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: 3855886
• 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/3855886
• 关键词: cell nucleus; confocal scanning microscopy; environmental toxicology; genetic transcription; inflammation; lipid metabolism; lung alveolus; phosphatidylcholines; phospholipids; protein biosynthesis; pulmonary surfactants; respiratory function; respiratory toxin; secretion; silicates; toxicant interaction

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 dipaimitoylphosphatidylcholine 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. 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. In addition, we have found that the 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. We are trying to identify those factors by studying the responses of the surfactant system to inflammatory conditions generated with a variety of different agents.

肺表面活性物质是一种由表面组成的多相复合体 类型菌合成和分泌的活性磷脂和特异性蛋白 肺泡内的II细胞。其主要脂质成分为 表面活性物质是二亚胺基磷脂酰胆碱和主要蛋白质 主要成分为表面活性蛋白A(SP-A)。SP-A是特定的 只在肺部发现的与表面活性物质相关的蛋白质。的功能 DPPC是为了降低空气/电池界面的表面张力而起作用的 SP-A的作用似乎是在这一过程中提供帮助。生物合成和生物合成 肺泡II型细胞分泌这些物质对 肺的稳定和功能。二氧化硅粉尘导致大量 肺表面活性物质磷脂含量增加 SP-A。我们已经证明，这些增加是由于一些， 但不是全部，II型细胞：激活的II型细胞制造和分泌 表面活性磷脂和蛋白质的速度比 正常的II型细胞。为了了解硅尘是如何导致 激活II型细胞，我们正在研究表面活性物质的调节 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。我们已经绘制了 激光共聚焦技术检测SP-A在分离的II型细胞中的分布 扫描显微镜观察发现SP-A主要定位于板层 身体。然而，我们也在II型细胞的细胞核中发现了SP-A， 与核周膜相关。我们不知道它的功能 核SP-A，但推测它可能参与 表面活性剂体系的调节。此外，我们发现， 刺激II型细胞产生表面活性物质依赖于 由二氧化硅在肺部引起的炎症状态。我们假设 表面活性物质的影响是炎症状态的结果 因此，细胞因子可能是由炎症细胞释放的 能够调节肺泡II型细胞表面活性物质的产生。 我们正试图通过研究这些因素的反应来确定 表面活性物质体系能在各种炎症条件下产生 不同的特工。