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Pun C, Huang HC, Chang CC, Hsu SJ, Chuang CL, Huang YH, Hou MC, Lee FY. Low-dose alcohol exacerbates hyperdynamic circulation and shunting in non-alcoholic cirrhotic rats. Biosci Rep 2024; 44:BSR20240354. [PMID: 38967060 PMCID: PMC11263042 DOI: 10.1042/bsr20240354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Portal hypertension affects hepatic, splanchnic and portosystemic collateral systems. Although alcohol is a well-known risk factor for liver cirrhosis, it also affects vascular contractility. However, the relevant effects on portal hypertension have not been evaluated in non-alcoholic cirrhosis. The present study aimed to investigate the impacts of low-dose alcohol on portal hypertension-related derangements in non-alcoholic cirrhotic rats. METHODS Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The chronic or acute effects of low-dose alcohol (2.4 g/kg/day, oral gavage, approximately 1.3 drinks/day in humans) were evaluated. RESULTS The chronic administration of low-dose alcohol did not precipitate liver fibrosis in the sham or cirrhotic rats; however, it significantly increased splanchnic blood inflow (P=0.034) and portosystemic collaterals (P=0.001). Mesenteric angiogenesis and pro-angiogenic proteins were up-regulated in the alcohol-treated cirrhotic rats, and poorer collateral vasoresponsiveness to vasoconstrictors (P<0.001) was noted. Consistently, acute alcohol administration reduced splenorenal shunt resistance. Collateral vasoresponsiveness to vasoconstrictors also significantly decreased (P=0.003). CONCLUSIONS In non-alcoholic cirrhosis rats, a single dose of alcohol adversely affected portosystemic collateral vessels due to vasodilatation. Long-term alcohol use precipitated splanchnic hyperdynamic circulation, in which mesenteric angiogenesis played a role. Further studies are warranted to evaluate the benefits of avoiding low-dose alcohol consumption in patients with non-alcoholic cirrhosis.
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Affiliation(s)
- Chon Kit Pun
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Chih Chang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Xu Y, Dai ST, Lu HQ, Chen W, Xiong ZW, Liu J, Tang YJ, Guo SK, Gong KM. Correlation between white blood cell count and intestinal resection in patients with acute mesenteric vein thrombosis. BMC Gastroenterol 2024; 24:83. [PMID: 38395771 PMCID: PMC10885526 DOI: 10.1186/s12876-024-03172-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
OBJECTIVE Acute mesenteric vein thrombosis (AMVT) is an acute abdominal disease with onset, rapid progression, and extensive intestinal necrosis that requires immediate surgical resection. The purpose of this study was to determine the risk factors for nosocomial intestinal resection in patients with AMVT. METHODS We retrospectively analysed 64 patients with AMVT diagnosed by CTA at the Affiliated Hospital of Kunming University of Science and Technology from January 2013 to December 2021. We compared patients who underwent intestinal resection (42 patients) with those who did not undergo intestinal resection (22 patients). The area under the ROC curve was evaluated, and a forest map was drawn. RESULTS Among the 64 patients, 6 (9.38%) had a fever, 60 (93.75%) had abdominal pain, 9 (14.06%) had a history of diabetes, 8 (12.5%) had a history of deep vein thrombosis (DVT), and 25 (39.06%) had ascites suggested by B ultrasound or CT after admission. The mean age of all patients was 49.86 ± 16.25 years. The mean age of the patients in the enterectomy group was 47.71 ± 16.20 years. The mean age of the patients in the conservative treatment group (without enterectomy) was 53.95 ± 15.90 years. In the univariate analysis, there were statistically significant differences in leukocyte count (P = 0.003), neutrophil count (P = 0.001), AST (P = 0.048), total bilirubin (P = 0.047), fibrinogen (P = 0.022) and DD2 (P = 0.024) between the two groups. The multivariate logistic regression analysis showed that admission white blood cell count (OR = 1.153, 95% CI: 1.039-1.280, P = 0.007) was an independent risk factor for intestinal resection in patients with AMVT. The ROC curve showed that the white blood cell count (AUC = 0.759 95% CI: 0.620-0.897; P = 0.001; optimal threshold: 7.815; sensitivity: 0.881; specificity: 0.636) had good predictive value for emergency enterectomy for AMVT. CONCLUSIONS Among patients with AMVT, patients with a higher white blood cell count at admission were more likely to have intestinal necrosis and require emergency enterectomy. This study is helpful for clinicians to accurately determine whether emergency intestinal resection is needed in patients with AMVT after admission, prevent further intestinal necrosis, and improve the prognosis of patients.
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Affiliation(s)
- Yu Xu
- Panzhihua Central Hospital, 34 Yikang St, 617000, Panzhihua, Sichuan Province, China
| | - Shang-Tai Dai
- The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, 650500, Kunming City, Yunnan Province, P.R. China
| | - Hong-Qiao Lu
- The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, 650500, Kunming City, Yunnan Province, P.R. China
| | - Wei Chen
- Panzhihua Central Hospital, 34 Yikang St, 617000, Panzhihua, Sichuan Province, China
| | - Zhi-Wei Xiong
- Panzhihua Central Hospital, 34 Yikang St, 617000, Panzhihua, Sichuan Province, China
| | - Jiang Liu
- Panzhihua Central Hospital, 34 Yikang St, 617000, Panzhihua, Sichuan Province, China
| | - Yong-Jiang Tang
- Panzhihua Central Hospital, 34 Yikang St, 617000, Panzhihua, Sichuan Province, China.
| | - Shi-Kui Guo
- The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, 650500, Kunming City, Yunnan Province, P.R. China.
| | - Kun-Mei Gong
- The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, 650500, Kunming City, Yunnan Province, P.R. China.
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Jeong J, Tanaka M, Yang Y, Arefyev N, DiRito J, Tietjen G, Zhang X, McConnell MJ, Utsumi T, Iwakiri Y. An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver. Am J Physiol Gastrointest Liver Physiol 2023; 325:G379-G390. [PMID: 37605828 PMCID: PMC10887843 DOI: 10.1152/ajpgi.00139.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023]
Abstract
The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and coimmunolabeling protocol optimized for the tissue size and the processing time for three-dimensional (3-D) visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species. With this protocol, we have shown 3-D LVs configurations in relation to blood vessels and bile ducts in cholestatic mouse livers, in which LVs were highly dilated and predominantly found around highly proliferating bile ducts and peribiliary vascular plexuses in the portal tract. We also established a quantification method using a 3-D volume-rendering approach. We observed a 1.6-fold (P < 0.05) increase in the average diameter of LVs and a 2.4-fold increase (P < 0.05) in the average branch number of LVs in cholestatic/fibrotic livers compared with control livers. Furthermore, cholestatic/fibrotic livers showed a 4.3-fold increase (P < 0.05) in total volume of LVs compared with control livers. Our optimized protocol and quantification method demonstrate an efficient and simple liver tissue-clearing procedure that allows the comprehensive analysis of liver lymphatic system.NEW & NOTEWORTHY This article showed a comprehensive 3-D-structural analysis of liver lymphatic vessel (LV) in normal and diseased livers in relation to blood vessels and bile ducts. In addition to the LVs highly localized at the portal tract, we revealed capsular LVs in mouse, rat, and human livers. In cholestatic livers, LVs are significantly increased and dilated compared with normal livers. Our optimized protocol provides detailed spatial information for LVs remodeling in normal and pathological conditions.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Masatake Tanaka
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
- Division of Pathophysiology, Medical Institute of Bioregulation and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Nikolai Arefyev
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Jenna DiRito
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Gregory Tietjen
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Matthew J McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
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Yu F, Zhu Y, Li N, Fu HF, Jiang Z, Zhang XY, Zeng L, Hu XY. Gastro‑oesophageal reflux disease in liver cirrhosis: Possible pathogenesis and clinical intervention (Review). Exp Ther Med 2023; 26:414. [PMID: 37559931 PMCID: PMC10407984 DOI: 10.3892/etm.2023.12113] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/31/2023] [Indexed: 08/11/2023] Open
Abstract
Oesophageal variceal bleeding is a common complication of decompensated liver cirrhosis (LC). Some studies have reported that reflux oesophagitis (RE) is a risk factor for upper gastrointestinal bleeding, and greatly impacts the quality of life. However, the frequency and mechanism of gastro-oesophageal reflux disease (GERD) in LC remain unclear. The present review explored the possible pathogenesis, and analysed the advantages and disadvantages of the interventional measures and the need for implementation of these measures. By combining the comprehensive terms associated with LC, GERD and RE, EMBASE, Medline/PubMed and the Cochrane Library were systematically searched. The underlying pathological mechanism of GERD in LC was summarized: Transient relaxation of the lower oesophageal sphincter, delayed gastric emptying, increased intra-abdominal pressure, increased intragastric pressure and excessive nitric oxide production destroyed the 'anti-reflux barrier', causing gastric content reflux. Proton pump inhibitors (PPIs) have been widely used empirically to lower the risk of oesophageal venous rupture and bleeding. However, long-term use of acid inhibitors in patients with LC may induce complications, such as spontaneous bacterial peritonitis. The metabolic half-life of PPIs is prolonged in patients with severe liver function impairment. Therefore, the indications for using acid inhibitors lack clarity. However, after endoscopic oesophageal variceal eradication, additional benefits may be gained from the long-term use of PPIs in small doses.
