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Engin A. Reappraisal of Adipose Tissue Inflammation in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:297-327. [PMID: 39287856 DOI: 10.1007/978-3-031-63657-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Choromańska B, Myśliwiec P, Dadan J, Maleckas A, Zalewska A, Maciejczyk M. Effects of age and gender on the redox homeostasis of morbidly obese people. Free Radic Biol Med 2021; 175:108-120. [PMID: 34390781 DOI: 10.1016/j.freeradbiomed.2021.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/04/2021] [Accepted: 08/09/2021] [Indexed: 01/28/2023]
Abstract
Obesity is a chronic disease of complex etiology. Recent evidence suggests that obesity is caused by inflammation of adipose tissue leading to metabolic disorders, cardiovascular disease and cancer. This is the first study to evaluated the effects of age and gender on redox homeostasis, glutathione metabolism, and oxidative damage to plasma/serum lipids and proteins in morbidly obese patients. The study included 120 (60 men and 60 women) morbidly obese patients with class 3 obesity (BMI > 40 kg/m2), classified into three groups depending on age: 20-39 years (n = 20), 40-59 years (n = 20) and 60 years or older (n = 20). The number of patients was calculated a priori based on our previous experiment. We observed a reduction in serum activity of antioxidant enzymes (↓SOD) and plasma concentration of non-enzymatic antioxidants (↓GSH) in obese patients compared to the lean controls, which further decreased with age. Redox status (↑TAC, ↑TOS and ↓OSI) in morbidly obese men and women was shifted towards oxidation. Moreover, lipid (↑MDA and ↑LOOH) and protein (↑AOPP, ↑AGE and ↑Amadori products) damage products of oxidation and nitrosylation/nitration (↑total NO, ↑S-nitrosothiols, ↑peroxynitrite and ↑nitrotyrosine) were elevated in both genders of morbidly obese patients and were higher in the elderly. Interestingly, the concentrations of oxidative and nitrosative stress markers were generally higher in obese men compared to obese women at the same age. Summarizing, we showed that the total antioxidant/oxidant potential of obese patients is significantly increased and shifted towards oxidation. Obese patients have increased lipid and protein oxidation, glycation and nitration as compared to the lean controls. Disturbances in redox homeostasis increase with age in obese patients. Oxidative and nitrosative stress are more intense in men than in women at the same age.
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Affiliation(s)
- Barbara Choromańska
- 1st Department of General and Endocrine Surgery, Medical University of Bialystok, 24a M. Sklodowskiej-Curie Street, 15-276, Bialystok, Poland.
| | - Piotr Myśliwiec
- 1st Department of General and Endocrine Surgery, Medical University of Bialystok, 24a M. Sklodowskiej-Curie Street, 15-276, Bialystok, Poland.
| | - Jacek Dadan
- 1st Department of General and Endocrine Surgery, Medical University of Bialystok, 24a M. Sklodowskiej-Curie Street, 15-276, Bialystok, Poland.
| | - Almantas Maleckas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastrosurgical Research and Education, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Anna Zalewska
- Experimental Dentistry Laboratory, Medical University of Bialystok, 24a M. Sklodowskiej-Curie Street, 15-274, Bialystok, Poland.
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, 2c Mickiewicza Street, 15-233, Bialystok, Poland.
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The Impact of Hypertension and Metabolic Syndrome on Nitrosative Stress and Glutathione Metabolism in Patients with Morbid Obesity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1057570. [PMID: 32963689 PMCID: PMC7501544 DOI: 10.1155/2020/1057570] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/08/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023]
Abstract
In this pathbreaking study, we evaluated nitrosative stress in morbidly obese patients with and without metabolic syndrome. 62 women with class 3 obesity (BMI > 40 kg/m2) were divided into three subgroups: obese patients (OB), obese patients with hypertension (OB+HYP), and obese patients with metabolic syndrome (OB+MS). In comparison to the lean patients, OB had increased levels of serum myeloperoxidase (MPO), plasma nitric oxide (NO), S-nitrosothiols, and peroxynitrite (ONOO−), as well as nitrotyrosine, while oxidized glutathione (GSSG) rose only in OB+HYP group. Interestingly, ONOO− was significantly higher in OB+HYP and OB+MS as compared to OB group, while MPO only in OB+MS group. OB+MS had greater nitrotyrosine and S-nitrosothiol values than OB+HYP. Moreover, peroxynitrite could differentiate OB from OB+HYP and OB+MS (AUC 0.9292; p < 0.0001; 87.5% sensitivity, 90% specificity) as well as between OB and OB+MS group (AUC 0.9125; p < 0.0001; 81.25% sensitivity, 83.33%). In conclusion, we showed that MPO activity, NO formation, and nitrosative damage to proteins parallel the progression of metabolic disturbances of obesity. Evaluation of ONOO− concentrations may help predict the development of hypertension and metabolic syndrome in patients with morbid obesity; however, longer-term studies are required for larger numbers of patients.
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Tan S, Xu M, Ke B, Lu Y, Liu H, Jiang J, Wu B. IL-6-driven FasL promotes NF-κBp65/PUMA-mediated apoptosis in portal hypertensive gastropathy. Cell Death Dis 2019; 10:748. [PMID: 31582729 PMCID: PMC6776649 DOI: 10.1038/s41419-019-1954-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/02/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023]
Abstract
Mucosal epithelial apoptosis with non-specific inflammation is an essential pathological characteristic in portal hypertensive gastropathy (PHG). However, whether a coordinated crosstalk between myeloid cells and epithelial cells involved in PHG remains unclear. IL-6, which is induced in the mucosa of PHG patients and mice, promotes FasL production via enhancing NF-κBp65 activation in myeloid cells, while blockage of IL-6 signaling by Tocilizumab or deletion of NF-κBp65 in myeloid cells attenuates the inflammatory response and Fas/FasL-mediated epithelial apoptosis in PHG. IL-6-driven FasL from myeloid cells combines with epithelial Fas receptor to encourage NF-κBp65/PUMA-mediated epithelial apoptosis in PHG, and inhibition of NF-κBp65 or knockout of PUMA alleviates Fas/FasL-mediated epithelial apoptosis in PHG. These results indicate that IL-6 drives FasL generation via NF-κBp65 in myeloid cells to promote Fas/NF-κBp65/PUMA-mediated epithelial apoptosis in PHG, and this coordinated crosstalk between myeloid cells and epithelial cells may provide a potential therapeutic target for PHG.
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Affiliation(s)
- Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, 510630, Guangzhou, China
| | - Minyi Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China
| | - Bilun Ke
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China
| | - Yu Lu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, 510630, Guangzhou, China.
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Dymkowska D, Drabarek B, Michalik A, Nowak N, Zabłocki K. TNFα stimulates NO release in EA.hy926 cells by activating the CaMKKβ-AMPK-eNOS pathway. Int J Biochem Cell Biol 2019; 106:57-67. [PMID: 30471424 DOI: 10.1016/j.biocel.2018.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/06/2018] [Accepted: 11/20/2018] [Indexed: 12/28/2022]
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The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 960:221-245. [PMID: 28585201 DOI: 10.1007/978-3-319-48382-5_9] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Background Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core of this interesting research field. Summary Most investigators noted small intestinal dysmotility in their patients with liver cirrhosis. Marked changes in the contraction pattern were observed in early manometric studies. The orocecal transit time, particularly small intestinal transit, has generally been reported to be prolonged, which has been demonstrated in multiple investigations to be related to the severity of the liver disease (e.g., Child-Pugh class), the presence of small intestinal bacterial overgrowth (SIBO) and hepatic encephalopathy (HE) as well as a history of spontaneous bacterial peritonitis. Bacteriologically proven SIBO in proximal jejunal aspiration has been reported to be present in up to 59% of cirrhotic patients and is associated with systemic endotoxemia. Clinical and experimental studies suggest that delayed small bowel transit in liver cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea. In addition to autonomic neuropathy, metabolic derangements and diabetic state, SIBO itself may delay intestinal transit in cirrhotic patients. Several studies, both from the West and the East, have shown that the gut microbiota is altered in cirrhotic patients and particularly those with HE. Further, a quantitative change in Bacteroides/Firmicutes ratio, with a prevalence of potentially pathogenic bacteria (e.g., Enterobacteriaceae) and reduction in specific commensals (e.g., Lachnospiraceae), has been described. Structural and functional changes in the intestinal mucosa that contribute to increases in intestinal permeability for bacteria and their products have been observed in patients with liver cirrhosis, which is considered as an important pathogenetic factor for several complications. The mechanism of intestinal barrier dysfunction in cirrhosis is multifactorial, including alcohol, portal hypertension (vascular congestion and dysregulation), endotoxemia, SIBO, local inflammation and, most likely, immunological factors and medications. Key Messages This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research. The question of whether this intestinal barrier dysfunction is accompanied and/or at least partly caused by structural and functional changes in the epithelial tight junction proteins is as yet unsolved. Development of new strategies to modulate gut-liver interaction is urgently needed.
