Publications by authors named "Josephine A Grace"

6 Publications

  • Page 1 of 1

Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis.

Clin Gastroenterol Hepatol 2020 Nov 26. Epub 2020 Nov 26.

Department of Gastroenterology, Austin Health, Department of Medicine, Austin Academic Centre, University of Melbourne, Melbourne, Australia.

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http://dx.doi.org/10.1016/j.cgh.2020.07.046DOI Listing
November 2020

Proposed mechanism for increased COVID-19 mortality in patients with decompensated cirrhosis.

Hepatol Int 2020 Sep 4;14(5):884-885. Epub 2020 Sep 4.

Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.

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http://dx.doi.org/10.1007/s12072-020-10084-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471588PMC
September 2020

Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis.

Gastroenterology 2013 Oct 22;145(4):874-884.e5. Epub 2013 Jun 22.

Department of Medicine, The University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg, Melbourne, Victoria, Australia; Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia.

Background & Aims: Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis.

Methods: We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response.

Results: Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance.

Conclusions: In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.
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http://dx.doi.org/10.1053/j.gastro.2013.06.036DOI Listing
October 2013

Therapeutic potential of targeting the renin angiotensin system in portal hypertension.

World J Gastrointest Pathophysiol 2013 Feb;4(1):1-11

Chandana B Herath, Josephine A Grace, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesenteric and portal blood flow. Non-selective β-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis. However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients. Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding. This review briefly outlines current therapeutic approaches to the management of portal hypertension, and the evidence supporting the role of the renin angiotensin system (RAS) and the use of RAS blockers in this condition. It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.
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http://dx.doi.org/10.4291/wjgp.v4.i1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627462PMC
February 2013

Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment.

J Gastroenterol Hepatol 2013 Feb;28(2):213-9

Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.

Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10-30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ET(B) receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic HPS, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of HPS, and discuss current approaches to the investigation and treatment of this condition.
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http://dx.doi.org/10.1111/jgh.12061DOI Listing
February 2013

Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options.

Clin Sci (Lond) 2012 Aug;123(4):225-39

Department of Medicine, The University of Melbourne, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia.

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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http://dx.doi.org/10.1042/CS20120030DOI Listing
August 2012