Hepatic Fibrosis

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Lab Head: Associate Professor Grant A. Ramm

The Hepatic Fibrosis Group is principally involved in investigating the cell biology of hepatic stellate cells (HSC). HSC are transformed into myofibroblasts when exposed to liver toxins such as excess iron, alcohol, or bile salts due to cholestasis, viral infection or tumour invasion. HSC are responsible for excess collagen deposition, fibrosis and cirrhosis in liver injury. Over the past 18 months our studies have established that HSC are responsible for liver cirrhosis in a subset of patients with cystic fibrosis. We are currently investigating the role of chemoattraction as a mechanism for HSC migration and inflammatory cell infiltration of the peri-ductular region of the acinus in cystic fibrosis liver disease and biliary atresia. We have identified a number of potential serum markers of early fibrogenesis in these patients and are currently investigating their utility in clinical practice. Our work has also demonstrated a role for the iron-storage protein ferritin in the cytokine-like regulation of HSC activation, through the activation and translocation of NFkB. We believe that ferritin and another iron-binding protein, transferrin, may be involved in the development of fibrosis in haemochromatosis and we are currently investigating the cell signalling pathways which may be involved in HSC activation in iron overload.

Matrix synthesis and degradation: role of hepatic stellate cells in fibrogenesis associated with Haemochromatosis
We have shown that hepatic stellate cells are activated in haemochromatosis liver and that removing excess hepatic iron by venesection therapy results in the disappearance of the activated hepatic stellate cell phenotype (Ramm et al, 1997). We have also demonstrated that extracellular matrix components produced by hepatic stellate cells, such as collagen type IV, can be detected in the serum and are useful markers of the severity of fibrosis (George et al, 1998; George et al, 1999). Our recent work has shown a potential involvement for interferon-g in this disease suggesting that a submorphological inflammatory process may regulate hepatic stellate cell activation. Current studies centre around the role of the matrix degradation enzymes, matrix metalloproteinases (MMPs) and their regulating inhibitors, tissue inhibitors of MMPs (TIMPs) in stimulating hepatic stellate cells to activate and become profibrogenic.

Pathways of iron metabolism in hepatic stellate cells
We have shown that the iron-storage protein ferritin regulates the expression of the contractile protein a-smooth muscle actin in activated hepatic stellate cells (Ramm et al, 1994: Ramm et al, 1996). Recent studies have demonstrated that another iron protein, transferrin, appears to regulate the expression of collagen type I which may suggest a potential mechanism of hepatic stellate cell activation in haemochromatosis. This study is currently evaluating the role of transferrin and ferritin in the iron-induced activation of hepatic stellate cells. We have shown that the nuclear transcription factor, NFkB is activated and translocates to the nucleus of hepatic stellate cells following exposure to ferritin. It is hoped that an understanding of the basic iron biology of hepatic stellate cells may lead to strategies designed to abrogate the processes of fibrogenesis in haemochromatosis.

 

Expression of iron transporters in haemochromatosis
This project is designed to examine the expression and tissue and cellular distribution of a number of iron transporter proteins thought to be involved in the iron overload disease, haemochromatosis, such as HFE, DMT-1, Ireg, and hephaestin. These observations coupled together with collaborative work with Prof Greg Anderson and Dr Nathan Subramaniam from the Population Health and Clinical Sciences Division at QIMR, will assist in gaining a greater understanding of the mechanisms associated with excessive iron absorption from the intestine and iron deposition in the liver in subjects with this disease. Our ultimate goal in this project is to develop novel therapeutic strategies designed either inhibit excess iron absorption or deposition or indeed promote accelerated iron removal from the body in conditions of iron overload.

Mechanism of activation of hepatic stellate cells in Biliary Atresia
We have shown that hepatic stellate cells cause the cirrhosis which is characteristic in the congenital bile duct obstructive disease, biliary atresia (Ramm et al, 1998). However, the mechanisms responsible for hepatic stellate cell activation in this condition are not known. Our group leads a multi-centre collaborative project with Dr Darrell Crawford from the Princess Alexandra Hospital, and Dr Peter Lewindon and Prof Ross Shepherd from the Royal Children's Hospital. This project focuses on the mechanisms whereby bile duct epithelial cells are induced to release the profibrogenic cytokine transforming growth factor-beta (Ramm et al, 1998) which stimulates collagen production and cirrhosis. Further investigations will evaluate the potential aetiology of the fibrotic, obstructive bile duct disease in these children and evaluate the potential for chemoattraction of hepatic stellate cells and inflammatory cells to the site of injury surrounding the bile ducts.

