MOLECULAR MECHANISMS IN RADIATION PNEUMONITIS & FIBROSIS

本研究的总体目标是了解心绞痛的发病机制 新的分子生物学技术在辐射损伤中的应用 我们的处置权。我们目前的工作假说和最近的研究发现 关注电离辐射后的肺部事件序列 一个连续统，肺炎和肺炎之间没有明显的区别 纤维化期。我们建议控制肺腺癌的增殖。 成纤维细胞与细胞外基质的合成和转化 部件的生产是通过特定的本地产生的 调解人。这些因子通过作用于细胞的特定受体发挥作用 表面，改变生长速度或特定的基因表达 与其营业额直接相关的矩阵部件或产品。我们 意愿继续破译细胞间的通讯 许多不同的细胞受伤，认识到目标已经从 细胞本身到细胞对话；这就是相互作用 照射后的肺内实质细胞(II型肺泡细胞 和隔膜成纤维细胞)，并招募“视野外”的炎性细胞： 巨噬细胞、单核细胞、中性粒细胞，尤其是淋巴细胞。我们 认为辐射损伤的进行性因素可能在很大程度上 与“场内”辐射炎症反应的调节有关 通过复杂的细胞因子释放和它们的趋化作用 对“场外”免疫细胞的吸引力，如淋巴细胞和 单核细胞。一旦被招募到这个混乱的微环境中，这些 炎性细胞本身可能会受到刺激，产生其他 介体启动了一个复杂的“细胞因子级联反应”。重要的是要 认识到除了影响自然发展的速度外， 产生的因素，辐射暴露也可能直接改变能力 一种特定的细胞类型来响应这样的信号。该等更改可 通过特定生长因子的数量或亲和力的变化而发生 靶细胞上的受体。为了解决这一假设，我们建议 检测特定生长因子的mRNA和蛋白表达 我们认为细胞因子是人与人之间交流的关键成分 参与辐射反应的细胞。其中包括TGFAlpha和 β、PDGF、IL-1、肿瘤坏死因子、IL-8/NAP与新型趋化肽 MCP/MCAF，以及对种群的受体的测量 实质细胞。这些将在两个模型系统中进行检验 我们对辐射损伤有丰富的经验， 受辐射的兔子和小鼠。这两个系统都有独特的 我们计划在拟议的实验中利用的优势。

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.