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Wang X, Wang J, Peng H, Zuo L, Wang H. Role of immune cell interactions in alcohol-associated liver diseases. LIVER RESEARCH 2024; 8:72-82. [DOI: 10.1016/j.livres.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Simpson S, Mclellan R, Wellmeyer E, Matalon F, George O. Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders. J Neuroimmune Pharmacol 2022; 17:33-61. [PMID: 34694571 PMCID: PMC9074906 DOI: 10.1007/s11481-021-10022-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/06/2021] [Indexed: 02/07/2023]
Abstract
Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain's response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis.
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Affiliation(s)
- Sierra Simpson
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US.
| | - Rio Mclellan
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Emma Wellmeyer
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Frederic Matalon
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Olivier George
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
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Different Dietary Proportions of Fish Oil Regulate Inflammatory Factors but Do Not Change Intestinal Tight Junction ZO-1 Expression in Ethanol-Fed Rats. Mediators Inflamm 2017; 2017:5801768. [PMID: 29386752 PMCID: PMC5745723 DOI: 10.1155/2017/5801768] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 09/30/2017] [Accepted: 10/15/2017] [Indexed: 12/18/2022] Open
Abstract
Sixty male Wistar rats were fed a control or an ethanol-containing diet in groups C or E. The fat compositions were adjusted with 25% or 57% fish oil substituted for olive oil in groups CF25, CF57, EF25, and EF57. Hepatic thiobarbituric acid-reactive substance (TBARS) levels, cytochrome P450 2E1 protein expression, and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 levels, as well as intracellular adhesion molecule (ICAM)-1 levels were significantly elevated, whereas plasma adiponectin level was significantly reduced in group E (p < 0.05). Hepatic histopathological scores of fatty change and inflammation, in group E were significantly higher than those of group C (p < 0.05). Hepatic TBARS, plasma ICAM-1, and hepatic TNF-α, IL-1β, and IL-10 levels were significantly lower, and plasma adiponectin levels were significantly higher in groups EF25 and EF57 than those in group E (p < 0.05). The immunoreactive area of the intestinal tight junction protein, ZO-1, showed no change between groups C and E. Only group CF57 displayed a significantly higher ZO-1 immunoreactive area compared to group C (p = 0.0415). 25% or 57% fish oil substituted for dietary olive oil could prevent ethanol-induced liver damage in rats, but the mechanism might not be related to intestinal tight junction ZO-1 expression.
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Fish Oil Reduces Hepatic Injury by Maintaining Normal Intestinal Permeability and Microbiota in Chronic Ethanol-Fed Rats. Gastroenterol Res Pract 2016; 2016:4694726. [PMID: 27143963 PMCID: PMC4842064 DOI: 10.1155/2016/4694726] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/08/2016] [Accepted: 03/28/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to investigate the ameliorative effects of fish oil on hepatic injury in ethanol-fed rats based on the intestinal permeability and microbiota. Rats were assigned to 6 groups and fed either a control diet or an ethanol diet such as C (control), CF25 (control with 25% fish oil), CF57 (control with 57% fish oil), E (ethanol), EF25 (ethanol with 25% fish oil), and EF57 (ethanol with 57% fish oil) groups. Rats were sacrificed at the end of 8 weeks. Plasma aspartate aminotransferase (AST) and aminotransferase (ALT) activities, hepatic cytokines, and plasma endotoxin levels were significantly higher in the E group. In addition, hepatic histopathological analysis scores in the E group were significantly elevated. Rats in the E group also showed increased intestinal permeability and decreased numbers of fecal Bifidobacterium. However, plasma AST and ALT activities and hepatic cytokine levels were significantly lower in the EF25 and EF57 groups. Histological changes and intestinal permeability were also improved in the EF25 and EF57 groups. The fecal Escherichia coli numbers were significantly lower, but fecal Bifidobacterium numbers were significantly higher in the EF25 and EF57 groups.
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Chiu WC, Huang YL, Chen YL, Peng HC, Liao WH, Chuang HL, Chen JR, Yang SC. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. Food Funct 2016; 6:1692-700. [PMID: 25910227 DOI: 10.1039/c5fo00104h] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Clinical and animal experiments indicated that gut-derived endotoxin and imbalanced intestinal microbiota contribute to the pathogenesis of alcoholic liver disease (ALD). In this study, we investigated whether synbiotic supplementation could improve ALD in rats by altering the intestinal microbial composition and improving the intestinal integrity. Male Wistar rats were divided into four groups according to plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and subjected to either a normal liquid diet (C), a normal liquid diet with synbiotic supplementation (C + S), an ethanol liquid diet (E), or an ethanol liquid diet with synbiotic supplementation (E + S) for 12 weeks. Results revealed that the ethanol-fed group showed increases in plasma AST and ALT activities, the endotoxin level, the hepatic triglyceride (TG) level, and hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels, and a decrease in the hepatic IL-10 level. Ethanol-feeding also contributed to increased intestinal permeability and decreased fecal bifidobacteria and lactobacilli amounts. However, synbiotic supplementation effectively attenuated the plasma endotoxin, hepatic TG and TNF-α levels, and increased the hepatic IL-10 level. Furthermore, synbiotic supplementation protected the rats against ethanol-induced hyperpermeability of the intestine, and significantly increased amounts of bifidobacteria and lactobacilli in the feces. This study demonstrated that synbiotics possess a novel hepatoprotective function by improving the intestinal permeability and microbiota in rats with ethanol-induced liver injury.
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Affiliation(s)
- Wan-Chun Chiu
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110, Taiwan.
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Chen YL, Peng HC, Hsieh YC, Yang SC. Epidermal growth factor improved alcohol-induced inflammation in rats. Alcohol 2014; 48:701-6. [PMID: 25174268 DOI: 10.1016/j.alcohol.2014.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Revised: 04/22/2014] [Accepted: 07/24/2014] [Indexed: 12/12/2022]
Abstract
The purpose of this study was to investigate the effects of an epidermal growth factor (EGF) intervention on improving the inflammatory response of rats fed an ethanol-containing diet. Eight-week-old male Wistar rats were divided into ethanol (E) and control (C) groups. Rats in the E group were fed an ethanol liquid diet, while rats in the C group were pair-fed an isoenergetic diet without ethanol. After a 4-week ethanol-induction period, both the C and E group were respectively subdivided into 2 groups: a normal liquid diet without (C group, n = 8) or with EGF supplementation (C + EGF, n = 8), and the ethanol-containing diet without (E group, n = 8) or with EGF supplementation (E + EGF group, n = 8). The EGF (30 μg/kg body weight/day) intervention period was carried out for the following 8 weeks. At the end of the experiment, activity of aspartate transaminase (AST) and alanine transaminase (ALT) and hepatic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in group E were significantly higher than those in group C. In addition, alterations in the gut microbiota profile were found in group E. In contrast, activity of AST and ALT and levels of TNF-α, IL-1β, and IL-6 in group E + EGF were significantly lower than those in group E. Significantly lower intestinal permeability and lower numbers of Escherichia coli in the fecal microbial culture were also found in group E + EGF. These results suggest that EGF improved the intestinal integrity by decreasing E. coli colonization and lowering intestinal permeability, which then ameliorated the inflammatory response under chronic ethanol exposure.
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Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, Kwasny M, Lau CK, Keshavarzian A. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302:G966-78. [PMID: 22241860 PMCID: PMC3362077 DOI: 10.1152/ajpgi.00380.2011] [Citation(s) in RCA: 586] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 01/06/2012] [Indexed: 02/06/2023]
Abstract
Several studies indicate the importance of colonic microbiota in metabolic and inflammatory disorders and importance of diet on microbiota composition. The effects of alcohol, one of the prominent components of diet, on colonic bacterial composition is largely unknown. Mounting evidence suggests that gut-derived bacterial endotoxins are cofactors for alcohol-induced tissue injury and organ failure like alcoholic liver disease (ALD) that only occur in a subset of alcoholics. We hypothesized that chronic alcohol consumption results in alterations of the gut microbiome in a subgroup of alcoholics, and this may be responsible for the observed inflammatory state and endotoxemia in alcoholics. Thus we interrogated the mucosa-associated colonic microbiome in 48 alcoholics with and without ALD as well as 18 healthy subjects. Colonic biopsy samples from subjects were analyzed for microbiota composition using length heterogeneity PCR fingerprinting and multitag pyrosequencing. A subgroup of alcoholics have an altered colonic microbiome (dysbiosis). The alcoholics with dysbiosis had lower median abundances of Bacteroidetes and higher ones of Proteobacteria. The observed alterations appear to correlate with high levels of serum endotoxin in a subset of the samples. Network topology analysis indicated that alcohol use is correlated with decreased connectivity of the microbial network, and this alteration is seen even after an extended period of sobriety. We show that the colonic mucosa-associated bacterial microbiome is altered in a subset of alcoholics. The altered microbiota composition is persistent and correlates with endotoxemia in a subgroup of alcoholics.