 

Role of hepatic stellate cells in the focal biliary cirrhosis in Cystic Fibrosis liver disease
This is a collaborative project with Dr Peter Lewindon and Prof Ross Shepherd from the Royal Children's Hospital and Dr Jeffery Smith from The University of Queensland Department of Surgery. This study is designed to assess a number of serum markers of fibrosis for detecting early fibrogenesis, and the severity and progression of liver injury in children with cystic fibrosis liver disease. The study also utilises the isolated hepatic stellate cell to evaluate the potential mechanisms whereby these cells are activated to produce excess collagen leading to the focal biliary cirrhosis which characterises cystic fibrosis liver disease. Finally we are using cDNA array analysis to examine the expression of a number of known genes in the disease process and plan to investigate potential novel genes which may be involved in the fibrogenesis which leads to focal biliary cirrhosis in cystic fibrosis liver disease.

 

 

 

 

Staff

Labhead and NHMRC Senior Research Fellow:	Associate Professor Grant A. Ramm
Research Officers:	Dr Richard Ruddell Dr Tamara Pereira Dr Marie Bertrand Dr Meagan Walsh
Research Assistant:	Mrs Louise Ramm Mr Darryn Rowsell
PhD scholars:	Dr Marnie Wood Mr Peng Cheng Li Mrs Lynne Reid
Visiting Scientists:	Dr Peter Lewindon Dr Graeme Macdonald Dr Jeffery Smith

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Funding

NHMRC Program Grant (2005-2009)on Iron and Liver Disease
Role of iron biology in hepatic stellate cell activation in haemochromatosis.

NHMRC Program Grant (2008-2010)on
Role of Chemoattractants in hepatic stellate recruitment and fibrogenesis in Paediatric Cholestatic Liver Disease.

Collaborators

Dr Peter Lewindon, Department of Gastroenterology, Royal Children's Hospital, Brisbane
Dr Darrell Crawford, Department of Gastroenterology, Princess Alexandra Hospital, Brisbane
Dr Graeme Macdonald, Department of Medicine, Royal Brisbane Hospital, Brisbane
Prof Gregory Anderson, Iron Metabolism Laboratory, QIMR.
Assoc Prof Nathan Subramaniam, Cell Membrane Transport Laboratory, QIMR.
Assoc Prof John Olynyk, Department of Medicine, Fremantle Hospital, Fremantle
Prof. Tom Tracy, Department of Paediatric Surgery, Brown University, Rhode Island, USA
Prof Bruce Bacon, Department of Internal Medicine, St Louise University, St Louis, USA
Prof Paulo Arosio, University of Brescia, Brescia, ITALY
Prof Ross Shepherd, Washington University, St Louis, USA

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Key Publications

Harty MW, Papa EF, Huddleston HM, Young E, Nazareth S, Riley CA, RAMM GA, Gregory SH, Tracy TF, Jr, (2008). Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers. Surgery, 143(5): 667-678 [pubmed abstract]

Olynyk JK, Trinder D, RAMM GA, Britton RS and Bacon BR, (2008). Hereditary hemochromatosis: Recent developments. Hepatology, (in press).

Wood M, Powell LW and RAMM GA, (2008). Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood, 111(9):4456-4462.[pubmed abstract]

Ruddell RG, Mann DA and RAMM GA, (2008). The function of serotonin within the liver. J. Hepatol., 48(4):666-675. [pubmed abstract]

Milward E, Johnstone D, Trinder D, RAMM G and Olynyk J, (2007). The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs and ECSIT. Hepatology, 45(1):253-256. [pubmed abstract]

Philippe MA, Ruddell RG and RAMM GA, (2007). The role of iron in hepatic fibrosis: Another piece in the puzzle. World J. Gastroenterol., 13(35):4746-4754. [pubmed abstract]

Knight B, Akhurst B, Matthews VB, Ruddell RG, RAMM GA, Abraham LJ, Olynyk JK and Yeoh GC, (2007). Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J. Hepatol., 46(1):134-141. [pubmed abstract]