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Affiliation(s)
- Hiroshi Fukui
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Kashihara, Japan
| | - Reiner Wiest
- Department of Gastroenterology, University Hospital of Visceral Surgery and Medicine, Bern, Switzerland
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Fukui H, Wiest R. Changes of Intestinal Functions in Liver Cirrhosis. Inflamm Intest Dis 2016; 1:24-40. [PMID: 29922655 PMCID: PMC5988129 DOI: 10.1159/000444436] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/04/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core of this interesting research field. SUMMARY Most investigators noted small intestinal dysmotility in their patients with liver cirrhosis. Marked changes in the contraction pattern were observed in early manometric studies. The orocecal transit time, particularly small intestinal transit, has generally been reported to be prolonged, which has been demonstrated in multiple investigations to be related to the severity of the liver disease (e.g., Child-Pugh class), the presence of small intestinal bacterial overgrowth (SIBO) and hepatic encephalopathy (HE) as well as a history of spontaneous bacterial peritonitis. Bacteriologically proven SIBO in proximal jejunal aspiration has been reported to be present in up to 59% of cirrhotic patients and is associated with systemic endotoxemia. Clinical and experimental studies suggest that delayed small bowel transit in liver cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea. In addition to autonomic neuropathy, metabolic derangements and diabetic state, SIBO itself may delay intestinal transit in cirrhotic patients. Several studies, both from the West and the East, have shown that the gut microbiota is altered in cirrhotic patients and particularly those with HE. Further, a quantitative change in Bacteroides/Firmicutes ratio, with a prevalence of potentially pathogenic bacteria (e.g., Enterobacteriaceae) and reduction in specific commensals (e.g., Lachnospiraceae), has been described. Structural and functional changes in the intestinal mucosa that contribute to increases in intestinal permeability for bacteria and their products have been observed in patients with liver cirrhosis, which is considered as an important pathogenetic factor for several complications. The mechanism of intestinal barrier dysfunction in cirrhosis is multifactorial, including alcohol, portal hypertension (vascular congestion and dysregulation), endotoxemia, SIBO, local inflammation and, most likely, immunological factors and medications. KEY MESSAGES This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research. The question of whether this intestinal barrier dysfunction is accompanied and/or at least partly caused by structural and functional changes in the epithelial tight junction proteins is as yet unsolved. Development of new strategies to modulate gut-liver interaction is urgently needed.
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Affiliation(s)
- Hiroshi Fukui
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Kashihara, Japan
| | - Reiner Wiest
- Department of Gastroenterology, University Hospital of Visceral Surgery and Medicine, Bern, Switzerland
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9
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Abstract
Background Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core of this interesting research field. Summary Most investigators noted small intestinal dysmotility in their patients with liver cirrhosis. Marked changes in the contraction pattern were observed in early manometric studies. The orocecal transit time, particularly small intestinal transit, has generally been reported to be prolonged, which has been demonstrated in multiple investigations to be related to the severity of the liver disease (e.g., Child-Pugh class), the presence of small intestinal bacterial overgrowth (SIBO) and hepatic encephalopathy (HE) as well as a history of spontaneous bacterial peritonitis. Bacteriologically proven SIBO in proximal jejunal aspiration has been reported to be present in up to 59% of cirrhotic patients and is associated with systemic endotoxemia. Clinical and experimental studies suggest that delayed small bowel transit in liver cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea. In addition to autonomic neuropathy, metabolic derangements and diabetic state, SIBO itself may delay intestinal transit in cirrhotic patients. Several studies, both from the West and the East, have shown that the gut microbiota is altered in cirrhotic patients and particularly those with HE. Further, a quantitative change in Bacteroides/Firmicutes ratio, with a prevalence of potentially pathogenic bacteria (e.g., Enterobacteriaceae) and reduction in specific commensals (e.g., Lachnospiraceae), has been described. Structural and functional changes in the intestinal mucosa that contribute to increases in intestinal permeability for bacteria and their products have been observed in patients with liver cirrhosis, which is considered as an important pathogenetic factor for several complications. The mechanism of intestinal barrier dysfunction in cirrhosis is multifactorial, including alcohol, portal hypertension (vascular congestion and dysregulation), endotoxemia, SIBO, local inflammation and, most likely, immunological factors and medications. Key Messages This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research. The question of whether this intestinal barrier dysfunction is accompanied and/or at least partly caused by structural and functional changes in the epithelial tight junction proteins is as yet unsolved. Development of new strategies to modulate gut-liver interaction is urgently needed.
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Affiliation(s)
- Hiroshi Fukui
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Kashihara, Japan
| | - Reiner Wiest
- Department of Gastroenterology, University Hospital of Visceral Surgery and Medicine, Bern, Switzerland
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Rodriguez-Diaz E, Baffy G, Singh SK. Probe-based confocal laser endomicroscopy quantitative morphometric markers associated with portal hypertension in duodenal mucosa. Liver Int 2016; 36:223-31. [PMID: 26133980 DOI: 10.1111/liv.12906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 06/27/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Early detection of portal hypertension (PH) may help to prevent the morbidity of late-stage cirrhosis by stratifying disease severity and enabling disease-modifying interventions in potentially reversible conditions like non-alcoholic fatty liver disease and alcoholic hepatitis. This study seeks to correlate morphometric features by confocal endomicroscopy with established surrogate clinical markers of PH. METHODS Patients with and without PH scheduled for upper endoscopy at VA Boston participated in this IRB-approved study. Real-time probe-based confocal endomicroscopy (pCLE) was performed in the duodenum. Vascular and epithelial morphometry was performed off-line, in a blinded manner, using image-processing software. RESULTS Morphometric analysis of pCLE images from 16 patients with PH and 15 control patients was performed. Statistically significant differences were observed among control and PH patients for average vessel diameter (AVD: 11.7 μm vs. 17.1 μm), average vessel branching (AVB: 0.11 vs. 0.31 bifurcations per image frame), and average columnar cell height (ACCH: 40.0 μm vs. 52.0 μm). Spearman correlations comparing AVD, AVB and ACCH to portal gastropathy scores (0.86, 0.44 and 0.70) and to grade of oesophageal varices (0.88, 0.41 and 0.66) were statistically significant. Similarly, Pearson correlations of AVD and ACCH to spleen size (0.72 and 0.57), platelet count (-0.69 and -0.40) and the platelet count/spleen size ratio (-0.69 and -0.41) were also found to be statistically significant. CONCLUSIONS Duodenal pCLE reveals microvascular dilatation and altered epithelial cell volume/morphology in PH. These morphometric pCLE markers correlate with surrogate markers of PH. Additional studies will define the correlation between microscopic vascular patterns, epithelial cell volume and the hepatic venous pressure gradient.
