The purpose of this research is to determine the effects of ionizing radiation on cytokine production by subsets of lung fibroblasts and ascertain the key cytokines produced in lung during fibrosis induced by radiation. Lung fibrosis is characterized by extensive accumulation of extracellular matrix and increased cellularity of the fibroblast compartment. The causes of lung fibrosis are many and include treatment for malignancy with radiation. Research from this laboratory has shown that murine lung fibroblasts are divisible into two major subsets based on whether or not they express the Thy 1 antigen. Lines of Thy 1+ and Thy 1- fibroblasts differ in morphology, display of class II MHC antigens, ability to stimulate T lymphocytes, production of IL-1 and IL-1 receptors and amounts of extracellular matrix synthesized; including fibronectin and types I and III collagen. These fibroblast subsets may play differing roles in fibrotic development. The ability of a fibroblast subset to respond to or produce certain cytokines may lead to a reparative process or to a potentially fatal fibrosis. Thy 1+ and Thy 1- fibroblasts will be characterized for the cytokines they synthesize, both constitutively and after radiation treatment, using the polymerase chain reaction to detect cytokine mRNA. The products of these mRNAs will be detected and quantitated using specific bioassays or by ELISA. Determination of a specific cytokine profile or fingerprint may permit further subsetting of fibroblasts and elucidation of their role in radiation-induced lung fibrosis. Studies will also be performed with selected cytokines (e.g. IL- 1, TNFalpha, TGFbeta1, gamma-IFN) to assess their role in regulating proliferation and collagen production by fibroblast subsets. The important cytokines/growth factors involved in promoting radiation-induced fibrosis in a murine model will be determined. Characterization of the cytokines crucial for fibrotic development induced by radiation will allow new interventions to be developed. Novel treatments include using cytokines to inhibit lung fibroblast proliferation and collagen synthesis, or alternatively, using neutralizing antibodies or other cytokine inhibitors to block the stimulatory activity of pro-fibrotic cytokines. In this way it will be possible to block or arrest potentially fatal radiation-induced pulmonary fibrosis.
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