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: 3941507
• 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/3941507
• 关键词: density gradient ultracentrifugation; diagnostic respiratory lavage; dosage; environmental toxicology; extracellular; lipid metabolism; lung alveolus; phospholipids; pulmonary surfactants; respiratory toxin; secretion; silicates; toxicant interaction

Pulmonary surfactant is a complex mixture of lipids and proteins that prevents collapse of the alveoli and distal airways at low lung volumes. Silica dust causes a massive increase in the surfactant content of the lungs but the mechanisms through which this occurs are not known. Examination of the rates at which surfactant phospholipids are synthesized, secreted, and cleared from the lungs of silica-treated rats revealed that expansion of the intra and extracellular pools of surfactant could be accounted for by imbalances between the rates at which surfactant phospholipids are synthesized by alveolar Type II cells, secreted, and then cleared from the alveoli. Under normal circumstances these rates of synthesis, secretion, and clearance are the same the intra- and extra-cellular pools of surfactant do not change in size. Our studies further indicated that some, but not all Type II cells, were substantially increased in size. We hypothesize that the expanded surfactant pools are related to the appearance of these hypertrophic Type II cells. By using protease digestion and centrifugal elutriation procedures we have now succeeded in isolating hypertrophic Type II cells from the lungs of silica-treated rats and preliminary evidence indicates that these cells are hyperactive in their ability to synthesize surfactant. In future studies we will further characterize the changes that have occurred in the silica-exposed Type II cells and identify which steps in the biosynthetic pathway are responsible for the increased rate of biosynthesis of surfactant phospholipids. We will also investigate phospholipid biosynthesis in Type II cells under conditions of in vitro cultivation as a means of elucidating the mechanisms through which surfactant biosynthesis is affected by silica.

肺表面活性物质是脂质和蛋白质的复杂混合物 防止肺泡和远端气道塌陷， 卷 硅尘会导致表面活性剂的大量增加 肺的内容物，但通过这种机制， 发生的事情是未知的。 审查在某些情况下， 合成、分泌和清除表面活性剂磷脂 从二氧化硅处理的大鼠的肺中发现， 表面活性剂的细胞内和细胞外池可以被计算 因为表面活性剂 磷脂由肺泡II型细胞合成，分泌， 然后从肺泡中清除 在正常情况下，这些合成，分泌， 和清除率是相同的细胞内和细胞外池 表面活性剂尺寸不变。 我们的研究进一步表明 一些，但不是所有的II型细胞， 在尺寸上。 我们假设，扩大的表面活性剂池是 与这些肥大的II型细胞的出现有关。 通过 使用蛋白酶消化和离心淘洗程序， 现在已经成功地分离出肥大的II型细胞， 初步证据表明， 这些细胞的合成能力非常活跃 表面活性 在未来的研究中，我们将进一步描述 暴露于二氧化硅的II型细胞中发生的变化， 确定生物合成途径中的哪些步骤负责 用于增加表面活性剂磷脂的生物合成速率。 我们还将研究II型细胞中磷脂的生物合成 在体外培养条件下作为阐明 影响表面活性剂生物合成的机制 二氧化硅。