Revisiting Inflammation As A Target For Normal Tissue Damage Mitigation: Interplay Among Interleukin Expression, Parenchyma And Inflammatory Cells In Lung Effects

In this age of cost-effective therapy, improving therapeutic ratio by reducing normal tissue effects needs to be considered a high priority. Thus identifying targets for reducing late pulmonary sequelae as a consequence of radiation exposure has significant therapeutic relevance. Our group has focused on the role of the interleukin signaling family in the development and control of the inflammatory response in the lung, part of both the pneumonitic and fibrotic phases. Our group has made use of a number of strains of mouse known to have differential responses to lung irradiation. In addition, in order to provide information on the respective role of the injured parenchyma versus infiltrating immune and inflammatory cells, we have developed chimera models using genetically engineered mouse models as both hosts and donors, targeting members of the interleukin family as molecules of interest. We will present compelling evidence that identifies critical roles for interleukin (IL) 1A and 1B that not only differentiates response progression, both spatially and temporally, between pneumonitis and fibrosis, but also equates with the relative propensities of various murine strains to favor one pulmonary endpoint over another. In addition, we have shown that additional critical interactive pathways exist between IL1B and the principal macrophage-related chemokine, MCP-1. The results clearly demonstrate the relative roles played by signaling expressed by the injured parenchyma versus the response of the infiltrating inflammatory cells. Our studies of lung radiation late effects have shown that production of various inflammatory cytokines and chemokines play an important role in the initiation and progression of the pneumonitic and fibrotic process. Using transgenic, knockout and bone marrow chimera models, we now have compelling data revealing the relative contribution of inflammatory mediators and their cell(s) of origin in the lung. Our studies suggest that a complex interplay exists between infiltrating immune and inflammatory cells and the resident parenchymal cells and that this interplay is crucial to the development of late inflammation and fibrosis. Importantly, these pathways provide information on the relative risk of lung late effect development and offer targets and, critically, details on the time courses needed for mitigation.