Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

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Cadmium is a metallic element which is placed between Zn and Hg in Group I IB of the Periodic Table. It is divalent, as are the Group I IA elements Ca and Mg. In order of electropotential, Zn, Cd and Hg fal I below Ca and Mg but above the transition elements, with which they do not have close relationships. They have low melting points so their volatility, as in the case of Pb, is an industrial hazard. Cd has recently received prominence as a cause of environment pollution due to its accumulation in water supplies and crops from Zn mining operations and industrial effluents.

The cellular components of the blood, which become associated with fibrin through specific cellular adhesive processes, play a significant role in the breakdown of fibrin. Fibrinolysis by elastase and cathepsin G, enzymes present within the azurophilic granules of the neutrophil, has previously been shown. Recent studies have demonstrated neutrophil-mediated fibrinogenolysis by a membrane-associated protease which suggests that proteases connected with the neutrophil membrane might also be capable of clot dissolution. Investigations showed that neutrophil-mediated clot lysis was effected by a membrane-associated serine protease that can be dissociated by SDS-PAGE to bands that migrate to apparent molecular weights of 501 kDa, 398 kDa, 316 kDa, 245 kDa and 209 kDa. This degradation was distinct from that produced by plasmin, neutrophil lysosomal enzymes and purified human neutrophil elastase and enhanced the action of plasmin in clot solubilization. Preincubation of neutrophils with monoclonal antibodies directed against the CD 11 c/CD 18 integrin was able to significantly inhibit neutrophil membrane-dependent fibrinolytic activity. Upregulation of enzyme activity occurred following association of fibrin substrate with the cell membrane and was dependent on the activation of cellular kinases, in particular protein kinase C. Fibrin products generated by neutrophil membrane proteolytic activity were found to possess biological activity. The low molecular weight peptides effected substantial inhibition of thrombin-induced platelet aggregation while the presence of the higher molecular weight material could partially overcome platelet-induced resistance to plasmic lysis. No modulation of platelet-mediated fibrin clot retraction was observed using these same fibrin products. Neutrophil lysosomal enzyme activity was shown to further degrade the end products of plasmic fibrin degradation into low molecular weight material, followed by reassembly of higher molecular weight products in a process dependent on calcium and factor XIII. The reformed products have a similar molecular weight to those produced by plasmic lysis of fibrin, as well as a putative crosslinked site. However, the isoelectric point of these reformed products indicates they are distinctly different from plasmin-derived fibrin products. These reassembled products were recognized by a monoclonal antibody raised against D-dimer. Processing by neutrophils of the end products of plasmic fibrin degradation may have the potential for modulating the immune response as well as compromising the predictive value of tests measuring D-dimer, used as a laboratory marker of a number of thromboembolic disorders encountered in clinical practice.

Bibliography: leaves 142-170. / Fumonisin B₁ (FB₁‚ ) is a carcinogenic mycotoxin produced by the fimgus Fusarium moniliforme in maize, and is hepatotoxic and hepatocarcinogenic in rats. The goal of this dissertation was to characterise the FB₁-fed rat as a model for liver injury and carcinogenesis, and to examine the role of oval ('progenitor') cells during these processes. Male Fischer 344 rats were fed FB₁ 250 mg/kg diet for five weeks, and this basic feeding regimen was modified in individual experiments. Short-term feeding of FB₁ caused a severe 'toxic' hepatitis, apoptosis and regeneration of hepatocytes, fibrosis, proliferation of OV-6 positive oval cells, and formation of GST pi positive hepatic foci and nodules. Oval cells were noted inside some of the hepatic nodules. There were marked increases in the expression of mRNA transcripts for mature TGF-β1 and c-myc in livers of FB₁-fed animals. The overexpression of TGF-β1 by hepatocytes may be responsible for the prominent apoptosis and fibrosis seen with liver injury due to FB₁. Increased expression of c-myc and TGF-β1 may cooperate during FB₁-induced promotion of liver tumours, possibly by providing an environment that selects for the growth of TGFβ1-resistant transformed liver cells. In rats given FB₁ in the presence of dietary iron overload, FB₁ augmented iron-induced lipid peroxidation in the liver. However, dietary iron loading appeared to protect against the cancer-promoting properties of FB₁, possibly due to a stimulatory effect on hepatocyte regeneration. Long-term feeding of FB₁ caused fibrosis and regenerative nodules, dysplastic hepatic nodules, cholangiofibrotic lesions, intraductal cholangiocarcinomas, and a hepatocellular carcinoma. 2-Acetylaminofluorene enhanced the effects of FB₁ in the liver, presumably by blocking hepatocyte regeneration in response to FB₁ toxicity. Proliferating oval cells were found inside/adjacent to GST pi positive lesions, dysplastic nodules, and cholangiofibrotic lesions, suggesting that oval cells may be involved in FBI-induced hepato- and cholangiocarcinogenesis in the liver. Furthermore, the OV-6 antigen was expressed by proliferating oval cells and bile ductules, hepatic nodules, cholangiofibrotic lesions, and cystic lesions, indicating that all of these cells may have a common ('stem') cell of origin. In conclusion, the FB₁-fed rat is a promising model for the study of liver injury, oval ('progenitor') cell proliferation, and carcinogenesis.

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