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Affiliation(s)
- Fei Yu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Yue Zhu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Na Li
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Hong-Fang Fu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Zhi Jiang
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiao-Yi Zhang
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Liang Zeng
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiao-Yu Hu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
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Sturm L, Bettinger D, Roth L, Zoldan K, Stolz L, Gahm C, Huber JP, Reincke M, Kaeser R, Boettler T, Kreisel W, Thimme R, Schultheiss M. Plasma Cyclic Guanosine Monophosphate Is a Promising Biomarker of Clinically Significant Portal Hypertension in Patients With Liver Cirrhosis. Front Med (Lausanne) 2022; 8:803119. [PMID: 35059421 PMCID: PMC8764357 DOI: 10.3389/fmed.2021.803119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: Despite intensive research, reliable blood-derived parameters to detect clinically significant portal hypertension (CSPH) in patients with cirrhosis are lacking. As altered homeostasis of cyclic guanosine monophosphate (cGMP), the central mediator of vasodilatation, is an essential factor in the pathogenesis of portal hypertension, the aim of our study was to evaluate plasma cGMP as potential biomarker of cirrhotic portal hypertension. Methods: Plasma cGMP was analyzed in cirrhotic patients with CSPH (ascites, n = 39; esophageal varices, n = 31), cirrhotic patients without CSPH (n = 21), patients with chronic liver disease without cirrhosis (n = 11) and healthy controls (n = 8). cGMP was evaluated as predictor of CSPH using logistic regression models. Further, the effect of transjugular intrahepatic portosystemic shunt (TIPS) placement on plasma cGMP was investigated in a subgroup of cirrhotic patients (n = 13). Results: Plasma cGMP was significantly elevated in cirrhotic patients with CSPH compared to cirrhotic patients without CSPH [78.1 (67.6-89.2) pmol/ml vs. 39.1 (35.0-45.3) pmol/l, p < 0.001]. Of note, this effect was consistent in the subgroup of patients with esophageal varices detected at screening endoscopy who had no prior manifestations of portal hypertension (p < 0.001). Cirrhotic patients without CSPH displayed no significant elevation of plasma cGMP compared to patients without cirrhosis (p = 0.347) and healthy controls (p = 0.200). Regression analyses confirmed that cGMP was an independent predictor of CSPH (OR 1.042, 95% CI 1.008-1.078, p = 0.016). Interestingly, portal decompression by TIPS implantation did not lead to normalization of plasma cGMP levels (p = 0.101). Conclusions: Plasma cGMP is a promising biomarker of CSPH in patients with cirrhosis, especially with respect to screening for esophageal varices. The lacking normalization of plasma cGMP after portal decompression suggests that elevated plasma cGMP in cirrhotic portal hypertension is mainly a correlate of systemic and splanchnic vasodilatation, as these alterations have been shown to persist after TIPS implantation.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Lisa Roth
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Laura Stolz
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Chiara Gahm
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- IMM-PACT-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Kreisel
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Huang HC, Tsai MH, Chang CC, Pun CK, Huang YH, Hou MC, Lee FY, Hsu SJ. Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats. Clin Sci (Lond) 2021; 135:2709-2728. [PMID: 34870313 DOI: 10.1042/cs20210602] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/28/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis-related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation (BDL) in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P=0.010, 0.044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated endothelial nitric-oxide synthase (eNOS) was down-regulated. Portosystemic shunts determined by splenorenal shunt (SRS) flow decreased in both transplantation groups (P=0.037, 0.032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared with sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Hung Tsai
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chon Kit Pun
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Huang HC, Ho HL, Chang CC, Chuang CL, Pun CK, Lee FY, Huang YH, Hou MC, Hsu SJ. Matrix metalloproteinase-9 inhibition or deletion attenuates portal hypertension in rodents. J Cell Mol Med 2021; 25:10073-10087. [PMID: 34647412 PMCID: PMC8572799 DOI: 10.1111/jcmm.16940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/29/2022] Open
Abstract
Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague‐Dawley rats. Sham‐operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB‐3CT (MMP‐2 and −9 inhibitor) for 28 days in the first and second series, respectively. MMP‐9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB‐3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α‐SMA and mesenteric eNOS protein expressions compared to wild‐type BDL mice. Liver SMAD2 phosphorylation was down‐regulated in all series with MMP inhibition or knock‐out. In conclusion, MMP‐9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP‐9 may be targeted in the treatment of liver cirrhosis.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsin-Ling Ho
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chon Kit Pun
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Blanco-Rivero J, Xavier FE. Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases. Curr Pharm Des 2021; 26:3633-3651. [PMID: 32242780 DOI: 10.2174/1381612826666200403172736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/08/2020] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.
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Affiliation(s)
- Javier Blanco-Rivero
- Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
| | - Fabiano E Xavier
- Departamento de Fisiologia e Farmacologia, Centro de Biociencias, Universidade Federal de Pernambuco, Recife, Brazil
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Zhang B, Ji LH, Zhang CG, Zhao G, Wu ZY. Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats. World J Gastroenterol 2019; 25:5953-5960. [PMID: 31660032 PMCID: PMC6815798 DOI: 10.3748/wjg.v25.i39.5953] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/28/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Portal hypertension (PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.
AIM To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.
METHODS Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride (CCl4) in both male and female integral and castrated rats (ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.
RESULTS No significant difference in portal pressure was observed between integral and castrated male PHT rats (15.2 ± 2.1 mmHg vs 16.7 ± 2.7 mmHg, P > 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats (12.7 ± 2.7 mmHg vs 16.5 ± 2.4 mmHg, P < 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses (Emax) values were decreased and effective concentrations causing half maximum responses (EC50) values were increased, compared to those of non-PHT rats, both in male and female rats. Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased (P > 0.05). However, there was no difference between integral and ORX male rats with PHT. In integral female PHT rats, the concentration response curves were shifted to the left (P < 0.05), and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats.
CONCLUSION Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.
