Date of Award
Doctor of Philosophy (PhD)
The proliferative behaviour of human lung fibroblasts in vitro was examined. Fibroblasts derived from the lung of patients with idiopathic pulmonary fibrosis proliferated faster compared to fibroblasts from control lung tissue. An examination of clonally-derived fibroblast lines showed a substantial degree of fibroblast heterogeneity which followed a normal distribution, and also the existence of a significantly greater number of fast-growing clones in the panels of clones derived from primary fibroblast lines established from fibrotic tissue. Heterogeneity with respect to the expression of collagen genes was also documented.
The effect of an acute challenge of peripheral blood monocyte and/or alveolar macrophage supernatants on fibroblast proliferation was examined. Supernatants from peripheral blood monocytes and alveolar macrophages stimulated with lipopolysacharide elicited a dose-dependent inhibition of fibroblast proliferation, likely induced by interleukin 1. This effect could be prevented by pre-treating the fibroblasts with indomethacin and reconstituted by adding exogenous prostaglandin E$\sb2$, thus indicating the involvement of the prostaglandin E$\sb2$ pathway of the fibroblast. Exogenous prostaglandin E$\sb2$ directly caused an inhibition of fibroblast proliferation, and fibroblasts derived from fibrotic tissues were shown to be hyporesponsive to this mediator. Supernatants from unstimulated alveolar macrophages obtained from rats which had been given intratracheal bleomycin caused a similar effect on the proliferation of rat lung fibroblasts.
Primary lines of fibroblasts chronically exposed to peripheral blood monocyte supernatants became hyporesponsive to both these supernatants and prostaglandin E$\sb2$, and released greater amounts of prostaglandin E$\sb2$, upon rechallenge compared to unexposed fibroblasts. An examination of clonally-derived lines showed marked heterogeneity in the responsiveness of individual clones to peripheral blood monocyte supernatants and prostaglandin E$\sb2$ as well as a change in the clonal distribution after chronic exposure to peripheral blood monocyte supernatants. Chronic exposure of sensitive clones to peripheral blood monocyte supernatants did not alter their level of responsiveness.
Jordana, Manel, "Characterization of the human pulmonary fibroblast derived from the normal lung and from the lung of patients with idiopathic pulmonary fibrosis" (1991). Open Access Dissertations and Theses. Paper 3968.