Doctoral theses
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| Identifier |
39630 |
| Title |
Απομόνωση και βιολογική συμπεριφορά των κυττάρων των κολποειδών του ήπατος |
| Creator |
Valatas, Vassilios D
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| Abstract |
Hepatic homeostasis is the result of an intense communication between the hepatocytes and the sinusoidal cells. Due to their location the Kupffer cells, that is the resident liver macrophages, are the first cells of the mononuclear phagocyte system to be exposed to particulate and immunoreactive material absorbed from the gastrointestinal tract. This enables Kupffer cells to play a key role in host defense. However, current evidence indicates that they are also involved in the pathogenesis of liver disease through a variety of mechanisms. Isolation of Kupffer cells in adequate numbers and purity is often difficult owing to the similar physical properties of the sinusoidal cell subpopulations and the solid structure of the liver tissue. In order to do so, a combination of cell techniques that takes advantage of more that one mechanism of cell separation has to be applied. In the present thesis, we describe in detail such a methodology for the isolation of large and highly purified populations of Kupffer cells from human and rat liver. Isolated cells retain their functional integrity and their ability to respond to immune stimuli. We have also shown that isolated Kupffer cells in culture is a valuable tool in order to explore the liver primary immune responses and the pathophysiologic mechanisms leading to hepatotoxicity. Furthermore, they represent a suitable in vitro model for the study of the effects of immunomodulating drugs in the liver. Isolated Kupffer cells in culture have been shown to produce a variety of soluble mediators involved in liver inflammatory disorders. We have shown that Kupffer cells represent a major source of the cytokines TNFα, IL-6, IL-12, 1L-10, IL-13 and the chemokines IL-8, MIP-2, MCP-1, RANTES and they also produce metalloproteinases like the MMP-9 and nitric oxide. Lipopolysaccharide (LPS) is the initiating agent in many types of liver disease and LPS-activated Kupffer cells are currently being considered as the effector cells in various experimental hepatotoxicity models. In the present thesis we investigated the in vitro interaction of LPS and Kupffer cells. We showed that LPS activates isolated Kupffer cells leading to increased production of both inflammatory (TNFα, IL-6, IL-12) and anti-inflammatory (IL-10) cytokines, chemokines, nitric oxide and metalloproteinases and we explored part of the intracellular signaling mechanisms that take place following KC interaction with LPS. Finally we explored the immunomodulatory effects of the somatostatin analogue Octreotide on resting and LPS-activated Kupffer cells. We showed that octreotide decreases the production of IL-12 and MMP-9 and increases the production of IL-13 by resting Kupffer cells. Furthermore, acting through a Wortmannin-sensitive pathway, octreotide suppresses TNFα, nitric oxide and the CC chemokines MCP-1 and RANTES production by LPS-activated Kupffer cells. No effect was observed on IL-6, IL-10 and the CXC chemokines IL-8 and MIP-2 The physiological significance of immunomodulation by circulating or locally produced neuropeptides in the liver remains to be determined. However our data partly explain previous findings concerning the immunoregulatory (577-579, 600, 602, 604) and therapeutic (580) effects of octreotide in liver disorders and support the need for further studies and in vivo validation of the immunoregulatory properties of somatostatin and its analogues in liver disease.
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| Language |
Greek |
| Issue date |
2003-04-01 |
| Date available |
2003-07-10 |
| Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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| Permanent Link |
https://elocus.lib.uoc.gr//dlib/c/8/c/metadata-dlib-2003valatas.tkl
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| Views |
300 |
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