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Affiliation(s)
- Bin Zhang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Lin-Hua Ji
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Cheng-Gang Zhang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhi-Yong Wu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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10
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Gunarathne LS, Angus PW, Herath CB. Blockade of Mas Receptor or Mas-Related G-Protein Coupled Receptor Type D Reduces Portal Pressure in Cirrhotic but Not in Non-cirrhotic Portal Hypertensive Rats. Front Physiol 2019; 10:1169. [PMID: 31607942 PMCID: PMC6761391 DOI: 10.3389/fphys.2019.01169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022] Open
Abstract
Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl4) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro7-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl4 rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia
| | - Peter W Angus
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, VIC, Australia
| | - Chandana B Herath
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia
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11
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Boregowda U, Umapathy C, Halim N, Desai M, Nanjappa A, Arekapudi S, Theethira T, Wong H, Roytman M, Saligram S. Update on the management of gastrointestinal varices. World J Gastrointest Pharmacol Ther 2019; 10:1-21. [PMID: 30697445 PMCID: PMC6347650 DOI: 10.4292/wjgpt.v10.i1.1] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/24/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis of liver is a major problem in the western world. Portal hypertension is a complication of cirrhosis and can lead to a myriad of pathology of which include the development of porto-systemic collaterals. Gastrointestinal varices are dilated submucosal veins, which often develop at sites near the formation of gastroesophageal collateral circulation. The incidence of varices is on the rise due to alcohol and obesity. The most significant complication of portal hypertension is life-threatening bleeding from gastrointestinal varices, which is associated with substantial morbidity and mortality. In addition, this can cause a significant burden on the health care facility. Gastrointestinal varices can happen in esophagus, stomach or ectopic varices. There has been considerable progress made in the understanding of the natural history, pathophysiology and etiology of portal hypertension. Despite the development of endoscopic and medical treatments, early mortality due to variceal bleeding remains high due to significant illness of the patient. Recurrent variceal bleed is common and in some cases, there is refractory variceal bleed. This article aims to provide a comprehensive review of the management of gastrointestinal varices with an emphasis on endoscopic interventions, strategies to handle refractory variceal bleed and newer endoscopic treatment modalities. Early treatment and improved endoscopic techniques can help in improving morbidity and mortality.
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Affiliation(s)
- Umesha Boregowda
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | - Chandraprakash Umapathy
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | - Nasir Halim
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | - Madhav Desai
- Department of Gastroenterology and Hepatology, Kansas University Medical Center, Kansas City, KS 66160, United States
| | - Arpitha Nanjappa
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | | | - Thimmaiah Theethira
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | - Helen Wong
- Department of Gastroenterology and Hepatology, VA Central California Healthcare System, Fresno, CA 93703, United States
| | - Marina Roytman
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
| | - Shreyas Saligram
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93721, United States
- Department of Gastroenterology and Hepatology, VA Central California Healthcare System, Fresno, CA 93703, United States
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Vinholi A, Fagundes MDC, Pigozzo DC, Kubrusly FB, Kubrusly LF, Marques CAM. INVOLVEMENT OF CATECHOLAMINES IN THE MYOCARDIUM OF RATS SUBMITTED TO EXPERIMENTAL MODEL OF PORTAL HYPERTENSION. ACTA ACUST UNITED AC 2018; 31:e1383. [PMID: 30133675 PMCID: PMC6097112 DOI: 10.1590/0102-672020180001e1383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 05/24/2018] [Indexed: 11/21/2022]
Abstract
Background: The role of autonomic nervous system in the development and maintenance of
portal hypertension is not fully elucidated. It is known that the gene
expression of norepinephrine in the superior mesenteric artery varies with
time, and it may contribute for splanchnic vasodilation and its consequent
hemodynamic repercussions. It is still not known exactly how the adrenergic
expression behaves at the heart level in the initial stages of this process.
Aim: To evaluate the immunohistochemical expression of the enzyme tyrosine
hydroxylase (tyrosine 3-monooxygenase), involved in the synthesis of
norepinephrine, in the myocardium of rats submitted to partial ligation of
the portal vein. Methods: Twenty-four Wistar rats were divided into two groups: Sham
Operated and Portal Hypertension. The partial ligation was performed in the
Portal Hypertension group, and after 1/6/24 h and 3/5/14 days the animals
were euthanized. Immunohistochemical analysis was performed to quantify the
expression of the stained enzyme using the ImageJ program. Results: The Portal Hypertension group expressed percentages between 4.6-6% of the
marked area, while the Sham Operated group varied between 4-5%. Although
there was no statistical significance, the percentage stained in the Portal
Hypertension group followed an increasing pattern in the first 6 h and a
decreasing pattern after 24 h, which was not observed in the Sham Operated
group. Conclusion: The expression of noradrenaline in rat myocardium during the first two weeks
after partial ligation of the portal vein, with tyrosine hydroxylase as
marker, did not show differences between groups over time.
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Affiliation(s)
- Antonella Vinholi
- Faculdade Evangélica do Paraná and Institute of Medical Research/Post-Graduation in Principles of Surgery.,Denton Cooley Institute
| | - Marília Da Cruz Fagundes
- Faculdade Evangélica do Paraná and Institute of Medical Research/Post-Graduation in Principles of Surgery.,Denton Cooley Institute
| | - Danieli Cristina Pigozzo
- Faculdade Evangélica do Paraná and Institute of Medical Research/Post-Graduation in Principles of Surgery.,Denton Cooley Institute
| | | | - Luiz Fernando Kubrusly
- Faculdade Evangélica do Paraná and Institute of Medical Research/Post-Graduation in Principles of Surgery.,Denton Cooley Institute
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13
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Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution. Clin Sci (Lond) 2018; 132:669-683. [PMID: 29449343 DOI: 10.1042/cs20171370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 02/09/2018] [Accepted: 02/15/2018] [Indexed: 12/20/2022]
Abstract
Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague-Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.
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Bosch J, Iwakiri Y. The portal hypertension syndrome: etiology, classification, relevance, and animal models. Hepatol Int 2017; 12:1-10. [PMID: 29064029 DOI: 10.1007/s12072-017-9827-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/26/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Portal hypertension is a key complication of portal hypertension, which is responsible for the development of varices, ascites, bleeding, and hepatic encephalopathy, which, in turn, cause a high mortality and requirement for liver transplantation. AIM This review deals with the present day state-of-the-art preventative treatments of portal hypertension in cirrhosis according to disease stage. Two main disease stages are considered, compensated and decompensated cirrhosis, the first having good prognosis and being mostly asymptomatic, and the second being heralded by the appearance of bleeding or non-bleeding complications of portal hypertension. RESULTS The aim of treatment in compensated cirrhosis is preventing clinical decompensation, the more frequent event being ascites, followed by variceal bleeding and hepatic encephalopathy. Complications are mainly driven by an increase of hepatic vein pressure gradient (HVPG) to values ≥10 mmHg (defining the presence of Clinically Significant Portal Hypertension, CSPH). Before CSPH, the treatment is limited to etiologic treatment of cirrhosis and healthy life style (abstain from alcohol, avoid/correct obesity…). When CSPH is present, association of a non-selective beta-blocker (NSBB), including carvedilol should be considered. NSBBs are mandatory if moderate/large varices are present. Patients should also enter a screening program for hepatocellular carcinoma. In decompensated patients, the goal is to prevent further bleeding if the only manifestation of decompensation was a bleeding episode, but to prevent liver transplantation and death in the common scenario where patients have manifested first non-bleeding complications. Treatment is based on the same principles (healthy life style..) associated with administration of NSBBs in combination if possible with endoscopic band ligation if there has been variceal bleeding, and complemented with simvastatin administration (20-40 mg per day in Child-Pugh A/B, 10-20 mg in Child C). Recurrence shall be treated with TIPS. TIPS might be indicated earlier in patients with: 1) Difficult/refractory ascites, who are not the best candidates for NSBBs, 2) patients having bleed under NSBBs or showing no HVPG response (decrease in HVPG of at least 20% of baseline or to values equal or below 12 mmHg). Decompensated patients shall all be considered as potential candidates for liver transplantation. CONCLUSION Treatment of portal hypertension has markedly improved in recent years. The present day therapy is based on accurate risk stratification according to disease stage.
