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Gringeri E, Villano G, Brocco S, Polacco M, Calabrese F, Sacerdoti D, Cillo U, Pontisso P. SerpinB3 as hepatic marker of post-resective shear stress. Updates Surg 2023; 75:1541-1548. [PMID: 37204659 PMCID: PMC10435418 DOI: 10.1007/s13304-023-01531-6] [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: 10/26/2022] [Accepted: 05/10/2023] [Indexed: 05/20/2023]
Abstract
Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress.
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Affiliation(s)
- Enrico Gringeri
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences-DISCOG, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Gianmarco Villano
- Interdepartmental Center of Experimental Surgery, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences-DISCOG, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Silvia Brocco
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Marina Polacco
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences-DISCOG, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - David Sacerdoti
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Umberto Cillo
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences-DISCOG, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
| | - Patrizia Pontisso
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
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2
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Varga BT, Gáspár A, Ernyey AJ, Hutka B, Tajti BT, Zádori ZS, Gyertyán I. Introduction of a pharmacological neurovascular uncoupling model in rats based on results of mice. Physiol Int 2022. [PMID: 36057105 DOI: 10.1556/2060.2022.00226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/02/2022] [Accepted: 05/19/2022] [Indexed: 02/18/2024]
Abstract
Our aim was to establish a pharmacologically induced neurovascular uncoupling (NVU) method in rats as a model of human cognitive decline. Pharmacologically induced NVU with subsequent neurological and cognitive defects was described in mice, but not in rats so far. We used 32 male Hannover Wistar rats. NVU was induced by intraperitoneal administration of a pharmacological "cocktail" consisting of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH, a specific inhibitor of epoxyeicosatrienoic acid-producing epoxidases, 5 mg kg-1), L-NG-nitroarginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 10 mg kg-1) and indomethacin (a nonselective inhibitor of cyclooxygenases, 1 mg kg-1) and injected twice daily for 8 consecutive days. Cognitive performance was tested in the Morris water-maze and fear-conditioning assays. We also monitored blood pressure. In a terminal operation a laser Doppler probe was used to detect changes in blood-flow (CBF) in the barrel cortex while the contralateral whisker pad was stimulated. Brain and small intestine tissue samples were collected post mortem and examined for prostaglandin E2 (PGE2) level. Animals treated with the "cocktail" showed no impairment in their performance in any of the cognitive tasks. They had higher blood pressure and showed cca. 50% decrease in CBF. Intestinal bleeding and ulcers were found in some animals with significantly decreased levels of PGE2 in the brain and small intestine. Although we could evoke NVU by the applied mixture of pharmacons, it also induced adverse side effects such as hypertension and intestinal malformations while the treatment did not cause cognitive impairment. Thus, further refinements are still required for the development of an applicable model.
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Affiliation(s)
- Bence Tamás Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Attila Gáspár
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Aliz Judit Ernyey
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Barbara Hutka
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Brigitta Tekla Tajti
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán Sándor Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - István Gyertyán
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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Rodrigues SG, Mendoza YP, Bosch J. Investigational drugs in early clinical development for portal hypertension. Expert Opin Investig Drugs 2022; 31:825-842. [PMID: 35758843 DOI: 10.1080/13543784.2022.2095259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Advanced chronic liver disease is considered a reversible condition after removal of the primary aetiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trials sites and PubMed from the last 10 years. EXPERT OPINION A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis thus eliminating the need for treatment or screening of PH.
