The lung is subject to many potential Insults that can acutely infect or damage airways, parenchyma, or blood vessels. In most organs, such acute insults heal with a return to normal structure and function. However, in the lung there are situations where the healing is impaired, such that the lung returns to its normal condition either very slowly or not at all. The primary emphasis of this PPG will center on the mechanisms underlying this nonresolving inflammation that leads to a chronic pathophysiological progression. Why there is inadequate or incomplete wound healing in the lung is not well understood, but the preliminary data from all three projects in this program strongly supports a common role for lymphocytes and macrophages in implementing these chronic changes in function and mechanical properties. More specifically, the program will focus on the role of CD8+ T cells and macrophages in chronic emphysema following acute parenchymal injury (Project 1), a role for CD4+ T cells and macrophage activation in the progression of chronic pulmonary fibrosis (Project 2), and a role of CD4+ T cells and macrophages in blood vessel growtband stability following acute ischemic injury (Project 3). Although each of these pathologies has a very different pathophysiological manifestation, there are many similarities in the underlying immunologic mechanisms. Thus, in this Program, each project's specific aims are designed to investigate overlapping mechanistic pathways with each of the other projects. Common experimental approaches in all projects span the range from measurements of pulmonary function in intact animals, to quantitative morphology, to cellular and subcellular signaling pathways, and all projects will make considerable use the common core resources. This tightly integrated, synergistic program will thereby provide new insights into the mechanisms that underlie the pathogenic progression of chronic lung diseases.
(See.instruct'ons): The work in this research grant aims to shed light on novel mechanisms underlying common pathways in chronic lung diseases. Proposed experiments could have significant impact on our understanding of disease processes, that could ultimately lead to new therapies for several progressively destructive lung diseases.
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