Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice

Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l- N6-(1-iminoethyl)-lysine (l-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. l-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas l-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. l-NIL, but not l-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. l-NIL restored the sinusoidal perfusion, but l-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. l-NIL tended to minimize this infiltration, whereas l-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by l-NIL, whereas l-NAME further elevated it. l-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. l-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.

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Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1991.261.6.g1051 ◽

1991 ◽

Vol 261 (6) ◽

pp. G1051-G1056 ◽

Cited By ~ 24

Author(s):

H. Jaeschke ◽

A. Farhood ◽

C. W. Smith

Keyword(s):

Liver Injury ◽

Cell Injury ◽

Tissue Injury ◽

Oxidant Stress ◽

Parenchymal Cell ◽

Endotoxin Shock ◽

Liver Cell Injury ◽

Integrin Family ◽

Dependent Mechanism

To investigate the role of neutrophils (PMNs) and PMN-dependent adhesion molecules in the pathogenesis of liver injury in a model of endotoxin shock, male ICR mice received a dose of 700 mg/kg galactosamine and 100 micrograms/kg Salmonella abortus equi endotoxin. PMNs accumulated continuously in the liver, reaching values of 446 +/- 71 PMNs/50 high-power fields at 9 h (basal value 18 +/- 7). Plasma alanine aminotransferase activities as index of parenchymal cell injury did not change up to 5 h posttreatment (basal value 35 +/- 5 U/l) but increased to 1,950 +/- 460 U/l at 9 h. The formation of glutathione disulfide (GSSG) in plasma as an index of an extracellular oxidant stress also increased only at 9 h. Pretreatment of animals with monoclonal antibodies against the CD11b and CD18 subunits of the CD11/CD18 integrin family on the surface of the PMN reduced the number of PMNs in the liver by 50% and significantly attenuated liver injury and GSSG formation. An anti-CD11a and a nonbinding control antibody were ineffective. It is concluded that PMNs are actively involved in the pathogenesis of galactosamine and endotoxin shock and that at least in part the accumulation of PMNs, the subsequent oxidant stress, and the tissue injury in this model of experimental hepatitis are CD11b/CD18 (Mac-1) dependent.

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Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis

Mediators of Inflammation ◽

10.1155/2018/5871431 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Zhengyu Jiang ◽

Yan Meng ◽

Lulong Bo ◽

Changli Wang ◽

Jinjun Bian ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Great Part ◽

Protective Role ◽

Stress Indicators ◽

Oxidative Reaction ◽

Hepatic Expression ◽

Jnk Cascade ◽

Oxidative Stress Indicators

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H2O2, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia.

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MON-218 Protective role of TV-induced autophagy in an in vivo model of unilateral ureteral obstruction-induced renal cell injury

Kidney International Reports ◽

10.1016/j.ekir.2019.05.1019 ◽

2019 ◽

Vol 4 (7) ◽

pp. S390-S391

Author(s):

D.E. Choi ◽

K.W. Lee ◽

K.R. Na ◽

J.Y. Jeong ◽

Y.R. Ham ◽

...

Keyword(s):

Ureteral Obstruction ◽

Renal Cell ◽

Cell Injury ◽

Protective Role ◽

Unilateral Ureteral Obstruction ◽

In Vivo Model

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Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.267.6.g1135 ◽

1994 ◽

Vol 267 (6) ◽

pp. G1135-G1141 ◽

Cited By ~ 12

Author(s):

J. Nishida ◽

R. S. McCuskey ◽

D. McDonnell ◽

E. S. Fox

Keyword(s):

Hepatic Injury ◽

Protective Role ◽

No Production ◽

Leukocyte Adherence ◽

In Vivo Microscopy ◽

Hepatic Microcirculation ◽

Protective Function ◽

Microcirculatory Disturbances

Nitric oxide (NO) has been reported to have a protective function in attenuating hepatic injury during endotoxemia or sepsis. As a result, the role of NO in attenuating the hepatic microcirculatory alterations associated with endotoxemia was investigated in mice by in vivo microscopy. The livers were examined 2 h after intravenous injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS) alone or in combination with inhibitors of the synthesis of NO, NG-nitro-L-arginine methyl ester or NG-monomethyl-L-arginine. In the animals treated with the combination of NO synthase inhibitors and LPS, leukocyte adherence was increased threefold above that in animals treated with LPS alone. This was accompanied by a 33% reduction in sinusoidal blood flow. Simultaneous administration of L-arginine, but not D-arginine, eliminated these microcirculatory disturbances. The results demonstrate that inhibition of LPS-stimulated NO production results in an early hepatic microvascular inflammatory response to a dose of endotoxin which by itself is scarcely inflammatory. This suggests that NO plays a significant role in stabilizing the hepatic microcirculation during endotoxemia, thereby helping to protect the liver from ischemia and leukocyte-induced oxidative injury.