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Affiliation(s)
- Eladio Rodriguez-Diaz
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.,Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA
| | - György Baffy
- Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Satish K Singh
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.,Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.,Department of Biomedical Engineering, College of Engineering, Boston University, Boston, MA, USA
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Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63:1272-84. [PMID: 26192220 DOI: 10.1016/j.jhep.2015.07.004] [Citation(s) in RCA: 417] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/06/2015] [Accepted: 07/07/2015] [Indexed: 02/06/2023]
Abstract
The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences - Alma Mater Studiorum, University of Bologna, Italy; Semeiotica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
| | - Richard Moreau
- Inserm, U(1149), Centre de Recherche sur l'Inflammation (CRI), Paris, France; UMR_S(1149), Université Paris Diderot, Faculté de Médecine, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France
| | - Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, United States; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Vicente Arroyo
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques Agust Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Tan S, Li L, Chen T, Chen X, Tao L, Lin X, Tao J, Huang X, Jiang J, Liu H, Wu B. β-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy. Free Radic Biol Med 2015; 87:69-83. [PMID: 26119788 DOI: 10.1016/j.freeradbiomed.2015.06.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 06/05/2015] [Accepted: 06/09/2015] [Indexed: 01/12/2023]
Abstract
Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. β-Arrestins (β-arrestin-1 and β-arrestin-2) are well-established mediators of endocytosis of G-protein-coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of β-arrestin-1 (β-arr1) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of β-arr1 in PHG via its regulation of endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) apoptotic signaling. Gastric mucosal injury and apoptosis were studied in PHG patients and in PHG mouse models. The induction of β-arr1 and the ER stress/PUMA signaling pathway were investigated, and the mechanisms of β-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments. β-arr1 and ER stress/PUMA signaling elements were markedly induced in the gastric mucosa of PHG patients and mouse models. Blockage of ER stress demonstrably attenuated the mucosal apoptosis of PHG, while targeted deletion of β-arr1 significantly aggravated the injury and ER stress/PUMA-mediated apoptosis. β-arr1 limited the activation of p65 to repress TNF-α-induced inducible nitric oxide synthase (iNOS) expression and NO release, which could regulate ER stress/PUMA-mediated mucosal apoptosis in PHG. In vivo and in vitro experiments further demonstrated that β-arr1 protected against mucosal apoptosis by repressing TNF-α-induced iNOS expression via inhibiting the activation of p65. These results indicated that β-arr1 regulated ER stress/PUMA-induced mucosal epithelial apoptosis through suppression of the TNF-α/p65/iNOS signaling pathway activation and that β-arr1 is a potential therapeutic target for PHG.
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Affiliation(s)
- Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Leijia Li
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Tingting Chen
- Department of Gastroenterology, The No. 2 Hospital of Xiamen, Xiamen, China
| | - Xiaoliang Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li Tao
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xianyi Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jin Tao
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiaoli Huang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
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Kao JT, Yu CJ, Feng CL, Tsai SM, Chen YL, Wu YY. IL-6 significantly correlates with p-STAT3 expression and presents high variceal bleeding with mortality in cirrhotic patients: A cross-sectional study. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2015; 50:286-296. [PMID: 25899133 DOI: 10.1016/j.jmii.2015.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 02/06/2015] [Accepted: 03/05/2015] [Indexed: 01/27/2023]
Abstract
BACKGROUND/PURPOSE Effective mediators activate downstream transducers regulating inflammation and angiogenesis. Correlation among mediators IL-6, IL-27, TNF-α, and VEGF with STAT proteins at diverse clinical-pathologic stages of cirrhotic patients remains limited. METHODS Plasma mediators were assayed from 158 naïve liver cirrhosis (LC-total group) and 144 non-LC individuals. The LC-total group included 69 hepatitis B virus-infected (LC-HBV) patients, 40 hepatitis C virus-infected (LC-HCV) patients, and 49 patients without HBV-/HCV- infection (LC-NBNC). Another 144 non-LC individuals comprised 54 healthy persons (HG) and 90 chronic hepatitis patients (CH-total) as the control group. To correlate with plasma mediators, 52 paired liver tissues (CH: 41 and LC: 11 cases) served for p-STAT1 and p-STAT3 immunostaining. RESULTS Although IL-6, IL-27, TNF-α, and VEGF were expressed significantly in CH-total versus HG (p = 0.011, p < 0.001, p = 0.007, p = 0.004, respectively) and overall viral hepatitis patients versus HG (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively), only IL-6 presented the strongest correlation in cirrhotic patients than noncirrhotic patients (LC-HBV vs. HG, p < 0.001, vs. CH-HBV, p = 0.001; LC-HCV vs. HG, p = 0.001, vs. CH-HCV, p = 0.031; LC-NBNC vs. HG, p < 0.001). Over-expressed IL-6 linked with poorer liver function (albumin: r = -0.346, p < 0.001; bilirubin: r = 0.271, p = 0.001; INR: r = 0.308, p < 0.001; Child-Turcotte-Pugh Classification C vs. A or B, p = 0.001, p = 0.007, respectively), variceal severity (p = 0.045), and bleeding (p = 0.047), as well as patients' mortality (p = 0.005). Furthermore, plasma IL-6 significantly correlated with tissues p-STAT3 expression (r = 0.737, p = 0.010) (IL-27: r = 0.078, p = 0.820; TNF-α: r = -0.145, p = 0.670; VEGF: r = 0.142, p = 0.678) in cirrhotic patients than noncirrhotic patients. CONCLUSION Over-expression of IL-6 reflects hepatic dysfunction and varices bleeding with mortality, as well as correlates p-STAT3 expression in cirrhotic patients.
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Affiliation(s)
- Jung-Ta Kao
- School of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Ju Yu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Lung Feng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shu-Mei Tsai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yao-Li Chen
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
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Boltin D, Niv Y. Pharmacological and alimentary alteration of the gastric barrier. Best Pract Res Clin Gastroenterol 2014; 28:981-94. [PMID: 25439065 DOI: 10.1016/j.bpg.2014.09.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Revised: 07/28/2014] [Accepted: 09/15/2014] [Indexed: 02/07/2023]
Abstract
The gastric barrier contains several lines of defence which protect the epithelium from harmful microbes and toxins. Pre-mucosal defence mechanisms include secreted acid (HCl 0.1 mmol/L) and pepsin, which are capable of denaturing tissue. A tightly adherent mucous layer provides the next line of defence, and physically separates any potentially hazardous substance in the lumen from the mucosal surface. Apical secretion of HCO3(-) maintains a non-acidic microenvironment at the mucosal surface. Membrane-bound phospholipids repel soluble toxins, and sulphydryls scavenge reactive oxygen species. However, when noxious agents overwhelm these mechanisms, the epithelium is damaged. Herein, we discuss the pathological and physiological basis for several disease states which are associated with a breakdown in one or more components of the gastric barrier, including: Helicobacter pylori-associated gastritis, atrophic gastritis, stress-related mucosal disease, age-related gastropathy and portal hypertensive gastropathy. The effect of non-steroidal anti-inflammatory drugs and proton pump inhibitors on the gastric mucosa, is explored. Finally, we outline the alterations in mucosal defence caused by alcohol, caffeine, minerals and vitamins.
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Affiliation(s)
- Doron Boltin
- Department of Gastroenterology, Rabin Medical Center, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Israel.
| | - Yaron Niv
- Department of Gastroenterology, Rabin Medical Center, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Israel
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15
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Tarnawski AS, Ahluwalia A, Jones MK. Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging. J Gastroenterol Hepatol 2014; 29 Suppl 4:112-23. [PMID: 25521743 DOI: 10.1111/jgh.12734] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Angiogenesis (also referred to as neovascularization-formation of new blood vessels from existing vessels) is a fundamental process essential for healing of tissue injury and ulcers because regeneration of blood microvessels is a critical requirement for oxygen and nutrient delivery to the healing site. This review article updates the current views on angiogenesis in gastric mucosa following injury and during ulcer healing, its sequential events, the underlying mechanisms, and the impairment of angiogenesis in aging gastric mucosa. We focus on the time sequence and ultrastructural features of angiogenesis, hypoxia as a trigger, role of vascular endothelial growth factor signaling (VEGF), serum response factor, Cox2 and prostaglandins, nitric oxide, and importin. Recent reports indicate that gastric mucosa of aging humans and experimental animals exhibits increased susceptibility to injury and delayed healing. Gastric mucosa of aging rats has increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin, and other non-steroidal anti-inflammatory drugs because of structural and functional abnormalities including: reduced gastric mucosal blood flow, hypoxia, reduced expression of vascular endothelial growth factor and survivin, and increased expression of early growth response protein 1 (egr-1) and phosphatase and tensin homolog (PTEN). Until recently, postnatal neovascularization was assumed to occur solely through angiogenesis sprouting of endothelial cells and formation of new blood vessels from pre-existing blood vessels. New studies in the last decade have challenged this paradigm and indicate that in some tissues, including gastric mucosa, the homing of bone marrow-derived endothelial progenitor cells to the site of injury can also contribute to neovascularization by a process termed vasculogenesis.