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Affiliation(s)
- Ece A Mutlu
- Department of Medicine, Division of Digestive Diseases and Nutrition, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois 60612, USA
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Husić-Selimović A, Huskić J, Vukobrat-Bijedić Z, Mesihović R, Gribajcević M. The role of nitric oxide and ferritin in the pathogenesis of alcoholic liver disease: a controlled clinical study. Bosn J Basic Med Sci 2009; 9:204-9. [PMID: 19754474 DOI: 10.17305/bjbms.2009.2807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The role of ferritin in fibrogenesis of liver parenchyma in patients with alcoholic liver disease has been investigated in previous studies. Ferritin was shown to be an indirect marker of ferum deposition in liver parenchyma in alcohol liver disease. The aim of the present study was to examine the role of nitric oxide (NO) in the pathogenesis of alcoholic liver disease as well as the influence of NO on iron (ferritin) metabolism in patients with alcoholic liver disease. Serum concentrations of NO and iron markers (iron, total iron binding capacity, ferritin) were measured in 30 male patients (aged 20-60 years) with alcoholic liver disease, as well as from a control group (30 male patients (aged 20-60 years) without liver disease). NO concentration was detected by measuring production of nitrates and nitrites using classical colorimetric Griess reactions. There was a statistically significant increase in serum NO concentration in patients with alcoholic liver disease compared to the control group (mean +/- SEM; 41,2 +/- 25,3 vs. 28,9 +/- 12,3 mmol/dm3, respectively; p<0,03). Similarly, serum iron levels (18,7 +/- 8,2 vs. 13,2 +/- 10,2 g/100 cm3, respectively; p<0,03) and serum total iron binding capacity (51,3 +/- 13,9 vs. 41,4 +/- 11,4 micromol/dm3, respectively; p<0,005) were also significantly higher in patients with alcoholic liver disease compared to control patients. The serum concentration of ferritin was 27% higher in patients with alcoholic liver disease than in the control group; however this was not statistically significant (283,2 +/- 291,0 vs. 222,9 +/- 252,0 g, respectively; p<0,4). There was no correlation between NO and ferritin in the investigated groups. These results suggest a possible role of NO and iron in the pathogenesis of alcoholic liver disease. NO and iron may be used as non-invasive predictors of liver damage. Also the role of iron in sera, and its deposition in liver parenchyma, could be used in clinical practice, especially in regards to assessing the fibrogenesis of liver parenchyma induced by ferritin.
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Affiliation(s)
- Azra Husić-Selimović
- Gastroenterohepatology Clinic, University of Sarajevo Clinics Centre, Bosnia and Herzegovina
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Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res 2009; 33:1836-46. [PMID: 19645728 DOI: 10.1111/j.1530-0277.2009.01022.x] [Citation(s) in RCA: 292] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical and animal data indicate that gut-derived endotoxin and other luminal bacterial products are necessary cofactors for development of alcoholic liver disease (ALD). Although gut leakiness is clearly an important cause of endotoxemia in ALD, it cannot fully explain endotoxemia in all ALD subjects and thus other factors may be involved. One possible factor is a change in gut microbiota composition (dysbiosis). Thus, the aim of our study was to interrogate the gut bacterial microbiota in alcohol-fed rats to see if chronic alcohol consumption affects gut bacteria composition. METHOD Male Sprague-Dawley rats were given either alcohol or dextrose intragastrically by gavage twice daily for up to 10 weeks. A subgroup of rats was also given either a probiotic (lactobacillus GG) or a prebiotic (oats) by gavage. Ileal and colonic mucosal-attached microbiota composition were interrogated by Length Heterogeneity PCR (LH-PCR) fingerprinting. RESULTS Bacterial microbiota composition in alcohol-fed rats is not different from dextrose-fed rats at weeks 4 and 6. Mucosa-associated microbiota composition in the colon is altered at 10 weeks of daily alcohol gavage. Both LGG and oats prevented alcohol-induced dysbiosis up to 10 weeks of alcohol treatment. CONCLUSION Daily alcohol consumption for 10 weeks alters colonic mucosa-associated bacterial microbiota composition in rats. Our data showed, for the first time, that daily alcohol consumption can affect colonic microbiome composition and suggest that dysbiosis may be an important mechanism of alcohol-induced endotoxemia. Further studies are needed to determine how dysbiotic microbiota contributes to development of ALD and whether therapeutic interventions targeted towards dysbiotic microbiota can prevent complications of alcoholism like ALD.
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Affiliation(s)
- Ece Mutlu
- Rush University Medical Center, Division of Digestive Diseases and Nutrition, Nutrition Rush University Medical Center, Chicago, Illinois 60612, USA
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Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res 2009. [PMID: 19645728 DOI: 10.1111/j.1530-0277.2009.01022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Clinical and animal data indicate that gut-derived endotoxin and other luminal bacterial products are necessary cofactors for development of alcoholic liver disease (ALD). Although gut leakiness is clearly an important cause of endotoxemia in ALD, it cannot fully explain endotoxemia in all ALD subjects and thus other factors may be involved. One possible factor is a change in gut microbiota composition (dysbiosis). Thus, the aim of our study was to interrogate the gut bacterial microbiota in alcohol-fed rats to see if chronic alcohol consumption affects gut bacteria composition. METHOD Male Sprague-Dawley rats were given either alcohol or dextrose intragastrically by gavage twice daily for up to 10 weeks. A subgroup of rats was also given either a probiotic (lactobacillus GG) or a prebiotic (oats) by gavage. Ileal and colonic mucosal-attached microbiota composition were interrogated by Length Heterogeneity PCR (LH-PCR) fingerprinting. RESULTS Bacterial microbiota composition in alcohol-fed rats is not different from dextrose-fed rats at weeks 4 and 6. Mucosa-associated microbiota composition in the colon is altered at 10 weeks of daily alcohol gavage. Both LGG and oats prevented alcohol-induced dysbiosis up to 10 weeks of alcohol treatment. CONCLUSION Daily alcohol consumption for 10 weeks alters colonic mucosa-associated bacterial microbiota composition in rats. Our data showed, for the first time, that daily alcohol consumption can affect colonic microbiome composition and suggest that dysbiosis may be an important mechanism of alcohol-induced endotoxemia. Further studies are needed to determine how dysbiotic microbiota contributes to development of ALD and whether therapeutic interventions targeted towards dysbiotic microbiota can prevent complications of alcoholism like ALD.
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Affiliation(s)
- Ece Mutlu
- Rush University Medical Center, Division of Digestive Diseases and Nutrition, Nutrition Rush University Medical Center, Chicago, Illinois 60612, USA
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Tang Y, Forsyth CB, Farhadi A, Rangan J, Jakate S, Shaikh M, Banan A, Fields JZ, Keshavarzian A. Nitric oxide-mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage. Alcohol Clin Exp Res 2009; 33:1220-30. [PMID: 19389191 PMCID: PMC2950098 DOI: 10.1111/j.1530-0277.2009.00946.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) requires endotoxemia and is commonly associated with intestinal barrier leakiness. Using monolayers of intestinal epithelial cells as an in vitro barrier model, we showed that ethanol-induced intestinal barrier disruption is mediated by inducible nitric oxide synthase (iNOS) upregulation, nitric oxide (NO) overproduction, and oxidation/nitration of cytoskeletal proteins. We hypothesized that iNOS inhibitors [NG-nitro-l-arginine methyl ester (l-NAME), l-N(6)-(1-iminoethyl)-lysine (l-NIL)] in vivo will inhibit the above cascade and liver injury in an animal model of alcoholic steatohepatitis (ASH). METHODS Male Sprague-Dawley rats were gavaged daily with alcohol (6 g/kg/d) or dextrose for 10 weeks +/- l-NAME, l-NIL, or vehicle. Systemic and intestinal NO levels were measured by nitrites and nitrates in urine and tissue samples, oxidative damage to the intestinal mucosa by protein carbonyl and nitrotyrosine, intestinal permeability by urinary sugar tests, and liver injury by histological inflammation scores, liver fat, and myeloperoxidase activity. RESULTS Alcohol caused tissue oxidation, gut leakiness, endotoxemia, and ASH. l-NIL and l-NAME, but not the d-enantiomers, attenuated all steps in the alcohol-induced cascade including NO overproduction, oxidative tissue damage, gut leakiness, endotoxemia, hepatic inflammation, and liver injury. CONCLUSIONS The mechanism we reported for alcohol-induced intestinal barrier disruption in vitro - NO overproduction, oxidative tissue damage, leaky gut, endotoxemia, and liver injury - appears to be relevant in vivo in an animal model of alcohol-induced liver injury. That iNOS inhibitors attenuated all steps of this cascade suggests that prevention of this cascade in alcoholics will protect the liver against the injurious effects of chronic alcohol and that iNOS may be a useful target for prevention of ALD.