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Affiliation(s)
- Jaime Bosch
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, C.Villarroel 170, 08036, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain. .,Swiss Liver Center, Hepatology, UVCM, Inselspital, University of Bern, Bern, Switzerland.
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
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Di Pascoli M, Sacerdoti D, Pontisso P, Angeli P, Bolognesi M. Molecular Mechanisms Leading to Splanchnic Vasodilation in Liver Cirrhosis. J Vasc Res 2017; 54:92-99. [PMID: 28402977 DOI: 10.1159/000462974] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/06/2017] [Indexed: 12/12/2022] Open
Abstract
In liver cirrhosis, portal hypertension is a consequence of enhanced intrahepatic vascular resistance and portal blood flow. Significant vasodilation in the arterial splanchnic district is crucial for an increase in portal flow. In this pathological condition, increased levels of circulating endogenous vasodilators, including nitric oxide, prostacyclin, carbon monoxide, epoxyeicosatrienoic acids, glucagon, endogenous cannabinoids, and adrenomedullin, and a decreased vascular response to vasoconstrictors are the main mechanisms underlying splanchnic vasodilation. In this review, the molecular pathways leading to splanchnic vasodilation will be discussed in detail.
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Affiliation(s)
- Marco Di Pascoli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University of Padova, Padua, Italy
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Kim JH. Effects of portal hyperperfusion on partial liver grafts in the presence of hyperdynamic splanchnic circulation: hepatic regeneration versus portal hyperperfusion injury. Anesth Pain Med (Seoul) 2016. [DOI: 10.17085/apm.2016.11.2.117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Jong Hae Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Catholic University of Daegu, Daegu, Korea
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Hsu SJ, Lee FY, Wang SS, Hsin IF, Lin TY, Huang HC, Chang CC, Chuang CL, Ho HL, Lin HC, Lee SD. Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. Hepatology 2015; 61:1672-84. [PMID: 25557829 DOI: 10.1002/hep.27679] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 12/20/2014] [Indexed: 12/12/2022]
Abstract
UNLABELLED Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque-Dawley rats with common bile duct ligation-induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6-cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice-weekly for 8 weeks)-induced cirrhotic rats. Caffeine down-regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho-VEGFR2, and phospho-Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. CONCLUSIONS Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH-related complications in cirrhosis.
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Affiliation(s)
- Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University Hospital, Yilan, Taiwan
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Abstract
Portal hypertension is a major complication of liver disease that results from a variety of pathologic conditions that increase the resistance to the portal blood flow into the liver. As portal hypertension develops, the formation of collateral vessels and arterial vasodilation progresses, which results in increased blood flow to the portal circulation. Hyperdynamic circulatory syndrome develops, leading to esophageal varices or ascites. This article summarizes the factors that increase (1) intrahepatic vascular resistance and (2) the blood flow in the splanchnic and systemic circulations in liver cirrhosis. In addition, the future directions of basic/clinical research in portal hypertension are discussed.
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Zhang B, Zhang CG, Zhou QB, Chen W, Wu ZY. Estrogen improves the hyperdynamic circulation and hyporeactivity of mesenteric arteries by alleviating oxidative stress in partial portal vein ligated rats. World J Gastroenterol 2013; 19:6863-6868. [PMID: 24187462 PMCID: PMC3812486 DOI: 10.3748/wjg.v19.i40.6863] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/18/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of estrogen (E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.
METHODS: Fifty castrated female Sprague-Dawley rats were divided into five groups: sham operation (SO), partial portal vein ligation (PPVL) + placebo (PLAC), PPVL + E2, PPVL + ICI and PPVL + E2 + ICI. Hemodynamic measurements were performed using ultrasonography. Mesenteric arteriole contractility in response to norepinephrine was determined using a vessel perfusion system. Oxidative stress in the mesenteric artery was investigated by in situ detection of the superoxide anion (O2•−) and hydrogen peroxide (H2O2) concentrations.
RESULTS: Treatment with E2 resulted in a significant decrease of portal pressure (P < 0.01) and portal venous inflow (P < 0.05), and higher systemic vascular resistance (P < 0.05) and splanchnic arteriolar resistance (P < 0.01) in PPVL + E2 rats compared to PPVL + PLAC rats. In the mesenteric arterioles of PPVL + E2 rats, the dose-response curve was shifted left, and the EC50 was decreased (P < 0.01). E2 reduced O2•− production and H2O2 concentration in the mesenteric artery. However, ICI182, 780 reversed the beneficial effects of E2, therefore, the systemic and splanchnic hyperdynamic circulation were more deteriorated in ICI182, 780-treated rats.
CONCLUSION: Treatment with estrogen improved the systemic and splanchnic hyperdynamic circulation in PPVL rats, in part due to the alleviation of oxidative stress.
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Marques C, Licks F, Zattoni I, Borges B, de Souza LER, Marroni CA, Marroni NP. Antioxidant properties of glutamine and its role in VEGF-Akt pathways in portal hypertension gastropathy. World J Gastroenterol 2013; 19:4464-74. [PMID: 23901221 PMCID: PMC3725370 DOI: 10.3748/wjg.v19.i28.4464] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 03/15/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of glutamine on oxidative/nitrosative stress and the vascular endothelial growth factor (VEGF)-Akt-endothelial nitric oxide synthase (eNOS) signaling pathway in an experimental model of portal hypertension induced by partial portal vein ligation (PPVL). METHODS Portal hypertension was induced by PPVL. The PPVL model consists of a partial obstruction of the portal vein, performed using a 20 G blunt needle as a guide, which is gently removed after the procedure. PPVL model was performed for 14 d beginning treatment with glutamine on the seventh day. On the fifteenth day, the mesenteric vein pressure was checked and the stomach was removed to test immunoreactivity and oxidative stress markers. We evaluated the expression and the immunoreactivity of proteins involved in the VEGF-Akt-eNOS pathway by Western blotting and immunohistochemical analysis. Oxidative stress was measured by quantification of the cytosolic concentration of thiobarbituric acid reactive substances (TBARS) as well as the levels of total glutathione (GSH), superoxide dismutase (SOD) activity, nitric oxide (NO) production and nitrotyrosine immunoreactivity. RESULTS All data are presented as the mean ± SE. The production of TBARS and NO was significantly increased in PPVL animals. A reduction of SOD activity was detected in PPVL + G group. In the immunohistochemical analyses of nitrotyrosine, Akt and eNOS, the PPVL group exhibited significant increases, whereas decreases were observed in the PPVL + G group, but no difference in VEGF was detected between these groups. Western blotting analysis detected increased expression of phosphatidylinositol-3-kinase (PI3K), P-Akt and eNOS in the PPVL group compared with the PPVL + G group, which was not observed for the expression of VEGF when comparing these groups. Glutamine administration markedly alleviated oxidative/nitrosative stress, normalized SOD activity, increased levels of total GSH and blocked NO overproduction as well as the formation of peroxynitrite. CONCLUSION Glutamine treatment demonstrated to reduce oxidative damage but does not reduce angiogenesis induced by PH in gastric tissue, demonstrating a beneficial role for the PI3K-Akt-eNOS pathway.