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Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Yuly P Mendoza
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.,Graduate School for Health Sciences (GHS), University of Bern
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
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Gunarathne LS, Rajapaksha IG, Casey S, Qaradakhi T, Zulli A, Rajapaksha H, Trebicka J, Angus PW, Herath CB. Mas-related G protein-coupled receptor type D antagonism improves portal hypertension in cirrhotic rats. Hepatol Commun 2022; 6:2523-2537. [PMID: 35593203 PMCID: PMC9426402 DOI: 10.1002/hep4.1987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 04/04/2022] [Accepted: 04/15/2022] [Indexed: 12/04/2022] Open
Abstract
Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin‐(1–7), Mas‐related G protein‐coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D‐Pro7‐Ang‐(1‐7) (D‐Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up‐regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D‐Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D‐Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up‐regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Indu G Rajapaksha
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Stephen Casey
- Liver Unit, Austin Health, Heidelberg, Victoria, Australia
| | - Tawar Qaradakhi
- College of Health and Biomedicine, Victoria University, Werribee, Victoria, Australia
| | - Anthony Zulli
- College of Health and Biomedicine, Victoria University, Werribee, Victoria, Australia
| | | | - Jonel Trebicka
- Department of Internal Medicine, University Clinic Frankfurt, Frankfurt, Germany
| | - Peter W Angus
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.,Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia
| | - Chandana B Herath
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.,South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Victoria, Australia.,Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
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5
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Turkseven S, Bolognesi M, Di Pascoli M. Contribution of Splenic Resistance Arteries to Splanchnic Blood Overflow in Cirrhosis. Dig Dis Sci 2021; 66:796-801. [PMID: 32242304 DOI: 10.1007/s10620-020-06233-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/24/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND In liver cirrhosis, a marked splanchnic vasodilation causes an increase in portal blood flow, contributing to the development of portal hypertension. AIM To evaluate if, in experimental cirrhosis, a different vascular reactivity exists between splenic and mesenteric components of the splanchnic circulation. METHODS Liver cirrhosis was induced in Sprague Dawley rats by common bile duct ligation. In sections of splenic and superior mesenteric arteries, cumulative dose-response curves were obtained. mRNA expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and prostaglandin I2 synthase (PTGIS) was evaluated. RESULTS In cirrhotic rats, mesenteric but not splenic arteries showed a significant increase in endothelium-dependent relaxation to acetylcholine. In control and cirrhotic rats, COX inhibition alone did not significantly change the response of mesenteric arteries to acetylcholine; after inhibiting also NOS, the relaxation was completely abolished in control but only partially decreased in cirrhotic rats. After the inhibition of COX and NOS, the relaxation to acetylcholine was similarly decreased in splenic arteries from control and cirrhotic animals. The contraction induced by phenylephrine of both mesenteric and splenic arteries was decreased in cirrhotic rats. PTGIS mRNA expression did not differ in splenic and mesenteric arteries from control and cirrhotic rats; in cirrhotic rats, eNOS and iNOS mRNA expression was increased in mesenteric but not in splenic vascular bed. CONCLUSION In cirrhotic rats, a decreased splenic arterial response to vasoconstrictors, rather than an increased response to vasodilators, contributes to splanchnic vasodilation, while in mesenteric arteries also an increased response to vasodilators secondary to, but not only, eNOS and iNOS overexpression, plays a role.
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Affiliation(s)
- Saadet Turkseven
- Department of Medicine, Unit of Internal Medicine and Hepatology (UIMH), University of Padova, Padua, Italy.,Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey
| | - Massimo Bolognesi
- Department of Medicine, Unit of Internal Medicine and Hepatology (UIMH), University of Padova, Padua, Italy
| | - Marco Di Pascoli
- Department of Medicine, Unit of Internal Medicine and Hepatology (UIMH), University of Padova, Padua, Italy.