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Affiliation(s)
- Yueming Tang
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
| | - Christopher B. Forsyth
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
- Department of Biochemistry, Rush University, Chicago IL
| | - Ashkan Farhadi
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
- Department of Molecular Biophysics and Physiology, Rush University, Chicago IL
| | - Jayanthi Rangan
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
| | | | - Maliha Shaikh
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
| | - Ali Banan
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
- Department of Pharmacology, Rush University, Chicago IL
| | - Jeremy Z. Fields
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
| | - Ali Keshavarzian
- Department of Internal Medicine (Division of Digestive Diseases and Nutrition), Rush University, Chicago IL
- Department of Pharmacology, Rush University, Chicago IL
- Department of Molecular Biophysics and Physiology, Rush University, Chicago IL
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Keshavarzian A, Farhadi A, Forsyth CB, Rangan J, Jakate S, Shaikh M, Banan A, Fields JZ. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol 2009; 50:538-47. [PMID: 19155080 PMCID: PMC2680133 DOI: 10.1016/j.jhep.2008.10.028] [Citation(s) in RCA: 283] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Revised: 10/03/2008] [Accepted: 10/06/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Not all alcoholics develop liver disease (ALD). Thus, excessive ethanol consumption is necessary, but not sufficient, to induce alcoholic steatohepatitis (ASH) and ALD. Since endotoxemia is present in patients with ALD, it has been proposed that gut-derived, circulating endotoxin is the necessary co-factor for ASH. But, it is not known whether endotoxemia is the consequence or the trigger for ALD. Accordingly, the aim of the current study was to determine whether endotoxemia occurs prior to development of ASH and whether gut leakiness is the primary cause of the endotoxemia in an animal model of ASH. METHODS Time courses for development of gut hyperpermeability, nitric oxide production, oxidative injury to the gut, endotoxemia, and liver injury were assessed in rats during 10 weeks of daily alcohol gavage. RESULTS Liver fat and serum transaminase increased after 2 weeks, but evidence of liver cell injury and inflammation (ASH) occurred after 8 weeks. Gut leakiness, intestinal oxidative injury, and endotoxemia occurred in weeks 2-4 and progressed thereafter. CONCLUSIONS That alcohol-induced gut leakiness and endotoxemia preceded steatohepatitis indicates they are not the consequence of ALD. Our data support the hypothesis that gut leakiness resulting in endotoxemia is a key co-factor (trigger) for ASH.
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Affiliation(s)
- Ali Keshavarzian
- Department of Internal Medicine, Division of Digestive Disease and Nutrition, Rush University Medical Center, Chicago, IL 60612, USA.
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Iloprost Pretreatment Before Unilateral Nephrectomy: An Experimental Study in Rats. Asian J Surg 2008; 31:69-74. [DOI: 10.1016/s1015-9584(08)60061-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Tang Y, Banan A, Forsyth CB, Fields JZ, Lau CK, Zhang LJ, Keshavarzian A. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol Clin Exp Res 2007; 32:355-64. [PMID: 18162065 DOI: 10.1111/j.1530-0277.2007.00584.x] [Citation(s) in RCA: 222] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Alcohol-induced gut leakiness is a key factor in alcoholic liver disease (ALD); it allows endotoxin to enter the circulation and initiate liver damage. Zonula occludens 1 (ZO-1) protein is a major component of tight junctions that regulates intestinal permeability. microRNAs (miRNAs) are recently discovered regulatory molecules that inhibit expression of their target genes. THE AIMS OF OUR STUDY WERE (i) to investigate the effect of alcohol on miRNA-212 (miR-212) and on expression of its predicted target gene, ZO-1, (ii) to study the potential role of miR-212 in the pathophysiology of ALD in man. METHODS Using a TaqMan miRNA assay system, we measured miR-212 expression levels in colon biopsy samples from patients with ALD and in Caco-2 cells (a human intestinal epithelial cell line) treated with or without EtOH. We measured ZO-1 protein levels using western blots. ZO-1 mRNA was assayed using real-time PCR. Intestinal barrier integrity was measured using fluorescein sulfonic acid clearance and immunofluorescent staining for ZO-1. RESULTS Ethanol increased miR-212 expression, decreased ZO-1 protein levels, disrupted tight junctions, and increased the permeability of monolayers of Caco-2 cells. An miR-212 over-expression is correlated with hyperpermeability of the monolayer barrier. miR-212 levels were higher in colon biopsy samples in patients with ALD than in healthy controls; ZO-1 protein levels were lower. CONCLUSION These data suggest a novel mechanism for alcohol-induced gut leakiness, one in which EtOH induces miR-212 over-expression which causes gut leakiness by down-regulating ZO-1 translation. This mechanism is a potential therapeutic target for leaky gut in patients with or at risk for ALD.
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Affiliation(s)
- Yueming Tang
- Division of Digestive Disease and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois 60612, USA.
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López-Novoa JM, García-Estañ J. Nitric oxide and cirrhosis of the liver. Addict Biol 2006. [DOI: 10.1080/13556210020020085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Kumar AP, Ryan C, Cordy V, Reynolds WF. Inducible nitric oxide synthase expression is inhibited by myeloperoxidase. Nitric Oxide 2005; 13:42-53. [PMID: 15893945 DOI: 10.1016/j.niox.2005.04.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2004] [Revised: 03/23/2005] [Accepted: 04/01/2005] [Indexed: 12/18/2022]
Abstract
Nitric oxide (NO) plays key roles in vasodilation and host defense, yet the overproduction of NO by inducible nitric oxide synthase (iNOS) at inflammatory sites can also be pathogenic. Here, we investigate the role of MPO in modulating the induction of iNOS by IFNgamma/LPS (IL). In monocyte-macrophages (Mvarphi) treated with IL, MPO gene expression was found to be downregulated as iNOS was upregulated. In Mvarphi from MPO-knockout (KO) mice, the induction of iNOS by IL was earlier and higher than in MPO-positive cells, suggesting MPO is inhibitory. Consistent with that interpretation, the addition of purified MPO enzyme to cultured macrophages inhibited iNOS induction by IL. In addition, an inhibitor of MPO enzyme, 4-aminobenzohydrazide, enhanced iNOS induction in MPO-positive cells, but not in MPO-KO cells. Similarly, taurine, a scavenger of MPO-generated HOCl, enhanced iNOS induction in MPO-positive cells, but not in MPO-KO cells. MPO affects an early event, suppressing iNOS induction when added within 2h of IL, but not when added several hours after IL. The suppression by MPO was alleviated by NO donor, sodium nitroprusside, suggesting the suppression results from scavenging of NO by MPO. This interpretation is consistent with earlier reports that MPO consumes NO, and that low levels of NO donor augment induction of iNOS by IFNgamma/LPS. The implication of these findings is that MPO acts as gatekeeper, suppressing the deleterious induction of iNOS at inflammatory sites by illegitimate signals. The combined signaling of IFNgamma/LPS overrides the gatekeeper function by suppressing MPO gene expression.
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Affiliation(s)
- Alan P Kumar
- Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA
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Uzun H, Simsek G, Aydin S, Unal E, Karter Y, Yelmen NK, Vehid S, Curgunlu A, Kaya S. Potential effects of L-NAME on alcohol-induced oxidative stress. World J Gastroenterol 2005; 11:600-4. [PMID: 15641155 PMCID: PMC4250820 DOI: 10.3748/wjg.v11.i4.600] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Nitric oxide (NO) is a highly reactive oxidant synthesized from L-arginine by nitric oxide synthase (NOS). NO may cause injury through the generation of potent radicals. Nw- nitro-L-arginine methyl ester (L-NAME) is a non-selective inhibitor of NOS. We aimed to evaluate whether L-NAME treatment had protective effects against oxidative stress in rats intragastrically fed with ethanol during a 4 wk-period.