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Affiliation(s)
- Andrzej S Tarnawski
- Veterans Administration Long Beach Healthcare System, 5901 E. Seventh Street, Long Beach, CA, 90822, USA; The University of California, Irvine, CA, USA
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16
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Sansbury BE, Hill BG. Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 2014; 73:383-99. [PMID: 24878261 PMCID: PMC4112002 DOI: 10.1016/j.freeradbiomed.2014.05.016] [Citation(s) in RCA: 172] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 05/16/2014] [Accepted: 05/17/2014] [Indexed: 02/07/2023]
Abstract
Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.
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Affiliation(s)
- Brian E Sansbury
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Bradford G Hill
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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17
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Bergandi L, Cordero M, Anselmino M, Ferraro G, Ravera L, Dalmasso P, Moiraghi C, Trevi GP, Ghigo D, Bosia A, Bergerone S. Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes. Clin Res Cardiol 2010; 99:557-64. [PMID: 20467748 DOI: 10.1007/s00392-010-0157-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2009] [Accepted: 04/07/2010] [Indexed: 11/28/2022]
Abstract
This study was aimed at evaluating whether the nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway is altered in platelets from patients with an acute coronary syndrome (unstable angina and acute myocardial infarction). We investigated 10 patients with unstable angina (UA), 14 with acute myocardial infarction (AMI) and 14 age and sex-matched healthy subjects. The serum markers of platelet activation (sP-selectin), inflammation (TNF-alpha and erythrocyte sedimentation rate), thrombotic state (fibrinogen) and plaque disruption were significantly higher in both UA and AMI patients compared to the healthy controls. In their platelets we assessed the cGMP levels in basal conditions and after stimulation with sodium nitroprusside (SNP), and performed Western blot analysis of homogenates to measure the expression of soluble guanylate cyclase isoforms. Basal levels of cGMP (pmol/10(10) platelets) were significantly higher in platelets from UA patients (1,097 +/- 111; p < 0.0001) and AMI (1,122 +/- 77; p < 0.0001) compared to those collected from healthy controls (497 +/- 80). The platelets of AMI patients exhibited a lack of cGMP increase after SNP stimulation in comparison with UA patients. The phosphorylation of upstream (Akt1 protein kinase alpha and endothelial NO synthase) and downstream (vasodilator-stimulated phosphoprotein, VASP) signaling proteins of the NO/cGMP pathway was investigated: serine phosphorylation in Akt1, eNOS and VASP was enhanced in platelets from UA and AMI patients when compared to controls. Furthermore, in AMI patients the inhibitors of guanylate cyclase and cGMP-dependent protein kinase did not revert the VASP phosphorylation. These data suggest that platelets from AMI patients are more resistant to SNP stimulation, not only as cGMP production, but also in terms of VASP activation. From these ex vivo results we hypothesize that the increased inflammatory state which often accompanies patients with cardiovascular diseases might promote a platelet preactivation resulting in their reduced sensitivity to NO.
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Affiliation(s)
- Loredana Bergandi
- Dipartimento di Genetica, Biologia e Biochimica (Sezione di Biochimica), University of Torino, Via Santena 5/bis, 10126, Turin, Italy.
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18
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Enkhbaatar P, Traber L, Traber D. Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric Oxide. Intensive Care Med 2009. [DOI: 10.1007/978-0-387-77383-4_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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19
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Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135:41-60. [PMID: 18549814 DOI: 10.1053/j.gastro.2008.05.030] [Citation(s) in RCA: 448] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Revised: 04/07/2008] [Accepted: 05/05/2008] [Indexed: 02/06/2023]
Abstract
The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE(2) and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%-1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation >or=48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented.
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Affiliation(s)
- Loren Laine
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
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Colle I, Geerts AM, Van Steenkiste C, Van Vlierberghe H. Hemodynamic changes in splanchnic blood vessels in portal hypertension. Anat Rec (Hoboken) 2008; 291:699-713. [PMID: 18484617 DOI: 10.1002/ar.20667] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Portal hypertension (PHT) is associated with a hyperdynamic state characterized by a high cardiac output, increased total blood volume, and a decreased splanchnic vascular resistance. This splanchnic vasodilation is a result of an important increase in local and systemic vasodilators (nitric oxide, carbon monoxide, prostacyclin, endocannabinoids, and so on), the presence of a splanchnic vascular hyporesponsiveness toward vasoconstrictors, and the development of mesenteric angiogenesis. All these mechanisms will be discussed in this review. To decompress the portal circulation in PHT, portosystemic collaterals will develop. The presence of these portosystemic shunts are responsible for major complications of PHT, namely bleeding from gastrointestinal varices, encephalopathy, and sepsis. Until recently, it was accepted that the formation of collaterals was due to opening of preexisting vascular channels, however, recent data suggest also the role of vascular remodeling and angiogenesis. These points are also discussed in detail.
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Affiliation(s)
- Isabelle Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.
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21
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Geerts AM, Vanheule E, Van Vlierberghe H, Leybaert L, Van Steenkiste C, De Vos M, Colle I. Rapamycin prevents mesenteric neo-angiogenesis and reduces splanchnic blood flow in portal hypertensive mice. Hepatol Res 2008; 38:1130-9. [PMID: 18564143 DOI: 10.1111/j.1872-034x.2008.00369.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIM Increased angiogenesis in the mesenteric microvasculature of portal hypertensive animals may contribute to the development of splanchnic vasodilation associated with portal hypertension (PHT). Experimental data suggest that rapamycin may reduce angiogenesis and tumour growth by inhibiting the vascular endothelial growth factor (VEGF) pathway. This study determines whether rapamycin can prevent the neoangiogenesis in the mesentery of portal hypertensive mice and may influence the splanchnic vasodilation. METHODS PHT was induced by partial portal vein ligation (PPVL). PPVL and Sham mice were treated daily with rapamycin or placebo for 2 weeks. Protein expressions of VEGF, CD 31, Akt and p70S6 kinase (mTOR signalling pathway) were evaluated. Mesenteric blood flow (MBF) was measured by a perivascular flow probe. RESULTS Increased mesenteric angiogenesis and VEGF protein levels were observed in PPVL(placebo) mice compared to Sham(placebo) mice. Rapamycin treatment caused significant reduction in CD 31 positive endothelial cells and VEGF protein in the PPVL(rapamycine) group compared to the PPVL(placebo) group, to levels comparable with Sham(placebo) and Sham(rapamycine) groups. MBF was significantly higher in PPVL(placebo) mice compared to the Sham(placebo) mice. Rapamycin decreased significantly the MBF in PPVL(rapamycine) mice compared to PPVL(placebo) mice. Phospo-Akt and p70S6 kinase protein levels were increased in the mesenteric tissue of PPVL(placebo) mice compared to Sham(placebo) mice, which were also prevented by treatment with rapamycin. CONCLUSIONS An increased VEGF dependent neo-angiogenesis is present in the mesentery of portal hypertensive mice. Rapamycin prevents angiogenesis in the mesenteric tissue and decreases the mesenteric blood flow in portal hypertensive mice, at least in part through an anti-VEGF activity and influence on the mTOR signalling pathway.
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Affiliation(s)
- Anja M Geerts
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
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22
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Kai S, Ohta M, Tominaga M, Matsumoto T, Bandoh T, Kitano S. Reduction of ethanol-induced injury in portal hypertensive gastric mucosa of rats by induction of heat shock protein 72 by geranylgeranylacetone. Wound Repair Regen 2008; 15:875-80. [PMID: 18028136 DOI: 10.1111/j.1524-475x.2007.00302.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: 12/16/2022]
Abstract
Portal hypertensive (PHT) gastropathy has an increased susceptibility to damage due to noxious factors. Heat shock protein (HSP) 72 has a protective effect against gastric mucosal injury and geranylgeranylacetone (GGA) is an inducer of HSP 72. However, it remains unclear how HSP 72 influences the PHT gastric mucosa. The aim of the present study was to investigate HSP 72 induction by GGA and the protective effect to gastric mucosa in PHT rats. PHT rats were produced by staged portal vein occlusion, and GGA 200 mg/kg was orally administered. Expression of HSP 72 protein in the gastric mucosa was evaluated by enzyme-linked immunosorbent assay, and gastric mucosal damage against 70% ethanol (10 mL/kg) following GGA or vehicle treatment was also estimated. Expression of mucosal HSP 72 after vehicle administration was significantly higher in the PHT rats compared with the sham-operated rats. After GGA treatment, portal pressure did not change but HSP 72 was significantly increased in the gastric mucosa of both groups. Ethanol-induced gastric mucosal damage was significantly decreased due to GGA treatment in the PHT rats, but not in the sham-operated rats. These findings suggest that HSP 72 expression is enhanced in PHT gastric mucosa and plays an important role in gastric mucosal protection. The induction of HSP 72 by GGA may therefore effectively prevent mucosal injury in the PHT stomach.