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Abstract
Sex differences in the incidence of liver cirrhosis and portal hypertension have been reported by epidemiological studies. Previous studies have indicated that estrogen therapy improved hepatic fibrosis, inhibited the activation of hepatic stellate cells, and reduced portal pressure, whereas the administration of exogenous estrogens resulted in some potential risks, limiting their clinical use. However, the biological actions of estrogens are mediated by three subtypes of estrogen receptors (ERs): ERα, ERβ, and G-protein-coupled ER. These ER subtypes act in distinct ways and exert different biological effects that mediate genomic and nongenomic events, resulting in tissue-specific responses. In addition, active estrogen metabolites, with little or no affinity for ERs, could mediate the fibrosuppressive effect of estrogens through an ER-independent pathway. Taken together, such specific estrogen derivatives as ER selective agonists, or active estrogen metabolites, would provide novel therapeutic opportunities, stratifying this hormonal treatment, thereby reducing undesired side-effects in the treatment of liver cirrhosis and portal hypertension.
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Purnak T, Beyazit Y, Ibis M, Koklu S, Efe C, Ozaslan E, Ciftci A, Tenlik I. The involvement of nitric oxide in the physiopathology of hepatoportal sclerosis. Clin Biochem 2012; 45:1450-1454. [PMID: 22820432 DOI: 10.1016/j.clinbiochem.2012.07.091] [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] [Received: 03/05/2012] [Revised: 07/03/2012] [Accepted: 07/08/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Hepatoportal sclerosis (HPS) is a clinical syndrome of unspecified etiology depicted by enlarged spleen and portal hypertension in the lack of other chronic liver disease findings, hematological disorders or any infectious disease in the liver. Nitric oxide (NO) molecule has many important functions in human body including phagocytosis in macrophages, neural transmission and endothelial relaxation. Although there is no data in literature that depicts the role of NO in HPS pathogenesis, this study was conducted in order to evaluate the potential role of NO in patients with HPS. PATIENTS AND METHODS The study participants included 24 HPS patients and 20 healthy controls. The median age of HPS and control patients was 41.2 ± 13.9 and 46.5 ± 12.4 years, respectively. NO was predicted as nitric oxide metabolites (NOx) by Griess reaction after transformation of nitrate to nitrite by nitrate reductase using the commercially obtainable Nitric Oxide Assay Kit. RESULTS Serum NOx levels were 2.69 ± 2.98 μmol/L and 0.85 ± 1.05 μmol/L for the HPS patients and controls, respectively. Serum NO levels were significantly higher in patients with HPS compared to the control group (p<0.001). ROC curve analysis suggested that the optimum NOx cut-off point for HPS was 1.305 with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 83.3%, 90 %, 90.9 %, and 81.8% respectively. CONCLUSION Circulating NO concentration was notably higher in patients with HPS in comparison to the control group. Our study verified that an elevated level of NO might have a role in the pathogenesis of HPS.
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Affiliation(s)
- Tugrul Purnak
- MD, Department of Gastroenterology Ankara Numune Education and Research Hospital, Ankara, Turkey.
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Kobus K, Kopycinska J, Kozlowska-Wiechowska A, Urasinska E, Kempinska-Podhorodecka A, Haas TL, Milkiewicz P, Milkiewicz M. Angiogenesis within the duodenum of patients with cirrhosis is modulated by mechanosensitive Kruppel-like factor 2 and microRNA-126. Liver Int 2012; 32:1222-32. [PMID: 22574900 DOI: 10.1111/j.1478-3231.2012.02791.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Accepted: 02/22/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND The mechanism involved in neovascularization in splanchnic circulation and the main trigger that induces angiogenesis in patients with cirrhosis are not fully recognized. AIMS To explore the involvement of flow sensitive lung Kruppel-like factor (KLF2), microRNA-126 (miR-126), angiopoietin-2 (Ang-2) and heme oxygenase-1 (HO-1) in modulation of vascular endothelial growth factor (VEGF) signalling that have a critical effect on growth of new blood vessels. METHODS Duodenal biopsies from 22 patients with cirrhosis and 10 controls were obtained during routine endoscopy. The process of angiogenesis was evaluated by a measurement of CD31 concentration, immunodetection of CD34 protein and estimation of capillary densities. Messenger RNA (mRNA) and protein expressions were analysed by real-time PCR, Western blot or ELISA respectively. RESULTS Markers of angiogenesis (both, CD31 and CD34) were significantly enhanced in cirrhotic patients. In comparison to healthy controls, levels of Ang-2 and KLF-2 mRNAs as well as Ang-2, KLF-2, HO-1, VEGF protein expressions were considerably increased. Levels of sCD163, a surrogate marker of portal hypertension, correlated with levels of Ang-2, (P = 0.021) and VEGF (P = 0.009). The expression of miR-126, a KLF2-mediated regulator of the VEGF signalling was enhanced in cirrhotic patients. CONCLUSIONS Our results demonstrate, for the first time in humans, that neovascularization is induced in duodenal tissue of patients with cirrhosis and proangiogenic factors such as KLF-2, Ang-2, miR-126 and VEGF can contribute to the angiogenesis induced by hemodynamic forces. Thus, cirrhosis-induced blood flow and pressure within splanchnic vessels may be important hemodynamic triggers that initiate the angiogenic signalling cascade.
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Affiliation(s)
- Karolina Kobus
- Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland
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Piva A, Zampieri F, Di Pascoli M, Gatta A, Sacerdoti D, Bolognesi M. Mesenteric arteries responsiveness to acute variations of wall shear stress is impaired in rats with liver cirrhosis. Scand J Gastroenterol 2012; 47:1003-13. [PMID: 22774919 DOI: 10.3109/00365521.2012.703231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE In liver cirrhosis, excessive splanchnic vasodilation is due to abnormal synthesis of endogenous vasodilators and to decreased sensitivity to vasoconstrictors. The role of mechanical stimuli such as wall shear stress (WSS) on splanchnic circulation remains unclear. The aim of this study was to assess the vasodilation induced by wall shear stress (WSS) and acute changes in blood flow in the mesenteric arteries in an experimental model of liver cirrhosis. MATERIALS AND METHODS The effect of acute changes in intraluminal flow (0, 10, and 20 μl/min) and WSS on the diameter of the mesenteric arteries (diameters <500 μm) of control and cirrhotic rats was assessed, at baseline and after the inhibition of nitric oxide synthase, cyclooxygenase and hemeoxygenase. Concentration-response curves to phenylephrine were also obtained. RESULTS In controls, the increase in intraluminal flow led to a significant increase in arterial diameter (p < 0.05), while WSS remained stable; the effect was maintained in vessels pre-constricted with phenylephrine, blocked by the exposure to indomethacin and L-NAME and restored by the subsequent addition of chromium mesoporphyrin (p < 0.05). In cirrhotic arteries, arterial diameters did not change in response to acute increase in flow, neither at baseline nor after exposure to indomethacin and L-NAME, while WSS increased (p < 0.01). Responsiveness to flow was partially restored (p < 0.05) after exposure of the arteries to chromium mesoporphyrin in addition to indomethacin and L-NAME. CONCLUSIONS Arteries from cirrhotic rats showed an abolished responsiveness to acute variations in flow, which exposes the mesenteric endothelium to sudden variations in WSS.
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Affiliation(s)
- Anna Piva
- Clinica Medica 5, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy.
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Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin Sci (Lond) 2012; 123:225-39. [PMID: 22548407 DOI: 10.1042/cs20120030] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.
