REGULATION OF PULMONARY SURFACTANT SYSTEM AND ITS MODIFICATION BY TOXIC AGENTS

肺表面活性物质系统的调节及其有毒物质的修饰

• 批准号: 3841063
• 负责人: G R HOOK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3841063
• 关键词: cell nucleus; confocal scanning microscopy; environmental toxicology; genetic transcription; inflammation; interleukin 1; laboratory rat; lung alveolus; lysosomes; messenger RNA; nuclear membrane; phosphatidylcholines; phospholipids; protein biosynthesis; pulmonary surfactants; respiratory epithelium; respiratory function; respiratory toxin; secretion; silicates; toxicant interaction; tumor necrosis factor alpha

Pulmonary surfactant is a heterogeneous complex consisting of surface active phospholipids and specific proteins synthesized and secreted by Type II cells in the alveoli of the lungs. The major lipid component of surfactant is dipalmitoylphosphatidylcholine and the major protein component is surfactant protein A (SP-A). SP-A is a specific surfactant- associated protein found only in the lungs. The function of DPPC is to lower surface tension at the air/cell interface and the function of SP-A appears to be to assist in this process. Biosynthesis and secretion of these substances by alveolar Type II cells is critical for the stabilization and function of the lungs. Silica dust causes massive increases in the pulmonary content of both surfactant phospholipids and SP- A. We have shown that these increases are due to the activation of some, but not all, Type II cells: activated Type II cells make and secrete surfactant phospholipids and proteins at a rate many times faster than normal Type II cells. To understand how silica dust brings about the activation of Type II cells, we are studying regulation of surfactant protein genes in Type II cells and seeking to identify factors capable of upregulating the transcription of those genes. We have mapped the distribution of SP-A in isolated Type II cells using confocal laser scanning microscopy and found that SP-A is localized mainly in the lamellar bodies. However, we also found SP-A in the nucleus of the Type II cell and associated with the perinuclear membrane. In addition we have shown that extracellular SP-A is taken up by isolated Type II cells and distributed in the cell in a manner consistent with its localization in lysosomes and lamellar bodies. In addition, some of the ingested SP-A appears to be translocated to the perinuclear membrane and into the nucleus itself. We do not know the functions of nuclear SP-A at this time but speculate that it could be involved in regulation of the surfactant system. Stimulation of surfactant production in Type II cells is dependent upon the inflammatory condition generated in the lungs by silica. We hypothesize that the surfactant effects arise as a result of the inflammatory condition and, therefore, cellular factors may be released by inflammatory cells that are capable of regulating surfactant production in alveolar Type II cells. Evidence suggests that interleukin-1beta and tumor necrosis factor-alpha may be part of this stimulatory process because both mRNAs of both cytokines are elevated within a few hours following exposure of rats in silica.

肺表面活性物质是一种多相复合物， 型合成和分泌的活性磷脂和特异性蛋白质 II细胞在肺泡。 的主要脂质成分 表面活性剂是二棕榈酰磷脂酰胆碱， 表面活性蛋白A（SP-A）。 SP-A是一种特殊的表面活性剂- 这种蛋白质只存在于肺部。 DPPC的功能是 降低空气/细胞界面的表面张力和SP-A的作用 似乎是为了帮助这个过程。 生物合成和分泌 这些物质的肺泡II型细胞是至关重要的 肺的稳定和功能。 二氧化硅粉尘导致大量 肺表面活性剂磷脂和SP- a. 我们已经证明，这些增加是由于激活了一些， 但不是全部，II型细胞：活化的II型细胞产生并分泌 表面活性剂磷脂和蛋白质的速率比 正常的II型细胞 为了了解硅尘是如何导致 活化II型细胞，我们正在研究调节表面活性剂 II型细胞中的蛋白质基因，并寻求识别能够 上调这些基因的转录。 我们绘制了 用共聚焦激光在分离的II型细胞中分布SP-A 扫描显微镜观察发现SP-A主要定位于板层 尸体 然而，我们也发现SP-A在II型细胞的细胞核中， 与核周膜相连。 此外，我们还表明， 细胞外SP-A被分离的II型细胞摄取并分布在 以与其在溶酶体中的定位一致的方式， 板层体 此外，一些摄入的SP-A似乎是 转移到核周膜并进入核本身。 我们 目前尚不清楚核SP-A的功能，但推测， 它可能参与调节表面活性剂系统。 刺激 II型细胞中表面活性剂的产生取决于 二氧化硅引起的肺部炎症。 我们假设 表面活性剂的作用是由炎症引起的 因此，细胞因子可以由炎性细胞释放， 能够调节肺泡II型细胞中表面活性剂的产生。 有证据表明，白细胞介素1 β和肿瘤坏死因子α 可能是这一刺激过程的一部分，因为这两种基因的mRNA 细胞因子在大鼠暴露后数小时内升高， 硅石