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Affiliation(s)
- Seiichiro Kai
- Department of Surgery I, Oita University Faculty of Medicine, Yufu, Oita, Japan.
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Anegawa G, Kawanaka H, Yoshida D, Konishi K, Yamaguchi S, Kinjo N, Taketomi A, Hashizume M, Shimokawa H, Maehara Y. Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis. Hepatology 2008; 47:966-77. [PMID: 18167063 DOI: 10.1002/hep.22089] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In liver cirrhosis, down-regulation of endothelial nitric oxide synthase (eNOS) has been implicated as a cause of increased intrahepatic resistance. We investigated whether Rho-kinase activation is one of the molecular mechanisms involved in defective eNOS signaling in secondary biliary cirrhosis. Liver cirrhosis was induced by bile duct ligation (BDL). We measured mean arterial pressure (MAP), portal venous pressure (PVP), and hepatic tissue blood flow (HTBF) during intravenous infusion of saline (control), 0.3, 1, or 2 mg/kg/hour fasudil for 60 minutes. In BDL rats, 1 and 2 mg/kg/hour fasudil significantly reduced PVP by 20% compared with controls but had no effect on HTBF. MAP was significantly reduced in response to 2 mg/kg/hour fasudil. In the livers of BDL rats, 1 and 2 mg/kg/hour fasudil significantly suppressed Rho-kinase activity and significantly increased eNOS phosphorylation, compared with controls. Fasudil significantly reduced the binding of serine/threonine Akt/PKB (Akt) to Rho-kinase and increased the binding of Akt to eNOS. These results show in secondary biliary cirrhosis that (1) Rho-kinase activation with resultant eNOS down-regulation is substantially involved in the pathogenesis of portal hypertension and (2) Rho-kinase might interact with Akt and subsequently inhibit the binding of Akt to eNOS.
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Affiliation(s)
- Go Anegawa
- Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
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Malyshev E, Tazi KA, Moreau R, Lebrec D. Discrepant effects of inducible nitric oxide synthase modulation on systemic and splanchnic endothelial nitric oxide synthase activity and expression in cirrhotic rats. J Gastroenterol Hepatol 2007; 22:2195-201. [PMID: 18031380 DOI: 10.1111/j.1440-1746.2006.04608.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Arterial vasodilatation, which is a major factor in the pathogenesis of the hyperkinetic circulatory state and portal hypertension in cirrhosis, is due to arterial nitric oxide (NO) overproduction secondary to endothelial NO synthase (eNOS) and inducible NOS (iNOS) upregulation. However, in cirrhosis, the respective roles of eNOS and iNOS isoforms in NO overproduction are still unknown and the effect of iNOS modulation on eNOS activity and expression has not been evaluated in the systemic or splanchnic vessels. The aim of this study was to evaluate the effects of modulating aortic and superior mesenteric arteries (SMA) iNOS on arterial eNOS activity and expression in rats with cirrhosis. METHODS eNOS and iNOS protein expression and eNOS activity (assessed by its phosphorylation at serine 1177) were measured in the aortas and SMA in untreated and treated cirrhotic rats with lipopolysaccharide (LPS), N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, and LPS plus L-NIL. RESULTS LPS administration significantly increased eNOS and iNOS protein expression and eNOS activity in the aortas of both sham-operated and cirrhotic rats. However, in SMA, LPS administration induced a decrease in eNOS protein expression and activity and an increase in iNOS protein expression. CONCLUSION The results of this study may explain the worsening of the hyperdynamic state in cirrhosis during septic shock by direct LPS-induced eNOS activation in large systemic vessels, and its inhibition in concomitant small splanchnic vasculature by iNOS synthesized NO.
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Affiliation(s)
- Eugene Malyshev
- INSERM U773, Research Center Bichat Beaujon CRB3, Beaujon Hospital, Clichy, France
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Yamaguchi S, Kawanaka H, Yoshida D, Maehara Y, Hashizume M. Splenic hemodynamics and decreased endothelial nitric oxide synthase in the spleen of rats with liver cirrhosis. Life Sci 2007; 80:2036-44. [PMID: 17481668 DOI: 10.1016/j.lfs.2007.03.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Revised: 02/28/2007] [Accepted: 03/05/2007] [Indexed: 01/03/2023]
Abstract
The enlarged spleen in liver cirrhosis is considered to play a role in the pathogenesis of portal hypertension, but the splenic hemodynamics and molecular mechanisms behind the phenomenon have not been elucidated. The present study aimed to examine the splenic hemodynamics associated with splenic microcirculation and congestion, and to determine the status of the endothelial nitric oxide synthase (eNOS) signaling pathway in the spleen of rats with liver cirrhosis. Liver cirrhosis was induced by bile duct ligation. In rats with bile duct ligation (BDL rats) and control rats, splenic blood flow was measured using a laser Doppler flowmeter, and splenic blood volume was measured using a near-infrared spectrophotometer. The expressions of eNOS and its upstream effectors, Akt, TNF-alpha and VEGF, in the spleen were also determined. Specific splenic blood flow was significantly decreased in BDL rats compared with control rats. Specific splenic blood volume was also decreased in BDL rats, while their total splenic blood volume, especially the deoxygenated volume, was significantly increased. The expressions of phosphorylated and total eNOS, and the eNOS phosphorylation ratio, were all significantly decreased in the spleen of BDL rats. The Akt phosphorylation ratio and TNF-alpha concentration were also decreased in the spleen of BDL rats although the expression of VEGF was increased. These findings suggest that the eNOS signaling pathway is suppressed in the spleen of cirrhotic rats, and may contribute to the measured decreases in specific blood flow and volume in the spleen of liver cirrhosis. Determination of the factors influencing the suppression of eNOS in the spleen may shed light on how liver cirrhosis results in hypodynamic intrasplenic circulation.
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Affiliation(s)
- Shohei Yamaguchi
- Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Boursier J, Asfar P, Joly-Guillou ML, Calès P. Infection et rupture de varice œsophagienne au cours de la cirrhose. ACTA ACUST UNITED AC 2007; 31:27-38. [PMID: 17273129 DOI: 10.1016/s0399-8320(07)89324-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Endotoxemia and bacterial infection are frequent in patients with cirrhosis. They alter systemic and splanchnic hemodynamics, worsen coagulation disorders, impair liver function and thus may induce variceal bleeding. In variceal bleeding, bacterial infection favours failure to control bleeding, early rebleeding, and death. In patients with cirrhosis and variceal bleeding, antibiotic-prophylaxis decreases bacterial infection and the incidence of early rebleeding, and, more important, significantly decreases the death rate in these patients.
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Affiliation(s)
- Jérôme Boursier
- Laboratoire HIFIH, UPRES EA 3859, IFR 132, Université, Angers
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Abstract
Portal hypertension is a complication of diseases that obstruct portal blood flow, such as cirrhosis or portal vein thrombosis. In these diseases, increased vascular resistance to portal blood flow is the primary mechanism that increases portal pressure. In cirrhosis, increased intrahepatic vascular resistance is a result of both intrahepatic vasoconstriction and surrounding mechanical factors including collagen deposition and regenerative nodules. This article summarizes recent progress in the understanding of molecular mechanisms underlying the portal hypertension-associated arterial alterations in splanchnic systemic territories and those involved in the development of portal-systemic collateral circulation.
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Affiliation(s)
- Richard Moreau
- INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Hôpital Beaujon, Clichy 92118, France.