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Abstract
Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide, and favours vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation and develops portal hypertension. Portal hypertension, in turn, causes endothelial dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike dysfunction in LSECs, endothelial dysfunction in the splanchnic and systemic circulation causes overproduction of vasodilator molecules, leading to arterial vasodilation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathological consequences, such as oesophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension has been elucidated, the underlying cellular and molecular mechanisms causing endothelial dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on endothelial dysfunctions found during the development of cirrhosis and portal hypertension with a focus on the intra- and extrahepatic circulations. The article ends by discussing the future directions of the study for endothelial dysfunction.
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
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Halverscheid L, Deibert P, Schmidt R, Blum HE, Dunkern T, Pannen BHJ, Kreisel W. Phosphodiesterase-5 inhibitors have distinct effects on the hemodynamics of the liver. BMC Gastroenterol 2009; 9:69. [PMID: 19765284 PMCID: PMC2753560 DOI: 10.1186/1471-230x-9-69] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Accepted: 09/18/2009] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The NO--cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats. METHODS Hemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 microg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats. RESULTS Cardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 microg/kg was the most effective dose for both PDE-5 inhibitors. CONCLUSION Low doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.
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Affiliation(s)
| | - Peter Deibert
- Department of Preventive and Rehabilitative Sport Medicine, University Hospital Freiburg, Germany
| | - René Schmidt
- Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Germany
| | - Hubert E Blum
- Department of Medicine II, University Hospital Freiburg, Germany
| | | | | | - Wolfgang Kreisel
- Department of Medicine II, University Hospital Freiburg, Germany
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Hamza SM, Kaufman S. Role of spleen in integrated control of splanchnic vascular tone: physiology and pathophysiology. Can J Physiol Pharmacol 2009; 87:1-7. [PMID: 19142210 DOI: 10.1139/y08-103] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aside from its established immunologic and hematologic functions, the spleen also plays an important role in cardiovascular regulation. This occurs through changes in intrasplenic microvascular tone, as well as through splenic neurohormonal modulation of the renal and mesenteric vascular beds. Splenic regulation of blood volume occurs predominantly through fluid extravasation from the splenic circulation into lymphatic reservoirs; this is controlled by direct modulation of splenic pre- and postcapillary resistance by established physiologic agents such as atrial natriuretic peptide (ANP), nitric oxide (NO), and adrenomedullin (ADM). In addition to physiologic fluid regulation, splenic extravasation is a key factor in the inability to maintain adequate intravascular volume in septic shock. The spleen also controls renal microvascular tone through reflex activation of the splenic afferent and renal sympathetic nerves. This splenorenal reflex not only contributes to the physiologic regulation of blood pressure, but also contributes to the cardiovascular dysregulation associated with both septic shock and portal hypertension. In septic shock, the splenorenal reflex protectively limits splenic extravasation and potentially promotes renal sodium and water reabsorption and release of the vasoconstrictor angiotensin II; this function is eventually overwhelmed as shock progresses. In portal hypertension, on the other hand, the splenorenal reflex-mediated reduction in renal vascular conductance exacerbates sodium and water retention in the kidneys and may eventually contribute to renal dysfunction. Preliminary evidence suggests that the spleen also may play a role in the hemodynamic complications of portal hypertension via neurohormonal modulation of the mesenteric vascular bed. Lastly, the spleen itself may be a source of a vasoactive factor.
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Affiliation(s)
- Shereen M Hamza
- 473 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada
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Systemic and pulmonary hemodynamics in patients with extrahepatic portal vein obstruction is similar to compensated cirrhotic patients. Hepatol Int 2008; 3:384-91. [PMID: 19669365 DOI: 10.1007/s12072-008-9110-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Accepted: 10/30/2008] [Indexed: 01/25/2023]
Abstract
BACKGROUND Patients with cirrhosis and portal hypertension exhibit a hyperdynamic circulation manifesting as increased cardiac output, heart rate and plasma volume; and decreased arterial blood pressure, systemic vascular resistance, and pulmonary vascular resistance. It is believed that these changes are related to both hepatocellular dysfunction and portal hypertension. However, the role of portal hypertension per se in producing these changes in circulation has not been clear. Extrahepatic portal vein obstruction (EHPVO), a vascular disorder of the liver characterized by cavernomatous transformation of the main portal vein, is an excellent model to study the role of portal hypertension per se in producing these changes because there is no hepatic dysfunction in EHPVO. The main aim of our study was, therefore, to evaluate alterations of systemic and pulmonary vascular systems in patients with EHPVO and compare them with patients with compensated cirrhosis. PATIENTS AND METHODS Consecutive patients of EHPVO, 15 years or older, and past variceal bleeders were studied. For comparison, consecutive patients with compensated cirrhosis and history of variceal bleed, matched for variceal status, and body surface area were included. The hemodynamic studies included the measurements of cardiac index (by Fick's oxygen method), and systemic and pulmonary vascular resistance indices. RESULTS Fifteen patients of EHPVO and same number of controls (compensated cirrhotics) were included in the study. The baseline parameters in the two groups were comparable. Both EHPVO patients and cirrhotics had similar values in all the measured systemic and pulmonary hemodynamic parameters. The median (range) cardiac index in EHPVO was 3.8 (2.3-7.7) l min(-1) m(-2), whereas it was 4.4 (2.8-8.9) l min(-1) m(-2) in cirrhosis (P = 0.468). The median (range) systemic vascular resistance index in EHPVO was 1,835 (806-3400) dyne s cm(-5) m(-2), which was similar to that in cirrhotic patients (1,800 [668-3022], P = 0.520). Similarly, the values of median (range) pulmonary vascular resistance index were comparable in the two groups (71 [42-332] vs. 79 [18-428], P = 0.885). A subgroup analysis was done for 8 patients of EHPVO and 8 age-matched compensated cirrhotic patients, which also revealed similar values of cardiac index, cardiac output, systemic vascular resistance index, systemic vascular resistance, pulmonary vascular resistance index, and pulmonary vascular resistance in the two groups. CONCLUSIONS EHPVO patients have hyperdynamic circulation manifested by high cardiac index and low systemic and pulmonary vascular resistance indices. These hemodynamic changes are comparable with compensated cirrhotic patients who have similar grade of portal hypertension. This suggests a predominant role of portal hypertension per se in the genesis of systemic and pulmonary hemodynamic alterations.
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Coll M, Genescà J, Raurell I, Rodríguez-Vilarrupla A, Mejías M, Otero T, Oria M, Esteban R, Guardia J, Bosch J, Martell M. Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension. J Hepatol 2008; 49:43-51. [PMID: 18457899 DOI: 10.1016/j.jhep.2008.03.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 02/29/2008] [Accepted: 03/25/2008] [Indexed: 01/15/2023]
Abstract
BACKGROUND/AIMS Splanchnic vasodilation initiates the hyperdynamic syndrome in portal hypertension. We aimed to explore molecular mechanisms involved in the development of mesenteric vasodilation in portal hypertension. METHODS Superior mesenteric artery (SMA) samples from portal vein ligated (PVL) and sham rats were compared in a time course experiment using DNA microarrays. Selected genes were quantified by qRT-PCR in PVL and cirrhotic rats. Inmunohistochemistry of tyrosine hydroxylase (Th) and norepinephrine was assessed in SMA sections of PVL and sham rats. Western blot analysis of Th, dopamine beta-hydroxylase (Dbh) and synaptosome-associated protein (Snap-25) was performed in SMA and jejunum samples from the animal models. RESULTS Fifty differentially expressed genes implicated in neurotransmission, especially adrenergic, were detected in SMA samples from PVL rats. Sequential analysis showed a profound down-regulation at 14 days in PVL rats. These down-regulated genes were confirmed by RT-PCR in SMA from PVL and cirrhotic rats. Th and NE detection by immunohistochemistry was reduced in PVL compared to sham. Th, Dbh and Snap-25 expression was lower in SMA from 14-day PVL and cirrhotic rats compared to sham and control rats, respectively. CONCLUSIONS Genetic down-regulation of genes related to the adrenergic system might have a role in splanchnic vasodilation of portal hypertension.
