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Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha.
Hepatology. 1996 Nov; 24(5):1185-92.Hep

Abstract

Kupffer cells have been implicated in playing an important role in the pathogenesis of endotoxemia-associated liver injury. The present study was designed to investigate whether Kupffer cell-derived mediators alter the mitochondrial oxidative phosphorylation of hepatocytes in the endotoxemic condition. Liver cells were isolated from male Wistar rats. Oxidative phosphorylation was monitored as the fluorescence of rhodamine 123 (Rh123), which is the fluorescent cationic dye used to indicate mitochondrial energy synthesis. Two hours after coculture of hepatocytes with lipopolysaccharide (LPS)-pretreated Kupffer cells, a marked decrease in hepatocyte rhodamine 123 fluorescence was observed. The hepatocyte mitochondrial dysfunction was attenuated by the addition of either N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, or aminoguanidine, an inducible-type of NO synthase inhibitor, to the culture medium of cocultures, to the pretreatment of LPS-activated Kupffer cells with antisense oligodeoxynucleotides against iNOS messenger RNA (mRNA), or to tumor necrosis factor alpha (TNF-alpha) mRNA. Four hours after the coculture, hepatocyte Rh123 fluorescence further decreased, and an iNOS induction as well as an increased NO production were observed in hepatocytes that were cocultured with LPS-pretreated Kupffer cells. The membrane barrier dysfunction of hepatocytes, indicated by propidium iodide staining, was also induced by a 4-hour coculture with LPS-pretreated Kupffer cells. These late-phase changes were inhibited either by the pretreatment of hepatocytes with antisense oligodeoxynucleotides against iNOS mRNA or by treatments that are effective in the early phase (within 2 hours). Incubation with recombinant rat TNF-alpha decreased hepatocyte Rh123 fluorescence within 2 hours. Thus, the present study suggests that NO and TNF-alpha released from LPS-pretreated Kupffer cells directly inhibit the hepatocyte mitochondrial function in the early phase, and then NO synthesized by TNF-alpha-induced hepatocyte iNOS causes lethal hepatocyte injury, characterized by diminished mitochondrial energization and membrane barrier function in the late phase.

Authors+Show Affiliations

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8903396

Citation

Kurose, I, et al. "Increased Nitric Oxide Synthase Activity as a Cause of Mitochondrial Dysfunction in Rat Hepatocytes: Roles for Tumor Necrosis Factor Alpha." Hepatology (Baltimore, Md.), vol. 24, no. 5, 1996, pp. 1185-92.
Kurose I, Miura S, Higuchi H, et al. Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha. Hepatology. 1996;24(5):1185-92.
Kurose, I., Miura, S., Higuchi, H., Watanabe, N., Kamegaya, Y., Takaishi, M., Tomita, K., Fukumura, D., Kato, S., & Ishii, H. (1996). Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha. Hepatology (Baltimore, Md.), 24(5), 1185-92.
Kurose I, et al. Increased Nitric Oxide Synthase Activity as a Cause of Mitochondrial Dysfunction in Rat Hepatocytes: Roles for Tumor Necrosis Factor Alpha. Hepatology. 1996;24(5):1185-92. PubMed PMID: 8903396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha. AU - Kurose,I, AU - Miura,S, AU - Higuchi,H, AU - Watanabe,N, AU - Kamegaya,Y, AU - Takaishi,M, AU - Tomita,K, AU - Fukumura,D, AU - Kato,S, AU - Ishii,H, PY - 1996/11/1/pubmed PY - 1996/11/1/medline PY - 1996/11/1/entrez SP - 1185 EP - 92 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 24 IS - 5 N2 - Kupffer cells have been implicated in playing an important role in the pathogenesis of endotoxemia-associated liver injury. The present study was designed to investigate whether Kupffer cell-derived mediators alter the mitochondrial oxidative phosphorylation of hepatocytes in the endotoxemic condition. Liver cells were isolated from male Wistar rats. Oxidative phosphorylation was monitored as the fluorescence of rhodamine 123 (Rh123), which is the fluorescent cationic dye used to indicate mitochondrial energy synthesis. Two hours after coculture of hepatocytes with lipopolysaccharide (LPS)-pretreated Kupffer cells, a marked decrease in hepatocyte rhodamine 123 fluorescence was observed. The hepatocyte mitochondrial dysfunction was attenuated by the addition of either N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, or aminoguanidine, an inducible-type of NO synthase inhibitor, to the culture medium of cocultures, to the pretreatment of LPS-activated Kupffer cells with antisense oligodeoxynucleotides against iNOS messenger RNA (mRNA), or to tumor necrosis factor alpha (TNF-alpha) mRNA. Four hours after the coculture, hepatocyte Rh123 fluorescence further decreased, and an iNOS induction as well as an increased NO production were observed in hepatocytes that were cocultured with LPS-pretreated Kupffer cells. The membrane barrier dysfunction of hepatocytes, indicated by propidium iodide staining, was also induced by a 4-hour coculture with LPS-pretreated Kupffer cells. These late-phase changes were inhibited either by the pretreatment of hepatocytes with antisense oligodeoxynucleotides against iNOS mRNA or by treatments that are effective in the early phase (within 2 hours). Incubation with recombinant rat TNF-alpha decreased hepatocyte Rh123 fluorescence within 2 hours. Thus, the present study suggests that NO and TNF-alpha released from LPS-pretreated Kupffer cells directly inhibit the hepatocyte mitochondrial function in the early phase, and then NO synthesized by TNF-alpha-induced hepatocyte iNOS causes lethal hepatocyte injury, characterized by diminished mitochondrial energization and membrane barrier function in the late phase. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/8903396/Increased_nitric_oxide_synthase_activity_as_a_cause_of_mitochondrial_dysfunction_in_rat_hepatocytes:_roles_for_tumor_necrosis_factor_alpha_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913996004752 DB - PRIME DP - Unbound Medicine ER -