A major direction in our research of late effects is to study the spatial and temporal sequence of events since, with time, cytokine cascade expression is varied, can be concurrent and persistent. The paradigm we have proposed is that following irradiation, there is an elaboration of early response cytokines, in particular TNFalpha and IL-1, pro- inflammatory cytokines. The resident effector cells in the radiation field, usually a parenchymal cell, an endothelial cell, a fibroblast and a microphage, react to these early cytokines by triggering in turn the CC chemokine family of genes--monocyte chemoattractant proteins MCP-1, MCP-2, MCP-3, the macrophage inflammatory proteins MIP-1alpha, MIP-1beta, and RANTES--all of which have inflammatory activities. With the release of these chemokines into the vascular compartment, recruitment of non- resident immune cells occurs, namely the monocytes, macrophages, and T cells, with cells becoming adherent to the endothelial cell lining due to the expression of selectins, the vascular cell adhesion molecule (CAM) and the intercellular adhesion molecule (ICAM). The next phase is the extravasation of monocytes/macrophages into the interstitium in solid organs and then into the extravascular space, when these exist anatomically as in the lung. It is the incremental persistence of these families of cytokines--both pro-inflammatory (TNFalpha and IL-1) and the chemokines (MCP and MIP)--that results in the expression of pro-fibrotic cytokines (TGFbeta, bFGF and PDGF) and ultimately leads to late fibrosis through the stimulation of fibroblast proliferation and extracellular matrix formation. The university of deep tissue fibrosis as a late effect of radiation is the focus and keystone of CERRIS and is explore in three different and important, dose-limiting vital tissues. In lung (Program 1), the extravascular phase of the expression of cytokine cascades provides the broadest view; in CNS (Program B), the initial intravascular phase of expression is the major theme, with special interest in the blood-brain barrier; and in Program C, the extravasation phase in the interstitium of soft tissue and delayed subcutaneous radiation fibrosis as a result of the persistence of the cytokine cascade is presented. In summary, we believe that a molecular basis for radiation effects, based on such techniques as in situ hybridization, RNA protection assays, etc., will provide new insights, allowing us to identify the most basic mechanistic phenomena such as specific genes and pathways evoked in these late effects and new means of amelioration using anti-cytokines.
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