[Truncated abstract] Chronic liver injury results from many etiologies ranging from viral infection to inborn errors of metabolism. A common result of liver injury is activation of hepatic stellate cells and portal fibroblasts to myofibroblasts. In chronic injury, production of extracellular matrix by activated myofibroblasts results in liver fibrosis and ultimately cirrhosis. Kupffer cells and monocytes may play an important role in the pathogenesis of certain liver diseases. Endotoxin-responsive macrophages and recruited monocytes (CD14-positive cells) are potential sources of profibrogenic factors but their potential role in the pathogenesis of liver disease has not previously been examined. The first aim of this thesis described in chapter 3 was to evaluate the hypothesis that CD14-positive macrophages/monocytes are present in the livers of patients with hereditary haemochromatosis (HH), primary biliary cirrhosis (PBC), chronic hepatitis C (HCV) and nonalcoholic steatohepatitis (NASH) and contribute to the pathogenesis of fibrosis as evidenced by co-localization of these cells with activated myofibroblasts. Liver specimens from control subjects and those with HH, PBC, HCV and NASH were immunostained for CD14, CD68 and α-smooth muscle actin and the number of cells expressing these antigens was determined. The total number of hepatic CD68-positive cells was similar in diseased and control livers. The number of CD14-positive cells correlated with advanced fibrosis in HH, PBC, HCV but not in NASH. The number of CD14-positive cells was increased with advanced inflammatory activity in HCV. CD14-positive cells were often associated with α-smooth muscle actin-positive myofibroblasts in fibrous septa. In conclusion, many forms of human chronic liver disease demonstrate increased numbers of CD14-positive macrophages/monocytes which are associated with fibrous septa and myofibroblasts. To determine whether CD14-positive cells contribute to fibrogenesis, experimental models of liver injury were used in chapters 5 and 6. The aim of chapter 5 was to determine whether CD14-positive macrophages/monocytes are detected in a bile duct ligation model of liver injury. To accomplish this aim, a novel antibody to rat CD14 was developed as described in chapter 4. A time-course study was undertaken in rats following bile duct ligation for up to 14 days. An increase in the number of hepatic CD14-positive cells was detected early following bile duct ligation, and was associated with increased gene expression of α-smooth muscle actin and procollagen I. Thus, myofibroblastic transformation in this model was associated with increased numbers of CD14-positive cells suggesting a possible relationship between the two phenomena. In order to specifically evaluate the role of CD14 in myofibroblastic transformation, a final study in CD14 knockout (KO) mice was undertaken in chapter 6
| Identifer | oai:union.ndltd.org:ADTP/221146 |
| Date | January 2005 |
| Creators | Leicester, Katherine L. |
| Publisher | University of Western Australia. School of Medicine and Pharmacology |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Katherine L. Leicester, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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