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Affiliation(s)
- Daniel A Langer
- Gastroenterology Research Unit, Department of Physiology and Tumor Biology Program, Al 2-435, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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De Palma C, Meacci E, Perrotta C, Bruni P, Clementi E. Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arterioscler Thromb Vasc Biol 2005; 26:99-105. [PMID: 16269668 DOI: 10.1161/01.atv.0000194074.59584.42] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine acting on the endothelium, activates endothelial nitric oxide synthase (eNOS). We have examined the signaling pathway leading to this activation and its biological role in endothelium, which are still unknown. METHODS AND RESULTS In human endothelial cells, we found that eNOS activation by TNF-alpha is time dependent and requires activation of Akt, a known eNOS activator. eNOS activation was preceded by sequential activation of neutral-sphingomyelinase-2 (N-SMase2) and sphingosine-kinase-1 (SK1) and generation of sphingosine-1-phosphate (Sph1P). Inhibition of N-SMase2 inhibited Sph1P formation, whereas inhibition of SK1 did not affect N-SMase2 activation by TNF-alpha. Blockade of N-SMase2, SK1, or the Sph1P receptors S1P1 and S1P3, either by silencing or pharmacological inhibitors, prevented eNOS activation. Thus, eNOS is activated by TNF-alpha via S1P receptors, activated by Sph1P generated through N-SMase2 and SK1 activation. We found that nitric oxide generated through this pathway has a biological role, because it inhibits the expression of E-selectin and the adhesion of dendritic cells to the endothelium stimulated by TNF-alpha. CONCLUSIONS This study establishes a previously undescribed link among TNF-alpha, Sph1P, and eNOS in a same signaling pathway of biological relevance in the process of endothelial cell activation by TNF-alpha.
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Affiliation(s)
- Clara De Palma
- Department of Pharmaco-Biology, University of Calabria, Rende, Italy
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30
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Tazi KA, Moreau R, Hervé P, Dauvergne A, Cazals-Hatem D, Bert F, Poirel O, Rabiller A, Lebrec D. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling. Gastroenterology 2005; 129:303-14. [PMID: 16012955 DOI: 10.1053/j.gastro.2005.04.016] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Arterial vasodilation plays a role in the pathogenesis of the complications of cirrhosis. This vasodilation is caused by the overproduction of arterial nitric oxide (NO). Bacterial translocation may be involved in NO synthase (NOS) up-regulation by activating both endothelial NOS (eNOS) and inducible NOS (iNOS). The prevention of intestinal gram-negative translocation by norfloxacin administration corrects systemic circulatory changes by decreasing NO production in cirrhosis. However, the signaling mechanisms for NO overproduction from bacterial translocation are unknown. In this study, we investigated the signal transduction pathway of bacterial translocation-induced aortic NOS up-regulation in cirrhotic rats. METHODS Proinflammatory cytokine levels, Akt and NOS activities, eNOS phosphorylation, and NOS expressions were assessed in aorta from norfloxacin-treated and untreated cirrhotic rats. Norfloxacin was administered to reduce intestinal bacterial translocation. RESULTS Aortic eNOS and iNOS protein expressions, Akt activity, and eNOS phosphorylation by Akt at serine 1177 were up-regulated in cirrhotic rats. Norfloxacin administration significantly decreased the incidence of gram-negative translocation and proinflammatory cytokine (tumor necrosis factor-alpha, interferon-gamma, and interleukin-6) levels; norfloxacin also decreased aortic Akt activity, eNOS phosphorylation, and NOS expressions and activities. The decrease in aortic Akt activity and NOS expressions also was obtained after colistin or anti-tumor necrosis factor-alpha antibody administration to cirrhotic rats. CONCLUSIONS This study identifies a signaling pathway in which bacterial translocation induces aortic NOS up-regulation and thus NO overproduction in cirrhotic rats. These results strongly suggest that bacterial translocation and proinflammatory cytokines play a role in systemic NO overproduction in cirrhosis by the Akt pathway.
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Affiliation(s)
- Khalid A Tazi
- Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM, Hôpital Beaujon, Clichy, France.
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31
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Abstract
AIM: To investigate the expression of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) in the development of esophageal varices in portal hypertensive rats.
METHODS: Thirty male Sprague-Dawley (SD) rats in the model group in which a two-stage ligation of portal vein plus ligation of the left adrenal vein was performed, were divided into three subgroups (M7, M14, and M21) in which the rats were kiued on the seventh day, the 14th d and the 21 d after the complete portal ligation. Thirty male SD rats, which underwent the sham operation in the control group, were also separated into three subgroups (C7, C14 and C21) corresponding to the models. The expression of TNF-α and VEGF in the esophagus of all the six subgroups of rats were measured with immunohistochemical SP technique.
RESULTS: The portal pressure in the three model subgroups was significantly higher than that in the corresponding control subgroups (23.82±1.83 vs 11.61±0.86 cmH2O, 20.90±3.27 vs 11.43±1.55 cmH2O and 20.68±2.27 vs 11.87±0.79 cmH2O respectively, P<0.01), as well as the number (9.3±1.6 vs 5.1±0.8, 11.1±0.8 vs 5.4±1.3 and 11.7±1.5 vs 5.2±1.1 respectively, P<0.01) and the total vascular area (78972.6±3527.8 vs 12993.5±4994.8 μm2, 107207.5±46461.4 vs 11862.6±5423.2 μm2 and 110241.4±49262.2 vs 11973.7±3968.5 μm2 respectively, P<0.01) of submucosal veins in esophagus. Compared to the corresponding controls, the expression of TNF-α and VEGF in M21 was significantly higher (2.23±0.30 vs 1.13±0.28 and 1.65±0.38 vs 0.56±0.30 for TNF-α and VEGF respectively, P <0.01), whereas there was no difference in M7 (1.14±0.38 vs 1.06±0.27 and 0.67±0.35 vs 0.50±0.24 for TNF-α and VEGF respectively, P>0.05) and M14 (1.20±0.25 vs 1.04±0.26 and 0.65±0.18 vs 0.53±0.25 for TNF-α and VEGF respectively, P>0.05). And the expression of TNF-α and VEGF in M21 was significantly higher than that in M7 (2.23±0.30 vs 1.14±0.38 and 1.65±0.38 vs 0.67±0.35 for TNF-α and VEGF respectively, P<0.01) and M14 (2.23±0.30 vs 1.20±0.25 and 1.65±0.38 vs 0.65±0.18 for TNF-α and VEGF respectively, P<0.01), but there was no difference between M7 and M14 (1.14±0.38 vs 1.20±0.25 and 0.67±0.35 vs 0.65±0.18 for TNF-α and VEGF respectively, P >0.05).
CONCLUSION: In the development of esophageal varices in portal hypertensive rats, increased TNF-α and VEGF may be not an early event, and probably play a role in weakening the esophageal wall and the rupture of esophageal varices.
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Affiliation(s)
- Zhao-Hui Yin
- Division of Transplantation Surgery, Center for Surgical Sciences, Karolinska University Hospital, Huddinge B56, S-141 86 Stockholm, Sweden.
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32
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Connelly L, Madhani M, Hobbs AJ. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo. J Biol Chem 2005; 280:10040-6. [PMID: 15647265 DOI: 10.1074/jbc.m411991200] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The expression of inducible nitric-oxide synthase (iNOS) and subsequent "high-output" nitric oxide (NO) production underlies the systemic hypotension, inadequate tissue perfusion, and organ failure associated with septic shock. Therefore, modulators of iNOS expression and activity, both endogenous and exogenous, are important in determining the magnitude and time course of this condition. We have shown previously that NO from the constitutive endothelial NOS (eNOS) is necessary to obtain maximal iNOS expression and activity following exposure of murine macrophages to lipopolysaccharide (LPS). Thus, eNOS represents an important regulator of iNOS expression in vitro. Herein, we validate this hypothesis in vivo using a murine model of sepsis. A temporal reduction in iNOS expression and activity was observed in LPS-treated eNOS knock-out (KO) mice as compared with wild-type animals; this was reflected in a more stable hemodynamic profile in eNOS KO mice during endotoxaemia. Furthermore, in human umbilical vein endothelial cells, LPS leads to the activation of eNOS through phosphoinositide 3-kinase- and Akt/protein kinase B-dependent enzyme phosphorylation. These data indicate that the pathogenesis of sepsis is characterized by an initial eNOS activation, with the resultant NO acting as a co-stimulus for the expression of iNOS, and therefore highlight a novel pro-inflammatory role for eNOS.