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Affiliation(s)
- Mar Coll
- Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119-127, 08035 Barcelona, Spain
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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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Abstract
Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Henry and Lillian Stratton Basic Research Single Topic Conference was held on the topic of Vascular Biology and Pathobiology of the Liver. The course took place approximately 10 years after the first American Association for the Study of Liver Disease (AASLD)-sponsored conference on this topic that occurred in Reston, Virginia. The conference initiated with an introduction to basic vascular cell signaling and then explored vascular biology specifically as it relates to liver cells. Subsequently, specific disease syndromes were discussed in more detail including portal hypertension and IR injury. Finally, clinical and translational sessions focused on emerging therapies and technologies to treat vascular diseases of the liver.
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Matthew Grisham
- Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana 71130, USA
| | - Vijay Shah
- GI Research Unit and Fitterman Center for Digestive Disease, Mayo Clinic, Rochester, Minnesota 55905, USA
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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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de Cleva R, Herman P, D'albuquerque LAC, Pugliese V, Santarem OL, Saad WA. Pre- and postoperative systemic hemodynamic evaluation in patients subjected to esophagogastric devascularization plus splenectomy and distal splenorenal shunt: A comparative study in schistomomal portal hypertension. World J Gastroenterol 2007; 13:5471-5. [PMID: 17907290 PMCID: PMC4171281 DOI: 10.3748/wjg.v13.i41.5471] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the systemic hemodynamic effects of two surgical procedures largely employed for treatment of schistosomal portal hypertension.
METHODS: Thirty-six patients undergoing elective surgical treatment of portal hypertension due to hepatosplenic mansonic schistosomiasis were prospectively evaluated. All patients were subjected to preoperative pulmonary artery catheterization; 17 were submitted to esophagogastric devascularization and splenectomy (EGDS) and 19 to distal splenorenal shunt (DSRS). The systemic hemodynamic assessment was repeated 4 d after the surgical procedure.
RESULTS: Preoperative evaluation revealed (mean ± SD) an increased cardiac index (4.78 ± 1.13 L/min per m2), associated with a reduction in systemic vascular resistance index (1457 ± 380.7 dynes.s/cm5.m2). The mean pulmonary artery pressure (18 ± 5.1 mmHg) as well as the right atrial pressure (7.9 ± 2.5 mmHg) were increased, while the pulmonary vascular resistance index (133 ± 62 dynes.s/cm5.m2) was decreased. Four days after EGDS, a significant reduction in cardiac index (3.80 ± 0.4 L/min per m2, P < 0.001) and increase in systemic vascular resistance index (1901.4 ± 330.2 dynes.s/cm5.m2, P < 0.001) toward normal levels were observed. There was also a significant reduction in pulmonary artery pressure (12.65 ± 4.7 mmHg, P < 0.001) and no significant changes in the pulmonary vascular resistance index (141.6 ± 102.9 dynes.s/cm5.m2). Four days after DSRS, a non-significant increase in cardiac index (5.2 ± 0.76 L/min per m2) and systemic vascular resistance index (1389 ± 311 dynes.s/cm5.m2) was observed. There was also a non-significant increase in pulmonary artery pressure (19.84 ± 5.2 mmHg), right cardiac work index (1.38 ± 0.4 kg.m/m2) and right ventricular systolic work index (16.3 ± 6.3 g.m/m2), without significant changes in the pulmonary vascular resistance index (139.7 ± 67.8 dynes.s/cm5.m2).
CONCLUSION: The hyperdynamic circulatory state observed in mansonic schistosomiasis was corrected by EGDS, but was maintained in patients who underwent DSRS. Similarly, the elevated mean pulmonary artery pressure was corrected after EGDS and maintained after DSRS. EGDS seems to be the most physiologic surgery for patients with schistosomal portal hypertension.
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Affiliation(s)
- Roberto de Cleva
- Gastroenterology Department, University of Sao Paulo Medical School, Rua Cel. Artur Godoy 125, Apto 152. Vila Mariana, Sao Paulo, SP 04018-050, Brazil.
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36
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The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007; 41 Suppl 3:S288-94. [PMID: 17975478 DOI: 10.1097/mcg.0b013e3181468b4c] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A hyperdynamic splanchnic and systemic circulation is typical of cirrhotic patients and has been observed in all experimental forms of portal hypertension. The hyperdynamic circulation is most likely initiated by arterial vasodilatation, leading to central hypovolemia, sodium retention, and an increased intravascular volume. Arterial vasodilatation is regulated by a complex interplay of various vasodilator molecules and factors that influence the production of those vasodilator molecules. Nitric oxide (NO) has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilatation observed in portal hypertension. The aims of this review are (1) to categorize NO synthase isoforms involved in NO overproduction; (2) to explain the mechanisms of endothelial NO synthase up-regulation; and (3) to summarize other molecules involved in the arterial vasodilatation.
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37
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Abstract
Experimental models are a sine qua non condition for unraveling the specific components and mechanisms contributing to vascular dysfunction and arterial vasodilation in portal hypertension. Moreover, a careful selection of the type of animal model, vascular bed, and methodology is crucial for any investigation of this issue. In this review, some critical aspects related to experimental models in portal hypertension and the techniques applied are highlighted. In addition, a detailed summary of the mechanisms of arterial vasodilation in portal hypertension is presented. First, humoral and endothelial vasodilators, predominantly nitric oxide but also carbon monoxide and endothelium-derived hyperpolarizing factor, and others are discussed. Second, time course and potential stimuli triggering and/or perpetuating splanchnic vasodilation are delineated. Finally, a brief general overview of vascular smooth muscle signaling sets the stage for a discussion on cotransmission, receptor desensitization, and the observed impairment in vasoconstrictor-induced smooth muscle contraction in the splanchnic and systemic circulation during portal hypertension.
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38
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Abstract
Endothelial dysfunction is regarded as an early key event in multiple diseases. The assessment of vascular nitric oxide (NO) level is an indicative of endothelial dysfunction. In liver cirrhosis, on one hand, endothelial dysfunction is known as impaired endothelium-dependent relaxation in the liver microcirculation and contributes to increased intra-hepatic vascular resistance, leading to portal hypertension. On the other, increased production of vasodilator molecules mainly NO contributes to increased endothelium-dependent relaxation in the arteries of the systemic and splanchnic circulation. The aims of this review are to summarize and discuss: (1) unique characteristics of sinusoidal endothelial cell (SECs) and SEC dysfunctions in cirrhosis, and (2) endothelial dysfunctions in the arterial splanchnic and systemic circulation in cirrhosis with portal hypertension.
