The fibrogenic response to tissue damage

Thompson, W. D (1980) The fibrogenic response to tissue damage. PhD thesis, University of Glasgow.

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Abstract

This thesis is a study of the control of fibrogenesis following tissue damage. Existing knowledge of the relevant cells, macrophage and fibroblast, is reviewed. Previous work from this laboratory concerning factors extracted from damaged tissue which stimulate collagen synthesis in vitro is discussed and extended. The distribution of macrophages has been studied in mouse tissue sections by immunohistochemistry using an antimacrophage antibody. The normal macrophage population has been demonstrated in a wide variety of mouse tissues, the shared common antigen confirming the unity of the mononuclear phagocyte system. The technique was employed at the electron microscopic level showing that staining of Kupffer cells in liver was located at the surface membrane. The technique was applied to animal models' of liver and lung injury used in subsequent work. The sequence of events leading to transient giant cell formation after carbon tetrachloride liver injury is defined using immunohistochemistry and electron microscopy. The results support the concept that such giant cells arise by fusion of macrophages around necrotic debris. The role of the macrophage in recovery from experimental liver injury produced by carbon tetrachloride was investigated. It was found that the healing process could be manipulated in various ways by impeding macrophage function with corticosteroid or carrageenin. Interference with normal macrophage function in clearing necrotic debris in turn interfered with the normal phase of increased fibrogenesis, as assessed histologically and biochemically. The findings support the initial hypothesis that macrophages influence fibroblast collagen synthesis at sites of damage. Experimental paraquat poisoning provides a striking histological example of rapid fibrogenesis following extensive pulmonary alveolar epithelial destruction. Collagen prolyl hydroxylase activity, an index of collagen synthesis, was found to increase five-fold in rat lung with parallel changes in serum but not in other organs. The pattern of biochemical changes has been related to the time-course of the histological changes. Collagen stimulating factors, previously described in experimental liver injury and healing skin wounds, have been demonstrated in paraquat lung injury. This finding suggests that such factors may be involved in the chronic inflammatory process at any site. Arterial collagen synthesis is increased in experimental hypertension in the rat. The absence of a macrophage component and of necrosis in this model was the reason for its choice. The time-course of increased collagen synthesis in the aortic wall was defined by measurement of prolyl hydroxylase activity. Collagen stimulating factors were found to be present as the blood pressure rose to its highest level after six weeks. The implications of this finding are discussed with regard to the pathogenesis of hypertension and the possible source of the factors. In attempts to quantify the effect of collagen stimulating factors, molecular filters rather than column chromatography were tried. The results with cultured fibroblasts as the test system for stimulation of collagen synthesis show that both the stimulating factors and toxic component are of higher molecular weight than previously described but can still be separated by the method. Initial results from intra- peritoneal injection of filtrates into mice show that the factors stimulate increased collagen synthesis in vivo, and are not merely an in vitro phenomenon. Recent work is described concerning preliminary in vitro experiments with supernatant from cultured macrophages and fibrin. When applied to chromatography columns, this gives fractions which stimulate collagen synthesis in cultured fibroblasts. The pattern obtained resembles that of collagen stimulating factors as obtained from damaged tissue. The major hypothesis that has emerged from the present work is that the enhanced collagen synthesis, characteristic of the chronic inflammatory response is controlled by macrophages, and possibly endothelial cells. This is achieved by degradation of necrotic tissue and fibrin by enzymes from these cells producing small peptides with collagen stimulating activity.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: R S Patrick
Keywords: Immunology
Date of Award: 1980
Depositing User: Enlighten Team
Unique ID: glathesis:1980-74018
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33
URI: http://theses.gla.ac.uk/id/eprint/74018

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