METHODS: Thirty-six male Wistar rats were divided into 3 equal groups: group 1 (control group-isocaloric dextrose was given), group 2 (6 g/kg·d ethanol-induced group) and group 3 (both ethanol 6 g/kg·d and L-NAME 500 mg/L in drinking water-given group). Animals were sacrificed at the end of 4 wk-experimental period, and intracardiac blood and liver tissues were obtained. Biochemical measurements were performed both in plasma and in homogenized liver tissues. Alanine amino transferase (ALT), aspartate amino transferase (AST), malondialdehyde (MDA), NO, superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels were measured by spectrophotometry.
RESULTS: ALT and AST in group 2 (62 U/L and 128 U/L, respectively) were higher than those in group 1 (24 U/L and 38 U/L) and group 3 (37 U/L and 81 U/L) (P<0.001 for both). Plasma and tissue levels of MDA in group 2 (4.66 μmol/L and 0.55 nmol/mg protein) were higher than in group 1 (2.65 μmol/L and 0.34 nmol/mg protein) and group 3 (3.43 μmol/L and 0.36 nmol/mg protein) (P<0.001 for both). Plasma and liver tissue levels of NO in group 2 (54.67 μmol/L and 586.50 nmol/mg protein) were higher than in group 1 (34.67 μmol/L and 435.33 nmol/mg protein) and group 3 (27.50 μmol/L and 412.75 nmol/mg protein ) (P<0.001 for both). Plasma and liver tissue SOD activities in group 2 (15.25 U/mL and 5.38 U/ mg protein, respectively) were lower than in group 1 (20.00 U/mL and 8.13 U/ mg protein) and group 3 (19.00 U/mL and 6.93 U/ mg protein) (P<0.001 for both). Plasma and liver tissue CAT activities in group 2 (145 U/mL and 37 U/ mg protein, respectively) were lower than in group 1 (176 U/mL and 73 U/mg protein) and group 3 (167 U/mL and 61 U/mg protein) (P<0.001 for both). Meanwhile, erythrocytes and liver tissue levels of GSH in group 2 (4.12 mg/g Hb and 5.38 nmol/mg protein, respectively) were lower than in group 1 (5.52 mg/g Hb and 4.49 nmol/mg protein) and group 3 (5.64 mg/g Hb and 4.18 nmol/mg protein) (P<0.001 for both).
CONCLUSION: Our findings show that L-NAME may produce a restorative effect on ethanol-induced liver damage via decreasing oxidative stress and increasing antioxidant status.
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Affiliation(s)
- Hafize Uzun
- Department of Biochemistry, Istanbul University, Cerrahpata School of Medicine, Istanbul, Turkey.
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18
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Yang YY, Lin HC, Huang YT, Lee TY, Hou MC, Lee FY, Liu RS, Chang FY, Lee SD. Effect of 1-week losartan administration on bile duct-ligated cirrhotic rats with portal hypertension. J Hepatol 2002; 36:600-6. [PMID: 11983442 DOI: 10.1016/s0168-8278(02)00037-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND/AIMS Nitric oxide and angiotensin play important roles in the pathogenesis of the hemodynamic derangement in cirrhosis and portal hypertension. The hemodynamic effects of losartan, an angiotensin II type 1 receptor antagonist, in cirrhotic patients with portal hypertension are conflicting. This study was undertaken to explore the possible mechanism of action of losartan on portal hypertension in cirrhotic rats produced by bile duct ligation (CBL). METHODS Three weeks after surgery, CBL and sham-operated rats randomly received vehicle or losartan (3 mg/kg per 12 h by gavage) for 1 week. Hemodynamic values, hormone levels, and aortic eNOS protein expression were measured after drug administration. RESULTS In CBL rats, 1-week losartan treatment decreased portal pressure and ameliorated hyperdynamic circulation associated with a blunted vascular response to N(omega)-nitro-L-arginine methyl ester infusion. The hematocrit increased and the plasma volume, aldosterone, plasma renin activity, norepinephrine, and nitrate and nitrite levels decreased. The eNOS protein expression was reduced in CBL rats receiving losartan compared with those receiving vehicle. CONCLUSIONS One-week losartan treatment in CBL rats decreased portal pressure and ameliorated hyperdynamic circulation. In addition to the suppression of renin-angiotensin axis, the reduced aortic eNOS protein expression may play a partial role for the mechanism of action of losartan in CBL rats.
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Affiliation(s)
- Ying-Ying Yang
- Division of Gastroenterology, Department of Medicine, National Yang-Ming University School of Medicine and Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan
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19
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Saibara T, Ono M, Iwasaki S, Maeda T, Onishi S, Hayashi And Y, Enzan H. Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production. Alcohol Clin Exp Res 2001. [PMID: 11410740 DOI: 10.1111/j.1530-0277.2001.tb02416.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat-storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine. The precise mechanism that controls NO production in stellate cells was characterized recently. METHODS Kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L-arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. RESULTS The L-arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT-1 and CAT-2B (Km approximately 50 microM). IFN-gamma in combination with TNF-alpha induced NO production with an enhancement in CAT-2B mRNA expression and L-arginine transport, whereas L-arginine transport and NO production were suppressed by coincubated ethanol. CONCLUSIONS In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L-arginine transport in the presence of TNF-alpha and IFN-gamma. The estimated Km of L-arginine transporter in hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L-arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.
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Affiliation(s)
- T Saibara
- First Department of Medicine, Kochi Medical School, Nankoku 783, Japan.
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20
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Yang YY, Lin HC, Huang YT, Lee TY, Lee WC, Hou MC, Lee FY, Chang FY, Lee SD. Adaptive vasodilatory response after octreotide treatment. Am J Physiol Gastrointest Liver Physiol 2001; 281:G117-23. [PMID: 11408262 DOI: 10.1152/ajpgi.2001.281.1.g117] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Despite the suppression of glucagon release, an adaptive response aimed at maintaining vasodilatation after octreotide treatment may exist in portal hypertension. The present study was undertaken to evaluate the possible interaction between endothelium and non-endothelium-derived vasodilators after 1-wk octreotide administration in cirrhotic rats. Rats were allocated to receive either vehicle or octreotide (30 or 100 microg/kg every 12 h subcutaneously). Hemodynamic values, plasma glucagon levels, endothelium-related vasodilatory activities, and aortic endothelial nitric oxide synthase (eNOS) expression were determined after treatment. Octreotide administration decreased plasma glucagon and increased serum 6-keto-PGF(1 alpha) and NOx levels without affecting the hemodynamic values. In cirrhotic rats receiving octreotide, there was a blunt response to either L-NAME or indomethacin administration alone, but this blunt pressor response disappeared after simultaneous administration of the two drugs. Additionally, an increased aortic eNOS expression was observed in cirrhotic rats receiving 1-wk octreotide. It is concluded that 1-wk octreotide treatment did not correct the hemodynamic derangement in cirrhotic rats. The enhanced endothelium-related vasodilatory activity was noted after octreotide treatment that overcame the octreotide-induced hemodynamic effects in portal hypertension.
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Affiliation(s)
- Y Y Yang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taiwan
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21
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Saibara T, Ono M, Iwasaki S, Maeda T, Onishi S, Hayashi And Y, Enzan H. Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production. Alcohol Clin Exp Res 2001; 25:39S-45S. [PMID: 11410740 DOI: 10.1097/00000374-200106001-00010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat-storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine. The precise mechanism that controls NO production in stellate cells was characterized recently. METHODS Kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L-arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. RESULTS The L-arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT-1 and CAT-2B (Km approximately 50 microM). IFN-gamma in combination with TNF-alpha induced NO production with an enhancement in CAT-2B mRNA expression and L-arginine transport, whereas L-arginine transport and NO production were suppressed by coincubated ethanol. CONCLUSIONS In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L-arginine transport in the presence of TNF-alpha and IFN-gamma. The estimated Km of L-arginine transporter in hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L-arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.
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Affiliation(s)
- T Saibara
- First Department of Medicine, Kochi Medical School, Nankoku 783, Japan.