Wallace DF, Dixon JL, RAMM GA, Anderson GJ, Powell LW and Subramaniam VN, (2007). A novel mutation in ferroportin implicated in iron overload. J. Hepatol., 46(5):921-926.[pubmed abstract]

Kobayashi Y, Bridle KR, RAMM GA, O'Neill R, Britton RS and Bacon BR, (2007). Effect of phorbol esters and platelet-derived growth factor on protein kinase C in rat hepatic stellate cells. Liver Int., 27(8):1066-1075. [pubmed abstract]

Shteyer E, RAMM GA, Xu C, White FV and Shepherd RW, (2006). Outcome after Portoenterostomy in Biliary Atresia: Pivotal Role of Degree of Liver Fibrosis and Intensity of Stellate Cell Activation. J. Pediatr. Gastr. Nutr., 42(1):93-99. [pubmed abstract]

Powell LW, Dixon JL, RAMM GA, Purdie DM, Lincoln DJ, Anderson GJ, Subramaniam VN, Hewett DG, Searle JW, Fletcher LM, Crawford DH, Rodgers H, Allen KJ, Cavanaugh JA and Bassett ML, (2006). Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch. Intern. Med., 166:294-301. * These authors contributed equally to this paper - Equal FIRST Authors. [pubmed abstract]

Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, RAMM GA and Mann DA, (2006). A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am. J. Pathol., 169(3):861-876.[pubmed abstract]

Arnold JM, Huggard PR, Pandeya N, Cummings M, Purdie DM, RAMM GA and Chenevix-Trench G, (2005). Monocyte Chemoattractant Protein-1 (MCP-1) expression is reduced in ovarian adenocarcinoma and re-expression suppresses in vitro growth and soft agar clonicity. Brit. J. Cancer, 92(11):2024 31.[pubmed abstract]

Harty MW, Huddleston HM, Papa EF, Puthawala T, Tracy AP, RAMM GA, Gehring S, Gregory SH, and Tracy TF, Jnr., (2005), Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity. Surgery, 138(2):313-20. [pubmed abstract] RAMM GA and Ruddell RG, (2005). Hepatotoxicity of iron overload: Mechanisms of iron-induced hepatic fibrogenesis. Semin. Liver Dis., 25(4):433-449.[pubmed abstract]

Milward EA, Trinder D, Wilcox CEJ, Britton RS, RAMM GA and Olynyk JK, (2005). Is HFE involved in increased hepcidin expression and hypoferremia in inflammation and anemia of chronic disease? Hepatology. 41(4):936-938. [pubmed abstract]

Smith JL, Lewindon PJ, Hoskins AC, Pereira TN, Setchell KDR, O'Connell NC, Shepherd RW and RAMM GA, (2004). Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic fibrosis. Hepatology. 39:1673-1682. [pubmed abstract]

Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, RAMM GA, Buchler M, Friess H, McCarroll JA, Keogh G, Merrett N, Pirola R and Wilson JS, (2004). Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 29(3):179-187. [pubmed abstract]

Pereira TN, Lewindon PJ, Smith JL, Murphy TL, Lincoln DJ, Shepherd RW and RAMM GA, (2004). Serum markers of hepatic fibrogenesis in cystic fibrosis liver disease. J. Hepatol. 41(4):576-583. [pubmed abstract]

RAMM GA, Hoskins AC, Greco SA, Pereira TN and Lewindon PJ, (2004). Signals for hepatic fibrogenesis in pediatric cholestatic liver disease: Review and hypothesis. Comp. Hepatol. 3;(Suppl.1):S5(1-5). [pubmed abstract]

Anderson GJ, Frazer DM, Bridle KR, Subramaniam VN, Crawford DHG, Powell LW and RAMM GA, (2004). Hepcidin in HFE-associated hemochromatosis: anotherpiece of the "iron" puzzle - Reply. Gastroenterology. 126(2):616.

Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DHG, Subramaniam VN, Powell LW, Anderson GJ and RAMM GA, (2003). Disrupted hepcidin upregulation in HFE-associated hemochromatosis and liver as a regulator of body iron homeostasis. The Lancet. 361:669-73. [pubmed abstract]

Bridle KR, Crawford DHG, Fletcher LM, Smith JL, Powell LW and RAMM GA, (2003). Evidence for a sub-morphological inflammatory process in the liver in haemochromatosis. J. Hepatol. 38(4):425-432. [pubmed abstract]

RAMM GA, Li L, Britton RS, O'Neill R, and Bacon BR, (2003). Effect of protein kinase C activation and inhibition on rat hepatic stellate cell activation . Dig. Dis. Sci. 48(4):790-796. [pubmed abstract]

Bridle KR, Crawford DHG and RAMM GA, (2003). Identification and characterization of the hepatic stellate cell transferrin receptor. Am. J. Pathol. 162:1661-1667. [pubmed abstract]

Lewindon PJ, Pereira TN, Hoskins AC, Williamson RM, Bridle KR, Shepherd RW and RAMM GA, (2002). The role of hepatic stellate cells and transforming growth factor-b1 in cystic fibrosis liver disease. Am. J. Pathol. 160(5):1705-1715. [pubmed abstract]

Olynyk JK, Khan NA, RAMM GA, Brown KE, O'Neill R, Britton RS and Bacon BR, (2002). Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells. J. Gastroenterol. Hepatol. 17(7):785-790. [pubmed abstract]

Bridle KR, Crawford DHG, Powell LW and Ramm GA, (2001). Role of myofibroblasts in tumour encapsulation of hepatocellular carcinoma in haemochromatosis. Liver, 21(2):96-104. [pubmed abstract]

Young J, Biden KG, Simms LA, Huggard PR, Karamatic R, Eyre HJ, Sutherland GR, Herath N, Barker M, Anderson GJ, Fitzpatrick D, Ramm GA, Jass JR and Leggett BA, (2001). HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proc. Natl. Acad. Sci. USA., 98(1):265-270. [pubmed abstract]

Macdonald GA, Bridle KR, Ward PJ, Walker NI, Houglum K, George DK, Smith JL, Powell LW, Crawford DHG and RAMM GA, (2001). Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominantly in acinar zone 3. J. Gastroenterol. Hepatol. 16(6):599-606. [pubmed abstract]

Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M and Ramm GA, (2000). Repetitive acute pancreatic injury in the mouse induces procollagen alpha1 (I) mRNA expression colocalized to pancreatic stellate cells. Lab. Invest., 80(2):143-50. [pubmed abstract]

Ramm GA, Carr SC, Bridle KR, Li L, Crawford DHG, Vogler CA, Britton RS, Bacon BR and Tracy TF, Jr, (2000). The morphology of liver repair following cholestatic liver injury: resolution of ductal hyperplasia, matrix deposition and regression of myofibroblasts. Liver, 20(5):387-396. [pubmed abstract]

Haber PS, Keogh GW, Apte MV, Moran CS, Stewart NL, Crawford DHG, Pirola RC, McCaughan GW, Ramm GA and Wilson JS, (1999). Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am. J. Pathol., 155:1087-1095. [pubmed abstract]

George DK, Ramm GA, Walker NI, Powell LW and Crawford DHG, (1999). Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis. J. Hepatol., 31(1):47-52. [pubmed abstract]

Ramm GA, Nair VG, Bridle KR, Shepherd RW and Crawford DHG, (1998). Contribution of hepatic parenchymal and non-parenchymal cells to hepatic fibrogenesis in biliary atresia. Am. J. Pathol., 153(2):527-535. [pubmed abstract]

Ooi LLPJ, Crawford DHG, Gotley DC, Clouston AD, Strong RW, Gobé GC, Halliday JW, Bridle KR and Ramm GA, (1997). Evidence that "myofibroblast-like" cells are the cellular source of capsular collagen in hepatocellular carcinoma. J. Hepatol., 26(4):798-807. [pubmed abstract]

RAMM GA, (1998). Isolation and culture of rat hepatic stellate cells. J.Gastroenterol. Hepatol. 13:845-850. [pubmed abstract]

Houglum K, Ramm GA, Crawford DHG, Witztum J, Powell LW and Chojkier M, (1997). Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis. Hepatology, 27:605-610. [pubmed abstract]

Ramm GA, Britton RS, O'Neill R, Kohn HD and Bacon BR, (1996). Rat liver ferritin selectively inhibits the expression of alpha-smooth muscle actin in cultured rat lipocytes. Am. J. Physiol., 270:G370-G375. [pubmed abstract]

Ramm GA, Britton RS, O'Neill R and Bacon BR, (1994). Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes. J. Clin. Invest., 94:9-15. [pubmed abstract]

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