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Affiliation(s)
- Yasuko Iwakiri
- Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT, USA
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39
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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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40
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Kwon SY, Groszmann RJ, Iwakiri Y. Increased neuronal nitric oxide synthase interaction with soluble guanylate cyclase contributes to the splanchnic arterial vasodilation in portal hypertensive rats. Hepatol Res 2007; 37:58-67. [PMID: 17300699 DOI: 10.1111/j.1872-034x.2007.00005.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Splanchnic arterial vasodilation represents the pathophysiological hallmark of the hemodynamic dysfunction observed in portal hypertensive states. The role of neuronal nitric oxide synthase (nNOS) in the splanchnic arterial vasodilation remains to be elucidated. We therefore investigated: (i) if nNOS is involved in the splanchnic arterial vasodilation; and (ii) the possible interaction of nNOS with soluble guanylate cyclase (sGC) in superior mesenteric arterial (SMA) beds in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL). To determine the role of nNOS, we removed endothelial layer and measured contractile response and nitric oxide (NO) release in the presence or absence of 7-nitroindazole (7-NI, 10 muM), an nNOS-specific inhibitor. In endothelium-removed vessels, nNOS inhibitor significantly increased the contractile response to methoxamine in SMA beds isolated from the portal hypertensive rats, compared to non-treated SMA beds (106.8 +/- 10.7 vs 86.8 +/- 7.2 mmHg, P = 0.003). This effect of nNOS inhibitor was accompanied with decreased NO production in SMA of portal hypertensive rats (321.3 +/- 18.6 vs 139.5 +/- 16.9 pmol/mL/min, P = 0.0001). Unlike endothelial NOS that is located in endothelial cells, nNOS protein is highly expressed in smooth muscle layers of SMA. Furthermore, there was a significant increase in ~90 kDa nNOS protein in the portal hypertensive group, compared to the sham-operated group (P < 0.01). Interestingly, this 90 kDa nNOS was coimmunoprecipitated with sGC. In conclusion, increased nNOS expression in smooth muscle layers of arteries in the splanchnic circulation may be an additional and more efficient pathway for the activation of sGC by NO, which sustains arterial vasodilation.
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Affiliation(s)
- So Young Kwon
- Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT
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41
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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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42
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Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 2006; 290:G980-7. [PMID: 16603731 DOI: 10.1152/ajpgi.00336.2005] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation.
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Affiliation(s)
- Juan G Abraldes
- Hepatic Hemodynamic Laboratory, Veterans Affairs Connecticut Healthcare System, Digestive Disease 111H, 950 Campbell Ave., New Haven, CT 06516, USA
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43
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Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006; 43:S121-31. [PMID: 16447289 DOI: 10.1002/hep.20993] [Citation(s) in RCA: 402] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.
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Affiliation(s)
- Yasuko Iwakiri
- Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT 06516, USA
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44
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Hernández-Guerra M, López E, Bellot P, Piera C, Turnes J, Abraldes JG, Bosch J, García-Pagán JC. Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd-Chiari syndrome. Hepatology 2006; 43:27-33. [PMID: 16374846 DOI: 10.1002/hep.20990] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Budd-Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 +/- 0.7 vs. 4.9 +/- 1.2 L.min(-1).m(-2); P < .001; systemic vascular resistance [SVR] index, 2,189 +/- 736 vs. 1,377 +/- 422 dyne.s.cm(-5).m(-2), P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 +/- 21.5 ng/mL . h, 76.7 +/- 106.8 ng/dL, 586 +/- 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis.
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Affiliation(s)
- Manuel Hernández-Guerra
- Hepatic Hemodynamic Laboratory, Institut de Malalties Digestives, Hospital Clinic, Institut d'Investigaciones Biomédiques August Pi i Sunyer, Barcelona, Spain
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45
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Abstract
The initial factor leading to portal hypertension is an increase in hepatic resistance. Later, an increase in portal blood flow contributes to maintain and exacerbate portal hypertension despite the development of portosystemic collaterals. The critical step in the development and acceptance of these concepts, which proved crucial for the management of patients with portal hypertension, was the development of animal models. These allowed the full characterization of the profound hemodynamic abnormalities in the systemic and splanchnic circulation associated with portal hypertension, and the elucidation of the molecular mechanisms implicated in these disturbances. This review traces how seminal clinical observations in the 1950s raised meaningful questions that were subsequently answered at the bench, leading to our current understanding of the pathophysiology of portal hypertension and of the pathogenesis of severe complications of cirrhosis, such as variceal bleeding or ascites.
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46
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Gooley TA, Rajvanshi P, Schoch HG, McDonald GB. Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation. Hepatology 2005; 41:345-52. [PMID: 15660388 DOI: 10.1002/hep.20529] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Many patients who undergo hematopoietic cell transplantation experience liver injury. We examined the association of serum bilirubin levels with nonrelapse mortality by day +200, testing the hypothesis that the duration of jaundice up to a given point in time provides more prognostic information than either the maximum bilirubin value or the value at that point in time. We studied 1,419 consecutive patients transplanted from allogeneic donors. Total serum bilirubin values up to day +100, death, or relapse were retrieved-along with nonrelapse mortality by day +200 as an outcome measure--using Cox regression models with each bilirubin measure modeled as a time-dependent covariate. The bilirubin value at a particular point in time provided the best fit to the model for mortality. With bilirubin at a point in time modeled as an 8th-degree polynomial, an increase in bilirubin from 1 to 3 mg/dL is associated with a mortality hazard ratio of 6.42. An increase from 4 to 6 mg/dL yields a hazard ratio of 2.05, and an increase from 10 to 12 mg/dL yields a hazard ratio of 1.17. Among patients who were deeply jaundiced, survival was related to the absence of multiorgan failure and to higher platelet counts. In conclusion, the value of total serum bilirubin at a particular point in time after transplant carries more informative prognostic information than does the maximum or average value up to that point in time. The increase in mortality for a given increase in bilirubin value is larger when the starting value is lower.
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Affiliation(s)
- Ted A Gooley
- Section of Clinical Statistics, Clinical Research Division, Fred Hutchinson Cancer Research Center, and the University of Washington School of Medicine, Seattle, WA 98109-1024, USA
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47
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Bexis S, Vandeputte C, McCormick PA, Docherty JR. Deletion of inducible nitric oxide synthase decreases mesenteric vascular responsiveness in portal hypertensive mice. Eur J Pharmacol 2004; 499:325-33. [PMID: 15381055 DOI: 10.1016/j.ejphar.2004.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2004] [Revised: 07/29/2004] [Accepted: 08/03/2004] [Indexed: 02/09/2023]
Abstract
The effects of pre-hepatic portal hypertension were examined on the responsiveness of aorta and mesenteric artery from wild-type, inducible nitric oxide synthase knockout (iNOS-KO) and endothelial nitric oxide synthase knockout (eNOS-KO) mice. Mice were sham-operated or made portal hypertensive by creating a calibrated portal vein stenosis. Acetylcholine produced marked relaxations in phenylephrine (10 microM) contracted aorta and mesenteric artery from wild-type and iNOS-KO, both sham and portal hypertensive, but relaxations were abolished in vessels from eNOS-KO mice. There were no significant differences between sham and portal hypertensive animals within groups in the effects of acetylcholine. The potency of KCl was significantly increased in aorta and mesenteric artery from eNOS-KO mice. The maximum contraction to the alpha(1)-adrenoceptor agonist phenylephrine was significantly increased in aorta from eNOS-KO, as compared with wild-type mice. There were no significant differences between sham and portal hypertensive animals within each group in contractions of aorta to KCl or phenylephrine. However, in mesenteric artery, although portal hypertension did not change responsiveness in wild-type or eNOS-KO as compared to sham animals, the potency of phenylephrine was significantly reduced in portal hypertensive iNOS-KO mice as compared to shams. Hence, portal hypertension as compared to sham operation did not affect responses to vasoconstrictors in mouse aorta, but in mouse mesenteric artery portal hypertension affected vascular responses in iNOS-KO mice, suggesting that iNOS is involved in the mesenteric vascular response to portal vein ligation.
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Affiliation(s)
- Sotiria Bexis
- Department of Physiology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
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48
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Abraldes JG, García-Pagán JC, Bosch J. Componente funcional de la hipertensión portal. GASTROENTEROLOGIA Y HEPATOLOGIA 2004; 27:377-87. [PMID: 15207139 DOI: 10.1016/s0210-5705(03)70480-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- J G Abraldes
- Hepatic Hemodynamic Laboratory, VA Healthcare System, West Haven, USA.
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