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Affiliation(s)
- Linda Connelly
- Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AE, UK
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33
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Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A. Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 2004; 24:2320-5. [PMID: 15374849 DOI: 10.1161/01.atv.0000145573.36113.8a] [Citation(s) in RCA: 217] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. High-mobility group box 1 (HMGB1) is a DNA-binding protein, which on release from cells exhibits potent inflammatory actions. We examined its expression in atherosclerotic lesions and regulation by cytokines. METHODS AND RESULTS In atherosclerotic lesions, HMGB1 protein is expressed by endothelial cells, some intimal smooth muscle cells, and macrophages. As atherosclerosis develops and progresses from fatty streaks to fibrofatty lesion, the number of HMGB1-producing macrophages increases markedly. Studies using the THP-1 cell line indicated that HMGB1 mRNA expression could be markedly upregulated by inflammatory cytokines, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and also transforming growth factor (TGF)-beta. IFN-gamma, TNF-alpha, TWEAK, and TGF-beta induced an intracellular redistribution of HMGB1 and stimulated secretion by THP-1 cells and human blood monocytes. Inhibitors of MEK1/MEK2, protein kinase C, and PI-3/Akt, which inhibit lysosomal degranulation and mRNA translation, attenuated cytokine-induced HMGB1 secretion. CONCLUSIONS Macrophage is the major cell type responsible for HMGB1 production in human atherosclerotic lesions. Inflammatory cytokines and TGF-beta increase HMGB1 expression and secretion by monocyte/macrophages. HMGB1 appears to be a common mediator of inflammation induced by inflammatory cytokines and is likely to contribute to lesion progression and chronic inflammation.
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MESH Headings
- Aorta, Abdominal/chemistry
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
- Aorta, Thoracic/chemistry
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Arteriosclerosis/metabolism
- Arteriosclerosis/pathology
- Cells, Cultured
- Cytokines/physiology
- Endothelium, Vascular/chemistry
- Endothelium, Vascular/cytology
- Endothelium, Vascular/pathology
- Gene Expression Regulation/physiology
- HMGB1 Protein/genetics
- HMGB1 Protein/immunology
- HMGB1 Protein/metabolism
- Humans
- Immunohistochemistry/methods
- Inflammation Mediators/physiology
- Macrophage Activation/physiology
- Macrophages/physiology
- Monocytes/chemistry
- Monocytes/cytology
- Monocytes/metabolism
- Muscle, Smooth, Vascular/chemistry
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiology
- Myocytes, Smooth Muscle/chemistry
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/physiology
- Protein Transport/physiology
- RNA, Messenger/biosynthesis
- Tunica Intima/chemistry
- Tunica Intima/pathology
- Tunica Intima/physiology
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Affiliation(s)
- N Kalinina
- Baker Heart Research Institute, Alfred Hospital, Melbourne, Australia
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34
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Elsasser TH, Kahl S, MacLeod C, Nicholson B, Sartin JL, Li C. Mechanisms underlying growth hormone effects in augmenting nitric oxide production and protein tyrosine nitration during endotoxin challenge. Endocrinology 2004; 145:3413-23. [PMID: 15044352 DOI: 10.1210/en.2004-0063] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The present study defined the effects of GH administration on components of the nitric oxide (NO)-generating cascade to account for observed increases in NO production and protein nitration after an immune challenge. Calves were assigned to groups with or without GH treatment (100 microg GH/kg body weight or placebo im, daily for 12 d) and with or without low-level endotoxin [lipopolysaccharide (LPS), 2.5 microg/kg, or placebo, iv]. Plasma was obtained for estimation of NO changes as [NO(2)(-) + NO(3)(-)] (NO(x)). Transcutaneous liver biopsies were collected for measurement of protein tyrosine nitration, cationic amino acid transporter (CAT)-2 mRNA transporter, and constitutive NO synthase (cNOS), inducible NOS (iNOS), and arginase activity. Liver protein nitration increased more than 10-fold 24 h after LPS and an additional 2-fold in animals treated with GH before LPS. GH increased plasma NO(x) after LPS to levels 27% greater than those measured in non-GH-treated calves. LPS increased CAT-2 mRNA after LPS; GH was associated with a 24% reduction in CAT-2 mRNA content at the peak time response. cNOS activity was 3-fold greater than iNOS after LPS. NOS activities were increased 140% (cNOS) at 3 h and 169% (iNOS) at 6 h, respectively, after LPS; GH treatment increased cNOS activity and the phosphorylation of endothelial NOS after LPS more than 2-fold over that measured in non-GH-treated calves. The data suggest that an increased production of nitrated protein develops in the liver during low-level, proinflammatory stress, and nitration is increased by GH administration through a direct effect on the competing activities of NOS and arginase, modulatable critical control points in the proinflammatory cascade.
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Affiliation(s)
- Ted H Elsasser
- United States Department of Agriculture, Agricultural Research Service, Growth Biology Laboratory, B-200, Room 201, Beltsville Agricultural Research Center-East, Beltsville, Maryland 20705, USA.
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35
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Chen L, Taishi P, Majde JA, Peterfi Z, Obal F, Krueger JM. The role of nitric oxide synthases in the sleep responses to tumor necrosis factor-alpha. Brain Behav Immun 2004; 18:390-8. [PMID: 15157956 DOI: 10.1016/j.bbi.2003.12.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2003] [Revised: 12/03/2003] [Accepted: 12/05/2003] [Indexed: 11/28/2022] Open
Abstract
It is well established that cytokines such as tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) are involved in physiological sleep regulation, yet their downstream somnogenic mechanisms remain largely uninvestigated. Nitric oxide (NO) is an effector molecule for some TNFalpha actions. Neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) gene knockout (KO) mice sleep differently than their respective controls. In this study, we tested the hypothesis that NO mediates TNFalpha-induced sleep using iNOS and nNOS KO mice and their corresponding wild-type controls. Systemic administration of TNFalpha increased non-rapid eye movement sleep (NREMS) in the two control strains and in the iNOS KO mice during the first 4 h post-injection but failed to increase NREMS in nNOS KO mice. Rapid eye movement sleep (REMS) was suppressed by TNFalpha in nNOS controls but not in the other strains examined. The results suggest that TNFalpha affects sleep, in part, through nNOS.
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Affiliation(s)
- Lichao Chen
- Department of VCAPP, Washington State University, Pullman, WA 99164-6520, USA
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36
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Tsugawa K, Jones MK, Akahoshi T, Moon WS, Maehara Y, Hashizume M, Sarfeh IJ, Tarnawski AS. Abnormal PTEN expression in portal hypertensive gastric mucosa: a key to impaired PI 3-kinase/Akt activation and delayed injury healing? FASEB J 2003; 17:2316-8. [PMID: 14525948 DOI: 10.1096/fj.02-1107fje] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a dual-specificity phosphatase that has activity toward both phosphorylated peptides and phospholipids. PTEN inhibits activation of Akt, the downstream effector of PI 3-kinase, which is integral to cell proliferation, migration, survival, and angiogenesis essential for tissue injury healing. PTEN expression and activation during injury healing remain unexplored. Portal hypertensive (PHT) gastric mucosa has impaired injury healing, but the underlying mechanisms remain unknown. We investigated whether impaired healing of injured PHT gastric mucosa is due to abnormal PTEN expression/activation that leads to decreased Akt activation. We also investigated the possible involvement of Egr-1, which regulates PTEN in some cells (e.g., fetal kidney epithelial cells), and TNF-alpha, which can induce Egr-1 expression. In PHT gastric mucosa 6 h after injury, PTEN protein levels were increased by 2.7-fold; unphosphorylated PTEN (reflecting activated PTEN) was increased by 2.4-fold; Akt phosphorylation (reflecting Akt activation) was reduced by 2-fold; and Egr-1 expression was increased by 3.3-fold vs. normal gastric mucosa. TNF-alpha neutralization reversed all of the above abnormalities in PHT gastric mucosa, reduced mucosal injury, and enhanced healing. We conclude that, in injured PHT gastric mucosa, overexpressed/activated PTEN leads to the reduced activation of the PI 3-kinase/Akt pathway that results in impaired injury healing.
