The overall goals of this research are to understand the mechanisms of radiation-induced injury using the new molecular biologic techniques at our disposal. Our current working hypothesis and recent research findings focus on the pulmonary sequence of events following ionizing radiation as a continuum, with no clear distinction between the pneumonitic and fibrotic phases. We propose that control of the proliferation of pulmonary fibroblasts and the synthesis and turnover of extracellular matrix components occurs through the production of specific locally generated mediators. These factors, acting through specific receptors on the cell surface, alter the rate of growth or specific gene expression of the matrix components or products that directly relate to their turnover. We intend to continue to decipher the intercellular communication between the many different cells injured, recognizing that the target has shifted from the cell per se to cellular conversation; that is the interaction between the irradiated """"""""infield"""""""" parenchymal cells of the lung (type II pneumocyte and septal fibroblast) and recruited """"""""out-of-field"""""""" inflammatory cells: macrophages, monocytes, neutrophils and, especially, the lymphocytes. We believe that the progressive elements of radiation injury may largely relate to modulation of the """"""""in-field"""""""" radiation inflammatory response through a complex cascade of cytokine release and by their chemotactic attraction for """"""""out-of-field"""""""" immune cells such as lymphocytes and monocytes. Once recruited into this disturbed microenvironment, these inflammatory cells may themselves become stimulated to produce other mediators initiating a complex """"""""cytokine cascade."""""""" It is important to recognize that in addition to influencing the rate of nature of the factors produced, radiation exposure may also directly alter the ability of a specific cell type to respond to such signals. Such alteration may occur through a change in the number or affinity of specific growth factor receptors on the target cells. To address this hypothesis we propose to examine the expression of mRNA and protein of specific growth factors and cytokines that we feel are critical components in the communication among the cells involved in the radiation response. These include TGFalpha and beta, PDGF, IL-1, TNF, IL-8/NAP and the novel chemotactic peptide MCP/MCAF, as well as measurement of receptors on populations of parenchymal cells. These will be examined in two model systems of radiation injury with which we have extensive experience, the unilung irradiated rabbit and the mouse. Both of these systems have unique advantages that we plan to exploit in the proposed experiments.
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