An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy

Tu, Wei; Kitade, Hiroaki; Kaibori, Masaki; Nakagawa, Manabu; Inoue, Tomohisa; Kwon, A‐Hon; Okumura, Tadayoshi; Kamiyama, Yasuo

doi:10.1016/s0168-8278(99)80151-2

Cited by 26 publications

(9 citation statements)

References 29 publications

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“…and CINC-1 is detrimental. We previously reported that NO production by iNOS reduced ATP synthesis (energy metabolism) through mitochondrial dysfunction in liver injury after partial hepatectomy (45), obstructive jaundice (46), and sepsis (47). In the current study, hepatic injury peaked at 9 h (Figs.…”

Section: Discussionsupporting

confidence: 53%

PROTECTIVE EFFECT OF FR183998, A Na+/H+ EXCHANGER INHIBITOR, AND ITS INHIBITION OF iNOS INDUCTION IN HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS

Ishizaki

Kaibori²,

Uchida³

et al. 2008

Shock

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Recent evidence indicates that inhibition of the Na+/H+ exchanger improves heart and brain injuries induced by I/R. Studies were performed to investigate whether FR183998, a Na/H exchanger inhibitor, has protective effects on hepatic I/R injury in rats. Male Sprague-Dawley rats were subjected to 70% hepatic ischemia by occluding the hepatic artery, portal vein, and bile duct associated with the left and median liver lobes with a microvascular clip for 2 h. FR183998 (1 mg/kg) was administered i.v. 10 min before the hepatic ischemia. Hepatic I/R increased the serum levels of aspartate transaminase, alanine transaminase, and lactate dehydrogenase, which peaked at 9 h after reperfusion. FR183998 reduced these injury markers and recovered liver functions. Histopathologic analysis revealed that FR183998 prevented the incidences of hepatic necrosis, apoptosis, and neutrophil infiltration at 6 and 9 h (P < 0.05). FR183998 reduced the increases in proinflammatory cytokines such as TNF-alpha (1-6 h), IL-6 (1-12 h), interferon-gamma (6-12 h), IL-1beta (1-3 h), and cytokine-induced neutrophil chemoattractant 1 (1-3 h), but enhanced the anti-inflammatory cytokine IL-10 (1 h). FR183998 inhibited the hepatic I/R-induced activation of the transcription factor nuclear factor-kappaB at 1 to 6 h and reduced the induction of iNOS at 6 to 12 h, followed by inhibition of nitric oxide production. Furthermore, FR183998 decreased the expression of the iNOS gene antisense transcript, which is involved in the stability of iNOS messenger RNA, at 9 to 12 h in the liver of hepatic I/R rats. These results demonstrate that FR183998 reduces the induction of proinflammatory cytokines and iNOS at least in part through inhibition of nuclear factor-kappaB activation and iNOS antisense transcript expression, thereby preventing hepatic I/R injury.

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Section: Discussionsupporting

confidence: 53%

PROTECTIVE EFFECT OF FR183998, A Na+/H+ EXCHANGER INHIBITOR, AND ITS INHIBITION OF iNOS INDUCTION IN HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS

Ishizaki

Kaibori²,

Uchida³

et al. 2008

Shock

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“…Excessive metabolic burden in remnant livers after major hepatectomy may lead to mitochondrial dysfunction. Indeed, ATP decreases markedly after partial hepatectomy (15,18,19). Decreased ATP production in small-for-size liver grafts is associated with increased injury, suppressed regeneration and higher mortality (20,21).…”

Section: Introductionmentioning

confidence: 99%

NIM811 Prevents Mitochondrial Dysfunction, Attenuates Liver Injury, and Stimulates Liver Regeneration After Massive Hepatectomy

et al. 2011

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Background Massive hepatectomy (MHX) leads to failure of remnant livers. Excessive metabolic burden in remnant livers may cause mitochondrial dysfunction. This study investigated whether blockade of the mitochondrial permeability transition (MPT) with N-methyl-4-isoleucine cyclosporin (NIM811) improves the outcome of MHX. Methods Mice were gavaged with NIM811 (10 mg/kg before surgery and 5 mg/kg daily afterwards) and underwent sham-operation or ~90%-partial hepatectomy. Results Serum alanine aminotransferase (ALT), necrosis and apoptosis increased, respectively, to ~1200 U/L, 6.1% and 7% after MHX. NIM811 decreased peak ALT release, necrosis and apoptosis by 70%, 100% and 42%. 5-Bromo-2′-deoxyuridine incorporation, proliferating cell nuclear antigen expression, and the remnant liver weights were all increased significantly by NIM811 treatment, indicating improved liver regeneration. NIM811 also blunted hyperbilirubinemia by 54%, increased serum albumin by 51% and improved survival from 6% to 40% after MHX. Hepatic mitochondrial depolarization, cell death and the MPT were detected by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide and calcein. Mitochondrial depolarization occurred in many viable hepatocytes (13 cells/hpf), and non-viable hepatocytes increased slightly to ~1 cell/hpf at 3 h after MHX. Entry of calcein into mitochondria after MHX indicated MPT onset. Importantly, NIM811 decreased mitochondria depolarization by >60%, blocked MPT onset, and prevented cell death. Decreases of hepatic ATP, mitochondrial cytochrome c release and caspase-3 activation after MHX were also partially blocked by NIM811. Conclusions NIM811 minimized liver injury and improved liver regeneration after MHX, at least in part, by preventing MPT onset and subsequent compromised energy supply and proapoptotic cytochome c release.

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“…In contrast, massive production of NO enhances hepatic injury in septic shock [18,19] and hemorrhagic shock [20]. NO inhibits Krebs cycle enzymes of mitochondria in hepatocytes [21], resulting in the decrease of hepatic ATP synthesis in animals with partial hepatectomy [22], obstructive jaundice [23] and sepsis [24].…”

Section: Introductionmentioning

confidence: 99%

Pirfenidone inhibits the induction of iNOS stimulated by interleukin-1β at a step of NF-κB DNA binding in hepatocytes

Nakanishi

Kaibori

Teshima

et al. 2004

Journal of Hepatology

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An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy

Cited by 26 publications

References 29 publications

PROTECTIVE EFFECT OF FR183998, A Na+/H+ EXCHANGER INHIBITOR, AND ITS INHIBITION OF iNOS INDUCTION IN HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS

PROTECTIVE EFFECT OF FR183998, A Na+/H+ EXCHANGER INHIBITOR, AND ITS INHIBITION OF iNOS INDUCTION IN HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS

NIM811 Prevents Mitochondrial Dysfunction, Attenuates Liver Injury, and Stimulates Liver Regeneration After Massive Hepatectomy

Pirfenidone inhibits the induction of iNOS stimulated by interleukin-1β at a step of NF-κB DNA binding in hepatocytes

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