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22
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Chu CJ, Wang SS, Lee FY, Chang FY, Lin HC, Hou MC, Chan CC, Wu SL, Chen CT, Huang HC, Lee SD. Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure. Eur J Clin Invest 2001; 31:156-63. [PMID: 11168455 DOI: 10.1046/j.1365-2362.2001.00775.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatic encephalopathy is a complex neuropsychiatric syndrome seen secondary to acute liver failure, chronic parenchymal liver disease, or portal-systemic anastomosis. Vasodilatation induced by nitric oxide (NO) may be involved in the development of hepatic coma. However, there are no comprehensive data concerning the effects of NO inhibition on the severity of hepatic encephalopathy. Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of thioacetamide (TAA, 350 mg kg-1 day-1) for 3 days. Rats were divided into two groups to receive either NG-nitro-L-arginine methyl ester (L-NAME, 20 mg kg-1 day-1 via intragastric gavage) or normal saline (N/S) from 2 days prior to TAA administration for 5 days. Severity of encephalopathy was assessed by counts of motor activity and neurobehaviour test scores. Plasma levels of endotoxin, tumour necrosis factor-alpha and nitrate/nitrite were determined by the chromogenic Limulus assay, enzyme-linked immunosorbent assay and colorimetric assay, respectively. Compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving L-NAME (59% vs. 18%, P < 0.01). Inhibition of NO had detrimental effects on the counts of motor activities (P < 0.05) and neurobehaviour score (P < 0.01). Rats treated with L-NAME had significantly higher plasma levels of endotoxin (26.7 +/- 3.8 pg mL-1) and tumour necrosis factor-alpha (29.4 +/- 6.5 pg mL-1) compared with rats treated with N/S (13.2 +/- 2.7 pg mL-1 and 11.2 +/- 2.6 pg mL-1, respectively, P < 0.01). Plasma levels of endotoxin and tumour necrosis factor-alpha, but not of nitrate/nitrite, were significantly correlated with the severity of hepatic encephalopathy (P < 0.05). Chronic L-NAME administration had detrimental effects on the severity of encephalopathy in TAA-treated rats, suggesting a protective role of NO in the development of fulminant hepatic failure.
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Affiliation(s)
- C J Chu
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China
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Zima T, Fialová L, Mestek O, Janebová M, Crkovská J, Malbohan I, Stípek S, Mikulíková L, Popov P. Oxidative stress, metabolism of ethanol and alcohol-related diseases. J Biomed Sci 2001; 8:59-70. [PMID: 11173977 DOI: 10.1007/bf02255972] [Citation(s) in RCA: 200] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Three metabolic pathways of ethanol have been described in the human body so far. They involve the following enzymes: alcohol dehydrogenase, microsomal ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals which affect the antioxidant system. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, which results in the production of superoxide. Lipid peroxidation and superoxide production correlate with the amount of cytochrome P450 2E1. MEOS aggravates the oxidative stress directly as well as indirectly by impairing the defense systems. Hydroxyethyl radicals are probably involved in the alkylation of hepatic proteins. Nitric oxide (NO) is one of the key factors contributing to the vessel wall homeostasis, an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metabolites--nitrites and nitrates--were increased in alcoholics (34.3 +/- 2.6 vs. 22.7 +/- 1.2 micromol/l, p < 0.001). High NO concentration could be discussed for its excitotoxicity and may be linked to cytotoxicity in neurons, glia and myelin. Formation of NO has been linked to an increased preference for and tolerance to alcohol in recent studies. Increased NO biosynthesis also via inducible NO synthase (NOS, chronic stimulation) may contribute to platelet and endothelial dysfunctions. Comparison of chronically ethanol-fed rats and controls demonstrates that exposure to ethanol causes a decrease in NADPH diaphorase activity (neuronal NOS) in neurons and fibers of the cerebellar cortex and superior colliculus (stratum griseum superficiale and intermedium) in rats. These changes in the highly organized structure contribute to the motor disturbances, which are associated with alcohol abuse. Antiphospholipid antibodies (APA) in alcoholic patients seem to reflect membrane lesions, impairment of immunological reactivity, liver disease progression, and they correlate significantly with the disease severity. The low-density lipoprotein (LDL) oxidation is supposed to be one of the most important pathogenic mechanisms of atherogenesis, and antibodies against oxidized LDL (oxLDL) are some kind of epiphenomenon of this process. We studied IgG oxLDL and four APA (anticardiolipin, antiphosphatidylserine, antiphosphatidylethanolamine and antiphosphatidylcholine antibodies). The IgG oxLDL (406.4 +/- 52.5 vs. 499.9 +/- 52.5 mU/ml) was not affected in alcoholic patients, but oxLDL was higher (71.6 +/- 4.1 vs. 44.2 +/- 2.7 micromol/l, p < 0.001). The prevalence of studied APA in alcoholics with mildly affected liver function was higher than in controls, but not significantly. On the contrary, changes of autoantibodies to IgG oxLDL revealed a wide range of IgG oxLDL titers in a healthy population. These parameters do not appear to be very promising for the evaluation of the risk of atherosclerosis. Free radicals increase the oxidative modification of LDL. This is one of the most important mechanisms, which increases cardiovascular risk in chronic alcoholic patients. Important enzymatic antioxidant systems - superoxide dismutase and glutathione peroxidase - are decreased in alcoholics. We did not find any changes of serum retinol and tocopherol concentrations in alcoholics, and blood and plasma selenium and copper levels were unchanged as well. Only the zinc concentration was decreased in plasma. It could be related to the impairment of the immune system in alcoholics. Measurement of these parameters in blood compartments does not seem to indicate a possible organ, e.g. liver deficiency.
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Affiliation(s)
- T Zima
- Institute of Clinical Chemistry, First Faculty of Medicine, Charles University, Karlovo nám. 32, CZ-121 11 Prague 2, Czech Republic.
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Abstract
Endotoxin induces nitric oxide (NO*) synthase and alters gastrointestinal functions. We explored the effect of lipopolysaccharide (LPS) on oesophageal motor function at 6, 12, 24, and 48 h. The effects of inhibiting inducible NO* synthase (iNOS) were studied 12 h after administration of LPS with/without aminoguanidine (AG). Oesophageal manometry was performed and tissue bath studies were performed with muscle strips from the oesophagus and lower oesophageal sphincter (LOS). Plasma nitrite/nitrate concentrations were determined. The amplitudes of peristaltic pressure waves, resting LOS pressure and the percentage LOS relaxations were diminished by LPS. AG attenuated the decrease in amplitude of oesophageal pressure waves, LOS pressure, and percentage relaxation of LOS brought about by LPS. LPS decreased electrical field stimulation (EFS)-induced relaxation of LOS muscle. AG attenuated this decrease in LOS relaxation. The off-response of transverse oesophageal muscle strips was decreased, and AG antagonized this effect. Plasma concentrations of nitrite/nitrate were increased. The increase in plasma nitrite/nitrate was attenuated by AG. These studies support the hypothesis that endotoxin modulates oesophageal motor function by increasing NO production and suggest that this results from the induction of iNOS.
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Affiliation(s)
- H Park
- Department of Internal Medicine, University of Iowa, College of Medicine and VA Medical Center, Iowa City, USA.
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25
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Martin JF, Smith RE, Mathur A. Endogenous mediators and thrombophilia. Best Pract Res Clin Haematol 1999; 12:373-86. [PMID: 10856976 DOI: 10.1053/beha.1999.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Platelets are one of the most important components of primary haemostasis. Since they lack a nucleus, their functional characteristics are determined at the time of production. The role of platelets in thrombosis is further modified by the interaction with vascular mediators that are endogenously produced in response to a variety of stimuli. This chapter discusses the factors that influence platelet production, the interaction with endogenous mediators, and the potential therapeutic benefits achieved by modifying this interaction in the clinical setting.