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Affiliation(s)
- Kouji Tsugawa
- Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA
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37
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Connelly L, Jacobs AT, Palacios-Callender M, Moncada S, Hobbs AJ. Macrophage endothelial nitric-oxide synthase autoregulates cellular activation and pro-inflammatory protein expression. J Biol Chem 2003; 278:26480-7. [PMID: 12740377 DOI: 10.1074/jbc.m302238200] [Citation(s) in RCA: 125] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Expression of inducible nitric-oxide (NO) synthase (iNOS) and "high-output" production of NO by macrophages mediates many cytotoxic actions of these immune cells. However, macrophages have also been shown to express a constitutive NOS isoform, the function of which remains obscure. Herein, bone marrow-derived macrophages (BMDMØs) from wild-type and endothelial NOS (eNOS) knock-out (KO) mice have been used to assess the role of this constitutive NOS isoform in the regulation of macrophage activation. BMDMØs from eNOS KO animals exhibited reduced nuclear factor-kappaB activity, iNOS expression, and NO production after exposure to lipopolysaccharide (LPS) as compared with cells derived from wild-type mice. Soluble guanylate cyclase (sGC) was identified in BMDMØs at a mRNA and protein level, and activation of cells with LPS resulted in accumulation of cyclic GMP. Moreover, the novel non-NO-based sGC activator, BAY 41-2272, enhanced BMDMØ activation in response to LPS, and the sGC inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one attenuated activation. These observations provide the first demonstration of a pathophysiological role for macrophage eNOS in regulating cellular activation and suggest that NO derived from this constitutive NOS isoform, in part via activation of sGC, is likely to play a pivotal role in the initiation of an inflammatory response.
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Affiliation(s)
- Linda Connelly
- Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095, USA
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38
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Barsacchi R, Perrotta C, Bulotta S, Moncada S, Borgese N, Clementi E. Activation of endothelial nitric-oxide synthase by tumor necrosis factor-alpha: a novel pathway involving sequential activation of neutral sphingomyelinase, phosphatidylinositol-3' kinase, and Akt. Mol Pharmacol 2003; 63:886-95. [PMID: 12644590 DOI: 10.1124/mol.63.4.886] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Activation of endothelial nitric-oxide synthase (eNOS) has been shown to occur through various pathways involving increases in the cytosolic Ca(2+) concentration, activation of the phosphatidylinositol-3' kinase/Akt pathway, as well as regulation by other kinases and by protein-protein interactions. We have recently reported that eNOS, expressed in an inducible HeLa Tet-off cell line, is activated by tumor necrosis factor-alpha (TNF-alpha) in a previously undescribed pathway that involves the lipid messenger ceramide. We have now characterized this pathway. We report here that eNOS activation in response to TNF-alpha correlated with phosphorylation of Akt at Ser 473 and of eNOS itself at Ser 1179. Akt and eNOS phosphorylation, as well as eNOS activation, were blocked by inhibitors of both phosphatidylinositol-3' kinase and neutral sphingomyelinase. In contrast, although acid sphingomyelinase was also stimulated by TNF-alpha, its inhibition was without effect. The activation of neutral sphingomyelinase triggered by TNF-alpha was insensitive to phosphatidylinositol-3' kinase inhibitors. Taken together, these results indicate that eNOS activation by TNF-alpha occurs through sequential activation of neutral sphingomyelinase and of the phosphatidylinositol-3' kinase/Akt pathway. The time course of eNOS activation induced through this pathway was markedly different from that triggered by ATP and epidermal growth factor, which activate eNOS through an increase in intracellular Ca(2+) concentration and through a sphingomyelinase-independent stimulation of the phosphatidylinositol-3' kinase/Akt pathway, respectively. The novel pathway of activation of eNOS described here may have broad biological relevance because neutral sphingomyelinase is activated not only by TNF-alpha but also by a variety of other physiological and pathological stimuli.
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Affiliation(s)
- Rico Barsacchi
- Vita-Salute University-DIBIT H San Raffaele Institute, Milan, Italy
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39
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Hilzenrat N, Yaari A, Sikuler E. Late hemodynamic changes following controlled hemorrhage and volume restitution with blood or Haemaccel in anesthetized portal hypertensive rats. J Gastroenterol Hepatol 2002; 17:1317-22. [PMID: 12423278 DOI: 10.1046/j.1440-1746.2002.02886.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM In portal hypertensive rats, hemorrhage and acute volume restitution with Haemaccel induced increased cardiac output and portal venous inflow. In the present study, the late hemodynamic effects of this procedure were explored. METHODS Portal hypertension was induced by portal vein constriction. Blood was withdrawn 11.2 +/- 3.2 days later, at a rate of 0.3 mL/min, for 15 min, followed by 15 min of stabilization. Haemaccel or blood were infused at the same rate and volume used for withdrawal. Hemodynamic measurements were performed after 24 h, using radioactive microspheres. Viscosity was measured with an Ostwald viscometer. Vascular hindrance was calculated as resistance/viscosity ratio. RESULTS Blood viscosity of the Haemaccel group (n = 11), was lower than in the blood group (n = 11): 2.7 +/- 0.2 versus 4.0 +/- 0.4 (P < 0.01). Arterial pressure, cardiac output, peripheral resistance, portal pressure, portal venous inflow and splanchnic arteriolar resistance were not significantly different. Splanchnic arteriolar and portocollateral hindrance were higher in the Haemaccel group (11.7 +/- 5.3 and 1.5 +/- 0.6 vs 7.7 +/- 3.0 and 0.9 +/- 0.4 mmHg x min x 100 gram body weight/mL, respectively, P < 0.05). CONCLUSION In portal hypertensive rats, vital organs perfusion, 24 h after hemorrhage and isovolemic volume restitution with Haemaccel and blood, was similar. However, in Haemaccel-transfused animals, a reduction in vascular hindrance, indicating vasoconstriction, was observed in the splanchnic organs, which drain into the portal circulation. Vasoconstriction of the portocollateral vascular bed was observed as well. We suggest that slow-rate volume replacement during a portal-hypertensive-related bleeding episode enables hemodynamic adaptation to occur. Thus, undesirable hyperdynamic changes, which may aggravate secondary bleeding, are attenuated.
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Affiliation(s)
- Nir Hilzenrat
- Liver Research Laboratory, The Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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40
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Figueroa XF, González DR, Martínez AD, Durán WN, Boric MP. ACh-induced endothelial NO synthase translocation, NO release and vasodilatation in the hamster microcirculation in vivo. J Physiol 2002; 544:883-96. [PMID: 12411531 PMCID: PMC2290640 DOI: 10.1113/jphysiol.2002.021972] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Studies in cultured cells show that activation of endothelial nitric oxide (NO) synthase (eNOS) requires the dissociation of this enzyme from its inhibitory association with caveolin-1 (Cav-1), and perhaps its translocation from plasma membrane caveolae to other cellular compartments. We investigated the hypothesis that in vivo NO-dependent vasodilatation is associated with the translocation of eNOS from the cell membrane. To this end, we applied ACh topically (10-100 microM for 10 min) to the hamster cheek pouch microcirculation and measured NO production, blood flow and vessel diameter, and assessed subcellular eNOS distribution by Western blotting. Baseline NO production was 54.4 +/- 5.2 pmol min(-1) (n = 16). ACh increased NO release, caused arteriolar and venular dilatation and elevated microvascular flow. These responses were inhibited by N(G)-nitro-L-arginine (30 microM). The maximal increase in NO production induced by 10 microM and 100 microM ACh was 45 +/- 20 % and 111 +/- 33 %, respectively; the corresponding blood flow increases were 50 +/- 10 % and 130 +/- 24 %, respectively (n = 4-6). Both responses followed a similar time course, although increases in NO preceded flow changes. In non-stimulated tissues, eNOS was distributed mainly in the microsomal fraction. ACh-induced vasodilatation was associated with eNOS translocation to the cytosolic and Golgi-enriched fractions. After 1.5, 3.0 or 6.0 min of application, 10 microM ACh decreased the level of membrane-bound eNOS by -13 +/- 4 %, -60 +/- 4 % and -19 +/- 17 %, respectively; at the same time points, 100 microM ACh reduced microsomal eNOS content by -38 +/- 9 %, -61 +/- 16 % and -40 +/- 18 %, respectively (n = 4-5). In all cases, microsomal Cav-1 content did not change. The close ACh concentration dependence and the concomitance between eNOS subcellular redistribution and NO release support the concept that eNOS translocation from the plasma membrane is part of an activation mechanism that induces NO-dependent vasodilatation in vivo.
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Affiliation(s)
- Xavier F Figueroa
- Unidad de Regulación Neurohumoral, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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