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6
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Novel therapeutics for portal hypertension and fibrosis in chronic liver disease. Pharmacol Ther 2020; 215:107626. [DOI: 10.1016/j.pharmthera.2020.107626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023]
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Abstract
Terlipressin, somatostatin, or octreotide are recommended as pharmacologic treatment of acute variceal hemorrhage. Nonselective β-blockers decrease the risk of variceal hemorrhage and hepatic decompensation, particularly in those 30% to 40% of patients with good hemodynamic response. Carvedilol, statins, and anticoagulants are promising agents in the management of portal hypertension. Recent advances in the pharmacologic treatment of portal hypertension have mainly focused on modifying an increased intrahepatic resistance through nitric oxide and/or modulation of vasoactive substances. Several novel pharmacologic agents for portal hypertension are being evaluated in humans.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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8
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Kuhn MJ, Putman AK, Sordillo LM. Widespread basal cytochrome P450 expression in extrahepatic bovine tissues and isolated cells. J Dairy Sci 2019; 103:625-637. [PMID: 31677841 DOI: 10.3168/jds.2019-17071] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/13/2019] [Indexed: 01/08/2023]
Abstract
Periparturient cattle face increased risk of both metabolic and infectious diseases. Factors contributing to this predisposition include oxidized polyunsaturated fatty acids, also known as oxylipids, whose production is altered during the periparturient period and in diseased cattle. Alterations in the production of oxylipids derived from cytochrome P450 (CYP450) enzymes are over-represented during times of increased disease risk and clinical disease, such as mastitis. Many of these same CYP450 enzymes additionally regulate metabolism of fat-soluble vitamins, such as A, D, and E. These vitamins are essential to maintaining immune health, yet circulating concentrations are diminished near calving. Despite this, a relatively small amount of research has focused on the roles of CYP450 enzymes outside of the liver. The aim of this paper is to describe the relative gene expression of 11 CYP450 in bovine tissues and common in vitro bovine cell models. Eight tissue samples were collected from 3 healthy dairy cows after euthanasia. In vitro samples included primary bovine aortic and mammary endothelial cells and immortalized bovine kidney and mammary epithelial cells. Quantitative real-time-PCR was carried out to assess basal transcript expression of CYP450 enzymes. Surprisingly, CYP450 mRNA was widely expressed in all tissue samples, with predominance in the liver. In vitro CYP450 expression was less robust, with several cell types lacking expression of specific CYP450 enzymes altogether. Overall, cell culture models did not reflect expression of tissue CYP450. However, when CYP450 were organized by activity, certain cell types consistently expressed specific functional groups. These data reveal the widespread expression of CYP450 in individual organs of healthy dairy cows. Widespread expression helps to explain previous evidence of significant changes in CYP450-mediated oxylipid production and fat-soluble vitamin metabolism in organ microenvironments during periods of oxidative stress or disease. As such, these data provide a foundation for targeted functional experiments aimed at understanding the activities of specific CYP450 and associated therapeutic potential during times of increased disease risk.
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Affiliation(s)
- M J Kuhn
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824
| | - A K Putman
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824
| | - L M Sordillo
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824.
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9
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Yeboah MM, Hye Khan MA, Chesnik MA, Skibba M, Kolb LL, Imig JD. Role of the cytochrome P-450/ epoxyeicosatrienoic acids pathway in the pathogenesis of renal dysfunction in cirrhosis. Nephrol Dial Transplant 2019; 33:1333-1343. [PMID: 29361048 DOI: 10.1093/ndt/gfx354] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/24/2017] [Indexed: 02/06/2023] Open
Abstract
Background Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acids. These eicosanoids regulate blood pressure, vascular tone and renal tubular sodium transport under both physiological and pathophysiological states. Methods Experiments were performed to investigate the role of the CYP system in the pathogenesis of renal dysfunction during cirrhosis. Rats underwent bile duct ligation (BDL) or sham surgery and were studied at 2, 4 and 5 weeks post-surgery. In additional experiments, post-BDL rats were treated with three daily intraperitoneal doses of either the selective epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH) or a vehicle, starting on Day 22 after surgery. Results BDL led to progressive renal dysfunction that was associated with reduced renal cortical perfusion but without any overt histologic changes, consistent with HRS. CYP isoform enzyme expression was significantly altered in BDL rats. In the kidney, CYP2C23 expression was upregulated at both the mRNA and protein levels in BDL rats, while CYP2C11 was downregulated. Histologically, the changes in CYP2C23 and CYP2C11 expression were localized to the renal tubules. EET production was increased in the kidneys of BDL rats as assessed by urinary eicosanoid levels. Finally, treatment with the selective epoxygenase inhibitor MSPPOH significantly reduced renal function and renal cortical perfusion in BDL rats, suggesting a homeostatic role for epoxygenase-derived eicosanoids. Conclusions The CYP/EET pathway might represent a novel therapeutic target for modulating renal dysfunction in advanced cirrhosis.