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Affiliation(s)
- J F Martin
- Centre for Vascular Biology and Medicine, Department of Medicine, University College London, UK
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Rich EA, Torres M, Sada E, Finegan CK, Hamilton BD, Toossi Z. Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB. TUBERCLE AND LUNG DISEASE : THE OFFICIAL JOURNAL OF THE INTERNATIONAL UNION AGAINST TUBERCULOSIS AND LUNG DISEASE 1999; 78:247-55. [PMID: 10209679 DOI: 10.1016/s0962-8479(97)90005-8] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SETTING Although nitric oxide (NO) is a major proximate mediator of microbicidal activity in murine macrophages against intracellular pathogens including mycobacteria, its production by and effector role in human macrophages is not clear. OBJECTIVE To determine the capacity of Mycobacterium tuberculosis (MTB) to stimulate NO in human monocytes (MN) and alveolar macrophages (AM) and to assess the relationship between NO production and intracellular growth of MTB. DESIGN NO production (measured as nitrite) by MTB (H37Ra)-infected macrophages and intracellular growth of MTB were measured in cells from 17 healthy subjects. RESULTS MTB (5:1, MTB:cells) stimulated little to no NO by MN, but induced NO in AM at days 4 and 7 after infection. There was, however, variability in the response by AM to MTB: among seven subjects MTB-induced NO was low (4 +/- 2 microM, mean +/- SE); six subjects were moderate (56 +/- 11); four subjects were high (502 +/- 167). NO synthase inhibitors inhibited the production of NO by AM but did not significantly affect the intracellular growth of MTB, although a trend towards increased intracellular growth was seen on day 4 of culture. Intracellular growth of MTB in AM from low NO producers was significantly higher than that in AM from moderate NO producers, P < or = 0.05. Inducible NO synthase (iNOS) mRNA by RT-PCR was constitutively expressed by both MN and AM, but was further stimulated by MTB in AM > MN; MTB-induced iNOS protein was present in both MN and AM by Western blot analysis. CONCLUSION Thus, MTB-infected human AM are capable of producing NO and NO production correlates with intracellular growth inhibition of MTB in AM suggesting that NO may serve either directly or indirectly as a mycobactericidal mediator in human tissue macrophages.
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Affiliation(s)
- E A Rich
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4984, USA
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27
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Weinberg JB. Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review. Mol Med 1999. [PMID: 9848075 PMCID: PMC2230318 DOI: 10.1007/bf03401758] [Citation(s) in RCA: 127] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Affiliation(s)
- J B Weinberg
- VA University Medical Center, Durham, North Carolina, USA.
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Garcia-Tsao G, Angulo P, Garcia JC, Groszmann RJ, Cadelina GW. The diagnostic and predictive value of ascites nitric oxide levels in patients with spontaneous bacterial peritonitis. Hepatology 1998; 28:17-21. [PMID: 9657091 DOI: 10.1002/hep.510280104] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Nitric oxide (NO) is a messenger molecule involved in pathogen suppression. Cirrhosis is characterized by an increased risk for infections, including spontaneous bacterial peritonitis (SBP). The role of NO in the infections that develop in cirrhosis has not been clearly established. The aim of this study was to investigate the utility of measuring ascites NO in the diagnosis of SBP and/or in determining the predisposition of cirrhotic patients to develop this infection. Nitric oxide metabolites (nitrites + nitrates [NOx]) were measured by chemiluminescence in 105 ascites samples obtained from 87 cirrhotic patients and in 87 simultaneously obtained serum samples. Ascites NO levels were not significantly different among ascites from patients with SBP (n = 39; median, 48 micromol/L), patients with sterile ascites (n = 54; median, 42 micromol/L), and samples obtained after patients with SBP had been treated (n = 12; median, 62 micromol/L). No differences in ascites NO levels were observed between culture-positive and culture-negative peritonitis. Among 50 patients with sterile ascites on initial paracentesis, 7 patients developed peritonitis during follow-up; no differences in baseline NO levels were observed between patients who developed peritonitis (median, 46 micromol/L) and those who did not (median, 41 micromol/L). Among patients with SBP, mortality was significantly higher in those with NO levels >60 micromol/L. A very significant direct correlation was found between ascites and serum NO levels (r2 = .86). In conclusion, ascites NO levels in cirrhotic patients are not useful either to diagnose or to determine predisposition to SBP. Rather, ascites NO levels reflect serum levels, are higher in cirrhotic patients with more severe liver disease, and may be a useful prognostic marker.
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Affiliation(s)
- G Garcia-Tsao
- Hepatic Hemodynamic Laboratory, West Haven VA Medical Center, CT, USA
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Sansone GR, Matin A, Wang SF, Bouboulis D, Frieri M. Theophylline inhibits the production of nitric oxide by peripheral blood mononuclear cells from patients with asthma. Ann Allergy Asthma Immunol 1998; 81:90-5. [PMID: 9690578 DOI: 10.1016/s1081-1206(10)63114-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Nitric oxide (NO), a reactive free radical synthesized from L-arginine by the enzyme NO synthase (NOS), may play a role in many pathophysiologic conditions, including asthma. OBJECTIVE The aim of this study was to investigate whether peripheral blood mononuclear cells (PBMCs) from asthmatics would spontaneously produce NO. A second objective was to ascertain whether commonly used asthma medications would modulate the production of NO. METHODS PBMCs were isolated from 24 subjects (10 with asthma, 4 with allergic rhinitis and 10 healthy controls) and were incubated either alone or in the presence of an RNA polymerase inhibitor (actinomycin D, 1 microg/mL), a NOS inhibitor (L-NG-nitroarginine methyl ester [L-NAME], 1 mM), and L-NAME plus L-arginine (5 mM). Furthermore, PBMCs were incubated with or without addition of therapeutic concentrations of hydrocortisone (15 microg/mL), theophylline (15 microg/mL), albuterol (15 microg/mL) and ipratropium bromide (12 microg/mL). Culture supernatants were collected and assayed for NO production. RESULTS NO production was significantly elevated in asthmatics compared with the control group (1.39+/-0.21 microM versus 0.46+/-0.01 microM; P < .05). L-NAME significantly reduced NO production in asthmatics (0.83+/-0.06 microM; P < .05), an effect completely reversed by L-arginine. Theophylline blocked NO production in asthmatics (1.39+/-0.21 microM to 0.92+/-0.11; P < .05). There was no significant effect with any of the other medications. CONCLUSION This study suggests that theophylline may be antiinflammatory by inhibiting the L-arginine-dependent production of NO in patients with asthma.
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Affiliation(s)
- G R Sansone
- Department of Pathology, Nassau County Medical Center, State University of New York at Stony Brook, East Meadow 11554, USA
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Calò L, Davis PA, Milani M, Antonello A, Cantaro S, D'Angelo A, Fagiolo U. Constitutive endothelial nitric oxide synthase (ecNOS) gene expression in human monocytes. Angiology 1998; 49:419-22. [PMID: 9631886 DOI: 10.1177/000331979804900601] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This study evaluates using a polymerase chain reaction (PCR)-based molecular biological approach to study the gene expression of the constitutive endothelial isoform of nitric oxide synthase (ecNOS) in human monocytes. When PCR was carried out with specific primers for ecNOS, 302 bp product was amplified, which sequence analysis determined as having 100% identity to the reported human ecNOS isoform gene sequence. The data presented here demonstrate a reliable technique for assessing ecNOS mRNA levels in circulating human monocytes. This then permits use of this easily available cell to monitor ecNOS levels and provides a means to investigate mechanisms involved in controlling NO synthase levels as well as NO synthesis.
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Affiliation(s)
- L Calò
- Institute of Internal Medicine, Division of Nephrology, Laboratory of Molecular Biology, University of Padova, Padua, Italy
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Saha DC, Astiz ME, Lin RY, Rackow EC, Eales LJ. Monophosphoryl lipid A stimulated up-regulation of nitric oxide synthase and nitric oxide release by human monocytes in vitro. IMMUNOPHARMACOLOGY 1997; 37:175-84. [PMID: 9403336 DOI: 10.1016/s0162-3109(97)00045-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Monophosphoryl lipid A (MPL) is a derivative of lipopolysaccharide (LPS) with reduced toxicity which has been shown to modulate various immune functions in monocytes. We examined whether human monocytes can be stimulated to produce nitric oxide (NO) and its catalytic enzyme nitric oxide synthase (NOS). Monocytes were stimulated with LPS or MPL and both NOS and NO (as nitrite) production were measured. MPL at high doses (> 100 micrograms/ml) stimulated monocytes to release NO that was significantly greater than both the control and LPS-treated monocytes (p < 0.05). NO release by control cells and the LPS treated cells was not significantly different. Both arginase and N-monomethyl arginine (NMLA) inhibited the MPL stimulated release of NO (p < 0.01). MPL significantly increased inducible NOS (iNOS) expression as measured by both fluorescent microscopy and flow cytometry (p < 0.05). Similarly, both soluble NOS (sNOS) and particulate NOS (pNOS) activity were significantly up-regulated by MPL (p < 0.05). Significant correlations were found between pNOS expression and sNOS release (r = 0.72, p < 0.0001) and between 12 h NO release and sNOS production (r = 0.44, p < 0.005). These experiments confirm that human monocytes can be stimulated with MPL to produce NO in vitro and suggest that up-regulation of pNOS does not preclude NO release.
