Signal transduction of lung surfactant synthesis, transport, and secretion in alveolar type II cell

肺表面活性物质是一种脂类和载脂蛋白的混合物，在肺泡II型细胞中合成，是维持肺内环境稳定所必需的物质。本研究项目揭示了以下几个方面。(1)磷脂酰胆碱是肺表面活性物质的主要脂类成分，由内质网合成，通过高尔基体非依赖途径运输和储存在板层小体中。相反，表面活性蛋白A是四种脱辅基蛋白之一，在内质网上合成，运输到高尔基体，糖基化，并从细胞中结构性地分泌出来。分泌的蛋白质被内吞入肺泡II型细胞，并运输到板层小体。(2)本研究还在凝胶过滤层析中鉴定并部分鉴定了一种约110kD的胞内分子，该分子可诱导表面活性物质胞吐。(3)霍乱毒素对腺苷环化酶相关的异三聚体G蛋白的ADP核糖基化反应，对肺表面活性物质的分泌有强烈的抑制作用。这些结果表明到目前为止肺表面活性物质的假设途径是错误的，并为肺表面活性物质生物学带来了新的方面。(4)此外，我们还考察了肺放气和几种药物对肺泡水清除的影响。综上所述，这些发现将有助于更好地理解急性呼吸衰竭的发病机制，并提出一种新的治疗策略。这些结果发表在医学期刊上，在医学会议上发表，并提交给医学书籍。尤其是发表在美国医学期刊上的论文共占影响因子的11.295。

Lung surfactant, a mixture of lipids and apoproteins, is synthesized in alveolar type II cells and is essential substance for maintaining lung homeostasis. This research project has revealed followings. (1) Phosphatidylcholine, a major lipidcomponent of lung surfactant, is synthesized in endoplasmic reticulum, transported to and stored in lamellar bodies via the Golgi-independent pathway. In contrast, surfactant protein A, one of the four apoproteins, is synthesized in endoplasmic reticulum, transported to the Golgi and is glycosylated, and is constitutively secreted out of the cells. The secreted protein is endocytosed into alveolar type II cells and transported to lamellar bodies. (2) The research also identified and partially characterized an intracellular molecule of an approximately 110 kD molecular weight on a gel filtration chromatography, which induces surfactant exocytosis. (3) ADP-ribosylation of adenylate cyclase-associated heterotrimeic G protein by cholera toxin unexpectedly but strongly inhibits lung surfactant secretion. These results indicate that the postulated pathway of lung surfactant so far is wrong, and have brought new aspects of lung surfactant biology. (4) Furthermore, we have investigated effects of lung deflation and several agents on alveolar water clearance. Taken together, these findings will lead to better understanding of pathogenesis of acute respiratory failure and a novel therapeutic strategy.These results were published in medical journals, presented in medical meetings, and submitted to medical books. Especially, these papers published in American medical journals counted totally 11.295 of Impact Factor (Journal Citation Report, ISI).