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Affiliation(s)
- Michael M Yeboah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Md Abdul Hye Khan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Marla A Chesnik
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Melissa Skibba
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Lauren L Kolb
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
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Chancharoenthana W, Leelahavanichkul A. Acute kidney injury spectrum in patients with chronic liver disease: Where do we stand? World J Gastroenterol 2019; 25:3684-3703. [PMID: 31391766 PMCID: PMC6676545 DOI: 10.3748/wjg.v25.i28.3684] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/13/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS–AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS–AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS–AKI and as well as AKI in other chronic liver diseases (non-HRS–AKI) so that early recognition of HRS–AKI and the appropriate management can be established.
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Affiliation(s)
- Wiwat Chancharoenthana
- Immunology Unit, Department of Microbiology, Faculty of Medicine Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, Faculty of Medicine Chulalongkorn University, Bangkok 10330, Thailand
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Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways. Sci Rep 2019; 9:6993. [PMID: 31061522 PMCID: PMC6502824 DOI: 10.1038/s41598-019-43513-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 04/15/2019] [Indexed: 12/15/2022] Open
Abstract
Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase –NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase –PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.
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Vilaseca M, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therap Adv Gastroenterol 2018; 11:1756284818811294. [PMID: 30505350 PMCID: PMC6256317 DOI: 10.1177/1756284818811294] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/15/2018] [Indexed: 02/04/2023] Open
Abstract
Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients' prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.
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Affiliation(s)
- Marina Vilaseca
- Hepatic Hemodynamic Laboratory, IDIBAPS
Biomedical Research Institute, Barcelona, Spain
| | - Sergi Guixé-Muntet
- Department of Biomedical Research, University of
Bern, Bern, Switzerland
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona
Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute,
CIBEREHD, Rosselló 149, 4th floor, 08036 Barcelona, Spain
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Huang Y, Qin J, Sun D, Jiang H, Zheng L, He Y, Gui L, Qian B, Zhang C, Luo M. Inhibition of soluble epoxide hydrolase reduces portal pressure by protecting mesenteric artery myogenic responses in cirrhotic rats. Prostaglandins Other Lipid Mediat 2017; 131:17-24. [DOI: 10.1016/j.prostaglandins.2017.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 03/26/2017] [Accepted: 03/30/2017] [Indexed: 12/15/2022]
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14
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Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis. Prostaglandins Other Lipid Mediat 2017; 131:67-74. [DOI: 10.1016/j.prostaglandins.2017.08.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Revised: 07/25/2017] [Accepted: 08/08/2017] [Indexed: 02/06/2023]
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15
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Adhoute X, Sellier F, Fontaine H, Castellani P, Bourlière M. Carcinome hépatocellulaire et traitements antiviraux contre le VHB et le VHC. ONCOLOGIE 2017. [DOI: 10.1007/s10269-017-2710-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5:90-103. [PMID: 28533907 PMCID: PMC5421460 DOI: 10.1093/gastro/gox011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 03/12/2017] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.
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Affiliation(s)
- Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wim Laleman
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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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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Bolognesi M, Di Pascoli M, Sacerdoti D. Clinical role of non-invasive assessment of portal hypertension. World J Gastroenterol 2017; 23:1-10. [PMID: 28104976 PMCID: PMC5221271 DOI: 10.3748/wjg.v23.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 09/27/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis (i.e., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field.
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