. Suramin decreased TNF-a and caspase activation in FPG. Transforming growth factor-b (TGF-b), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-b formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-a and TGF-b formation.

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Section: Acute Ethanol Treatment Causes Hepatic Steatosissupporting

confidence: 90%

“…RNS modify proteins thus altering their functions. Increased RNS formation is associated with more severe graft injury, poorer graft function and decreased survival (He et al, 2010;Shi et al, 2010;Liu et al, 2012b). Energy supply is essential for cell survival and function.…”

Section: Suramin and Transplantation Of Fatty Partial Liver Graftsmentioning

confidence: 99%

Suramin Decreases Injury and Improves Regeneration of Ethanol-Induced Steatotic Partial Liver Grafts

Rehman

Shi

et al. 2012

J Pharmacol Exp Ther

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“…The role of RNS in MPT is controversial [8, 36, 37]. In this study we showed that iNOS was upregulated markedly in CDD grafts and that iNOS-deficiency blunted mitochondrial depolarization, ATP depletion, and injury in CDD grafts ( Figs.…”

Section: Discussionmentioning

confidence: 56%

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice

Liu

Rehman

Krishnasamy

et al. 2015

Journal of Hepatology

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Background/Aims Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Methods Livers explanted from wild-type, iNOS−/−, JNK1−/− or JNK2−/− mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. Results After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS-deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS-deficiency. JNK inhibition and JNK2-deficiency, but not JNK1-deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS-deficiency, JNK inhibition and JNK2-deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. Conclusion The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization and is an attractive target to improve liver function and survival in CDD liver transplantation.

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“…However, one of the major mediators during intestinal inflammation process is iNOS [19][20][21]. Under various pathological conditions, iNOS is considered an important enzyme in the inflammatory response, leading to tissue injury by its multiple actions including apoptosis inducement, oxygen free-radical production, and mitochondrial injury effect [22][23][24]. Previous studies have shown that iNOS could mediate the intestinal inflammation, and lead to gastrointestinal dysmotility, while the iNOS inhibitor could reverse these effects in the gastrointestinal diseases [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…However, one of the major mediators during intestinal inflammation process is inducible nitric oxide synthesis (iNOS) [19][20][21]. Under various conditions, iNOS is considered an important enzyme in the inflammatory response, leading to tissue injury by its multiple actions including apoptosis inducement, oxygen free-radical production, and mitochondrial injury effect [22][23][24]. However, it is still unknown if iNOS is involved in the intestinal inflammation after CKD progression.…”

Section: Introductionmentioning

confidence: 99%

Chronic Kidney Disease Elicits an Intestinal Inflammation Resulting in Intestinal Dysmotility Associated with the Activation of Inducible Nitric Oxide Synthesis in Rat

et al. 2018

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This study was conducted to investigate whether chronic kidney disease (CKD) affects intestinal inflammation and intestinal motility and the underlying mechanisms. Rats were randomized into control group and uremic group. Uremia rats were induced by the 5/6 kidney resection, while the control went through the same procedures but without any kidney resection. Intestinal motility was assessed by charcoal transport assay; intestinal inflammation was assessed by analyses of levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the ileum tissue. The inducible nitric oxide synthesis (iNOS) activity was assessed in the ileum tissue. The results showed that the intestinal motility in uremic group was significantly decreased compared with that in the control group on postoperative weeks 8 and 10. Meanwhile, the uremic group presented significantly higher concentrations of TNF-α, IL-6, and IL-10 than control group on postoperative weeks 8 and/or 10, and higher gene expression on postoperative weeks 6, 8, and 10. Furthermore, the intestinal iNOS activity in the uremic group was significantly increased compared with that in control group on postoperative weeks 8 and 10. These results suggest that CKD could induce intestinal inflammation and lead to intestinal dysmotility, which may be associated with iNOS activation in the intestine.

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Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Cited by 19 publications

References 75 publications

Suramin Decreases Injury and Improves Regeneration of Ethanol-Induced Steatotic Partial Liver Grafts

Suramin Decreases Injury and Improves Regeneration of Ethanol-Induced Steatotic Partial Liver Grafts

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice

Chronic Kidney Disease Elicits an Intestinal Inflammation Resulting in Intestinal Dysmotility Associated with the Activation of Inducible Nitric Oxide Synthesis in Rat

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