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Affiliation(s)
- D C Saha
- Department of Medicine, Saint Vincents Hospital, New York, NY, USA
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Chu CJ, Lee FY, Wang SS, Chang FY, Tsai YT, Lin HC, Hou MC, Wu SL, Tai CC, Lee SD. Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide. Scand J Gastroenterol 1997; 32:841-6. [PMID: 9282979 DOI: 10.3109/00365529708996544] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.
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Affiliation(s)
- C J Chu
- Dept. of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taiwan
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Abstract
At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
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Affiliation(s)
- J MacMicking
- Department of Medicine, Cornell University Medical College, New York, NY 10021, USA
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Radomski MW, Moncada S. Regulation of Platelet Function by Nitric Oxide. ACTA ACUST UNITED AC 1997. [DOI: 10.1016/s1569-2558(08)60422-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
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Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 1996; 9:532-62. [PMID: 8894351 PMCID: PMC172909 DOI: 10.1128/cmr.9.4.532] [Citation(s) in RCA: 451] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
In the mid-1980s, Mosmann, Coffman, and their colleagues discovered that murine CD4+ helper T-cell clones could be distinguished by the cytokines they synthesized. The isolation of human Th1 and Th2 clones by Romagnani and coworkers in the early 1990s has led to a large number of reports on the effects of Th1 and Th2 on the human immune system. More recently, cells other than CD4+ T cells, including CD8+ T cells, monocytes, NK cells, B cells, eosinophils, mast cells, basophils, and other cells, have been shown to be capable of producing "Th1" and "Th2" cytokines. In this review, we examine the literature on human diseases, using the nomenclature of type 1 (Th1-like) and type 2 (Th2-like) cytokines, which includes all cell types producing these cytokines rather than only CD4+ T cells. Type 1 cytokines include interleukin-2 (IL-2), gamma interferon, IL-12 and tumor necrosis factor beta, while type 2 cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. In general, type 1 cytokines favor the development of a strong cellular immune response whereas type 2 cytokines favor a strong humoral immune response. Some of these type 1 and type 2 cytokines are cross-regulatory. For example, gamma interferon and IL-12 decrease the levels of type 2 cytokines whereas IL-4 and IL-10 decrease the levels of type 1 cytokines. We use this cytokine perspective to examine human diseases including infections due to viruses, bacteria, parasites, and fungi, as well as selected neoplastic, atopic, rheumatologic, autoimmune, and idiopathic-inflammatory conditions. Clinically, type 1 cytokine-predominant responses should be suspected in any delayed-type hypersensitivity-like granulomatous reactions and in infections with intracellular pathogens, whereas conditions involving hypergammaglobulinemia, increased immunoglobulin E levels, and/or eosinophilia are suggestive of type 2 cytokine-predominant conditions. If this immunologic concept is relevant to human diseases, the potential exists for novel cytokine-based therapies and novel cytokine-directed preventive vaccines for such diseases.
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Affiliation(s)
- D R Lucey
- Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA
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36
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Torre D, Ferrario G, Speranza F, Orani A, Fiori GP, Zeroli C. Serum concentrations of nitrite in patients with HIV-1 infection. J Clin Pathol 1996; 49:574-6. [PMID: 8813957 PMCID: PMC500573 DOI: 10.1136/jcp.49.7.574] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
AIMS To measure circulating concentrations of nitrite in patients with HIV-1 infection. METHODS Nitrite concentrations were measured using the Griess reaction adapted to microtitre plates in the serum of 10 asymptomatic HIV-1 positive patients, 33 patients with AIDS with cerebral disorders, 17 patients with AIDS with pulmonary involvement, and in eight patients with AIDS with other disorders. Nitrite concentrations were also measured in bronchoalveolar lavage (BAL) fluid and cerebrospinal fluid (CSF) of patients with AIDS with pulmonary involvement and cerebral disorders, respectively. RESULTS Increased serum concentrations of nitrite were observed in patients with pulmonary involvement, and in particular in serum and in BAL samples of patients with interstitial pneumonia (36.2 (26.2) mumol/l and 0.3 (0.4) mumol/l, respectively). Increased serum concentrations of nitrite were also noted in patients with retinitis caused by infection with cytomegalovirus. Serum nitrite concentrations were also raised in patients with cerebral toxoplasmosis, whereas normal serum concentrations were found in patients with HIV-1 encephalopathy and cryptococcal meningitis. Nitrite concentrations in CSF were not raised in patients with cerebral disorders. CONCLUSIONS These results suggest that production of nitrite in patients with AIDS with concomitant opportunistic infections may be part of the host defense against opportunistic organisms.
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Affiliation(s)
- D Torre
- Division of Infectious Diseases, Regional Hospital, Varese, Italy
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37
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Noris M, Ruggenenti P, Todeschini M, Figliuzzi M, Macconi D, Zoja C, Paris S, Gaspari F, Remuzzi G. Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury. Am J Kidney Dis 1996; 27:790-6. [PMID: 8651242 DOI: 10.1016/s0272-6386(96)90515-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The term thrombotic microangiopathy (TMA) has been used extensively to encompass hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, two syndromes of hemolytic anemia, and thrombocytopenia associated with renal or brain involvement or both. There is evidence that endothelial damage is a crucial feature in the sequence of events that precedes the development of microvascular lesions. More recent studies would suggest that endothelial dysfunction could be a consequence of neutrophil activation. Activated neutrophils generate superoxide anions (O2-) that, combining with endothelial-derived nitric oxide (NO), form the highly cytotoxic hydroxyl radical. Seven patients with recurrent forms of TMA and seven healthy volunteers were studied. Plasma concentrations of the NO metabolites, nitrites/nitrates, were elevated in the acute phase of TMA, indicating an increased NO synthesis in vivo. In addition, elevated serum concentrations of tumor necrosis factor, a potent inducer of endothelial NO synthase, were found in acute TMA. Serum from patients with acute TMA induced NO synthesis in cultured endothelial cells more than normal serum. Enhanced stimulatory activity was no longer found in the recovery phase. Release of O2- by neutrophils ex vivo was higher than normal in patients with acute TMA, but decreased in the recovery phase. Exactly the same trend was observed for plasma malondialdehyde and conjugated dienes, indicating that excessive oxygen radical formation in acute TMA is associated with increased lipid peroxidation. Thus, in recurrent forms of TMA, NO formation was increased as compared with controls. This was associated with signs of lipid peroxidation, likely the consequence of the interaction of NO with neutrophil-derived oxygen products.
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Affiliation(s)
- M Noris
- Mario Negri Institute for Pharmacological Research, Ospedali Riuniti diBergamo, Rome, Italy
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Nicholson S, Bonecini-Almeida MDG, Lapa e Silva JR, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, Linhares C, Rom W, Ho JL. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 1996; 183:2293-302. [PMID: 8642338 PMCID: PMC2192561 DOI: 10.1084/jem.183.5.2293] [Citation(s) in RCA: 349] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2.
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Affiliation(s)
- S Nicholson
- Beatrice and Samuel A. Seaver Laboratory, Division of Hematology-Oncology Cornell University Medical College, New York 10021, USA
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40
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Duchini A. The role of central nervous system endothelial cell activation in the pathogenesis of hepatic encephalopathy. Med Hypotheses 1996; 46:239-44. [PMID: 8676759 DOI: 10.1016/s0306-9877(96)90248-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
I propose that central nervous system endothelial cells are directly or indirectly responsible for the brain pathology in hepatic encephalopathy, and that this damage to the central nervous system is mediated by specific cytokines and nitric oxide which activate endothelial cells and thereby alter their cell functions. Liver diseases are conditions characterized by high circulating levels of cytokines, namely interleukin-1, interleukin-6 and tumor necrosis factor. Interactions between these cytokines and central nervous system endothelial cells may trigger a cascade of events including enhanced blood-brain barrier permeability, brain edema, astrocyte alterations and gliosis. Cytokine-induced production of nitrogen reactive molecules by endothelial cells themselves may also lead to further cellular damage and neuronal dysfunction. This hypothesis may explain several characteristics of hepatic encephalopathy including reversibility, disease progression and clinical features. It also suggests potential ways of intervention.