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Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00132.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. G965-G974 ◽

Cited By ~ 24

Author(s):

Xiaoying Liu ◽

Anne S. Henkel ◽

Brian E. LeCuyer ◽

Matthew J. Schipma ◽

Kristy A. Anderson ◽

...

Keyword(s):

Liver Injury ◽

Fatty Liver ◽

Cell Injury ◽

Binding Protein ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Hepatic Expression ◽

Huh7 Cells

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient ( Xbp1−/−) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1−/− mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1−/− mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1−/− mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1−/− compared with Xbp1fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

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The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice

Infection and Immunity ◽

10.1128/iai.69.12.7711-7717.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7711-7717 ◽

Cited By ~ 108

Author(s):

Charles A. Scanga ◽

Vellore P. Mohan ◽

Kathryn Tanaka ◽

David Alland ◽

JoAnne L. Flynn ◽

...

Keyword(s):

Nitric Oxide ◽

Mycobacterium Tuberculosis ◽

Nitric Oxide Synthase ◽

Protective Role ◽

Clinical Isolates ◽

Intravenous Route ◽

Tuberculous Infection ◽

Oxide Synthase

ABSTRACT Murine macrophages effect potent antimycobacterial function via the production of nitric oxide by the inducible isoform of the enzyme nitric oxide synthase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosisinfection has been well established in various murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. However, important questions remain about the in vivo importance of RNI in host defense against M. tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous,M. tuberculosis infection of mice. Furthermore, in vitro studies have demonstrated that different strains of M. tuberculosis, including clinical isolates, vary widely in their susceptibility to the antimycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates of M. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique M. tuberculosis strains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrupted mice. Regardless of the route of infection, NOS2−/− mice were much more susceptible than wt mice to any of the clinical isolates or to either the Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replicated to much higher levels in the organs of NOS2−/− mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence in NOS2−/− mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the control of murine tuberculous infection caused by both laboratory and clinical strains of M. tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.

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An in vivo study on the distinctive role of inducible and endothelial nitric oxide synthase in carbon tetrachloride-induced liver injury

10.5353/th_b3684680 ◽

2006 ◽

Author(s):

Tung-ming Leung

Keyword(s):

Nitric Oxide ◽

Carbon Tetrachloride ◽

Nitric Oxide Synthase ◽

Liver Injury ◽

Endothelial Nitric Oxide Synthase ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Distinctive Role

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Neuroinflammation and demyelination from the point of nitrosative stress as a new target for neuroprotection

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0060 ◽

2015 ◽

Vol 26 (1) ◽

Cited By ~ 7

Author(s):

Srdjan Ljubisavljevic ◽

Ivana Stojanovic

Keyword(s):

Nitric Oxide ◽

Nitrosative Stress ◽

Experimental Studies ◽

Protective Role ◽

Clinical Effects ◽

Inos Inhibitor ◽

Potential Mode ◽

Oxidative Processes ◽

Oxide Synthase

AbstractThe role of nitrosative stress in the early pathogenesis of neuroinflammation and demyelination is undoubtedly wide. This review summarizes and integrates the results, found in previously performed studies, which have evaluated nitrosative stress participation in neuroinflammation. The largest number of studies indicates that the supply of nitrosative stress inhibitors has led to the opposite clinical effects in experimental studies. Some results claim that attributing the protective role to nitric oxide, outside the total changes of redox oxidative processes and without following the clinical and paraclinical correlates of neuroinflammation, is an overrated role of this mediator. The fact is that the use of nitrosative stress inhibitors would be justified in the earlier phases of neuroinflammation. The ideal choice would be a specific inducible nitric oxide synthase (iNOS) inhibitor, because its use would preserve the physiological features of nitric oxide produced by the effects of constitutive NOS. This review discusses the antinitrosative therapy as a potential mode of therapy that aims to control neuroinflammation in early phases, delaying its later phases, which are accompanied with irreversible neurological disabilities. Some parameters of nitrosative stress might serve as surrogate biomarkers for neuroinflammation intensity and its radiological and clinical correlates.

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