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Affiliation(s)
- A Duchini
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030-2707, USA
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O'Brien L, Roberts B, Andrew PW. In vitro interaction of Mycobacterium tuberculosis and macrophages: activation of anti-mycobacterial activity of macrophages and mechanisms of anti-mycobacterial activity. Curr Top Microbiol Immunol 1996; 215:97-130. [PMID: 8791711 DOI: 10.1007/978-3-642-80166-2_5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- L O'Brien
- Department of Microbiology and Immunology, University of Leicester, UK
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42
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Dugas B, Mossalayi MD, Damais C, Kolb JP. Nitric oxide production by human monocytes: evidence for a role of CD23. IMMUNOLOGY TODAY 1995; 16:574-80. [PMID: 8579750 DOI: 10.1016/0167-5699(95)80080-8] [Citation(s) in RCA: 137] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nitric oxide (NO) appears to be an important and pleiotropic bioregulator of immune responses. The existence of the NO synthase (NOS) pathway in human monocytes/macrophages remains a subject of controversy, despite an increasing number of reports suggesting that human monocytes produce NO in vitro in response to various stimuli. Here, Bernard Dugas and colleagues consider the arguments supporting these conclusions, with particular emphasis on the results obtained by ligation of the low-affinity IgE receptor (Fcepsilon RIIb/CD23b).
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Affiliation(s)
- B Dugas
- Immunohematology group, CNRS URA 625, Hôpital La Pitié Salpêtrière, Paris, France
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43
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Fehsel K, Kröncke KD, Kolb-Bachofen V. The action of NO and its role in autoimmune diabetes mellitus. RESEARCH IN IMMUNOLOGY 1995; 146:711-5. [PMID: 8852617 DOI: 10.1016/0923-2494(96)84924-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- K Fehsel
- Immunobiology, Biomedical Research Centre, MED-Heinrich-Heine-University, Düsseldorf, Germany
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Reynolds PD, Middleton SJ, Shorthouse M, Hunter JO. The effects of aminosalicylic acid derivatives on nitric oxide in a cell-free system. Aliment Pharmacol Ther 1995; 9:491-5. [PMID: 8580268 DOI: 10.1111/j.1365-2036.1995.tb00411.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
AIMS AND METHODS To determine the effect of aminosalicylic acid derivatives on the concentration of nitric oxide produced in a cell-free system, by the use of a sensitive and specific polarographic meter. RESULTS The aminosalicylic acid derivatives 3-ASA (IC50 100 microM), 4-ASA (IC50 350 microM) and 5-ASA (IC50 5 microM) all decreased the nitric oxide signal. These drugs had a similar inhibitory effect on the formation in vitro of nitrite from sodium nitroprusside (IC50: 200 microM, 500 microM and 100 microM, respectively). Sulphasalazine (31.1 +/- 5% decrease in signal at 1 mM) was less effective than 5-ASA, but sulphapyridine, N-acetyl 5-ASA, indomethacin and hydrocortisone produced no decrease in nitric oxide signal at all. CONCLUSIONS Nitric oxide binding may be part of the mechanism by which ASA derivatives exert their therapeutic effect, and this work suggests that it may be an important factor in the pathogenesis of ulcerative colitis.
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Affiliation(s)
- P D Reynolds
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, UK
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45
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Stichtenoth DO, Fauler J, Zeidler H, Frölich JC. Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone. Ann Rheum Dis 1995; 54:820-4. [PMID: 7492221 PMCID: PMC1010017 DOI: 10.1136/ard.54.10.820] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES To determine daily production of nitric oxide (NO) measured as urinary nitrate excretion, and the effect of prednisolone in patients with rheumatoid arthritis (RA). METHODS Twenty four hour urinary nitrate was measured by gas chromatography in 10 patients with RA, before and two to four weeks after commencement of prednisolone 0.5 mg/kg body weight, and in 18 healthy controls. RESULTS Before the start of prednisolone treatment the urinary nitrate excretion in patients with RA was 2.7-fold greater (p < 0.001) than that in healthy volunteers. After prednisolone it decreased significantly, by 28%, at which time inflammatory activity (as indicated by C reactive protein, erythrocyte sedimentation rate, joint count, and early morning stiffness) was also reduced considerably. Despite this decrease, the urinary nitrate excretion in patients with RA remained twice that in the control group (p < 0.05). CONCLUSIONS Our data suggest that the endogenous production of NO is enhanced in patients with RA. Furthermore, the results indicate that, in parallel with suppression of inflammation, this increased NO synthesis could be reduced by prednisolone treatment.
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Affiliation(s)
- D O Stichtenoth
- Department of Clinical Pharmacology, Hannover Medical School, Germany
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46
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Affiliation(s)
- W E Lands
- Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland 20892-7003, USA
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47
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Kontoghiorghes GJ, Weinberg ED. Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches. Blood Rev 1995; 9:33-45. [PMID: 7795423 DOI: 10.1016/0268-960x(95)90038-1] [Citation(s) in RCA: 98] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
During the past 6 decades, much attention has been devoted to understanding the uses, metabolism and hazards of iron in living systems. A great variety of heme and non-heme iron-containing enzymes have been characterized in nearly all forms of life. The existence of both ferrous and ferric ions in low- and high-spin configuration, as well as the ability of the metal to function over a wide range of redox potentials, contributes to its unique versatility. Not surprisingly, the singular attributes of iron that permit it to be so useful to life likewise render the metal dangerous to manipulate and to sequester. All vertebrate animals are prone to tissue damage from exposure to excess iron. In order to protect them from this threat, a complex system has evolved to contain and detoxify this metal. This is known as the iron withholding defense system, which mainly serves to scavenge toxic quantities of iron and also for depriving microbial and neoplastic invaders of iron essential for their growth. Since 1970, medical scientists have become increasingly aware of the problems involved in cellular iron homeostasis and of the disease states related to its malfunctioning. Scores of studies have reported that excessive iron in specific tissue sites is associated with development of infection, neoplasia, cardiomyopathy, arthropathy and a variety of endocrine and neurologic deficits. Accordingly, several research groups have attempted to develop chemical agents that might prevent and even eliminate deposits of excess iron. A few of these drugs now are in clinical use, e.g. deferiprone (L1). In the present review, we focus on recent developments in (i) selected aspects of the iron withholding defense system, and (ii) pharmacologic methods that can assist the iron-burdened patient.
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Affiliation(s)
- G J Kontoghiorghes
- Department of Haematology, Royal Free Hospital School of Medicine, University of London
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Hiraoka E, Nonami T, Kurokawa T, Kobayashi H, Takagi H. The role of the spleen in endotoxin-induced liver injury. LIVER 1995; 15:35-8. [PMID: 7776855 DOI: 10.1111/j.1600-0676.1995.tb00104.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In these experiments, the role of the spleen in endotoxin-induced liver injury was evaluated, using rats which underwent splenectomy or splenic vein ligation with antecedent spleno-systemic shunt. Male Wistar rats were divided into three groups: a sham-operated group, a splenectomy group, and a splenic vein ligation group. In each animal, 48 h after surgery, 5 mg/kg lipopolysaccharide (LPS) were injected intravenously. Six rats from each group were sacrificed 6 or 12 h after LPS administration. Bronchoalveolar lavage fluid (BALF) and arterial blood were also collected. Splenectomy reduced the liver injury as indicated by the serum lactate dehydrogenase level. A decrease in liver tissue adenosine triphosphate and increase in lipid peroxide were induced by LPS administration and inhibited by splenectomy. Splenectomy also reduced alveolar protein release as indicated by the protein level in BALF. Splenic vein ligation provided similar protective effects on the liver, but did not affect lung injury. From these results, it appears that the spleen plays a significant role in endotoxin-induced liver injury, and a mediator derived from the spleen is likely associated with development of liver injury. This mediator may be cleared or inactivated by not only splenectomy but also splenic vein ligation.
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Affiliation(s)
- E Hiraoka
- Department of Surgery II, Nagoya University School of Medicine, Japan
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Pérez-Mediavilla LA, López-Zabalza MJ, Calonge M, Montuenga L, López-Moratalla N, Santiago E. Inducible nitric oxide synthase in human lymphomononuclear cells activated by synthetic peptides derived from extracellular matrix proteins. FEBS Lett 1995; 357:121-4. [PMID: 7528687 DOI: 10.1016/0014-5793(94)01322-r] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Synthetic peptides with sequences present in extracellular matrix proteins are capable of causing the expression of the inducible form of nitric oxide synthase (iNOS), detected by immunocytochemistry, and the release of NO by human lymphomononuclear cells incubated in their presence. Active peptides are 15-mers containing a characteristic 2-6-11 motif in which the amino acid residue at position 2 is Leu, Ile, Val, Gly, Ala or Lys; the residue at position 6 is always Pro; and residue 11 is Glu or Asp. The induction of iNOS in human monocytes and macrophages could be involved in the cytotoxicity against tumor cell lines also elicited by these peptides.
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Affiliation(s)
- C R Lyons
- Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque 87131, USA
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