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

肺表面活性剂是脂质和载脂蛋白的混合物，在肺泡II型细胞中合成，是维持肺内平衡的必需物质。这个研究项目揭示了以下几点。(1)磷脂酰胆碱是肺表面活性物质的主要脂质成分，在内质网合成，经高尔基非依赖性途径转运到板层体并在板层体中储存。相反，表面活性剂蛋白A，四载脂蛋白之一，在内质网合成，运输到高尔基体并糖基化，并组成性分泌出细胞。分泌的蛋白被内吞进入肺泡II型细胞并转运到板层体。(2)在凝胶过滤层析上发现并部分表征了一个分子量约为110 kD的细胞内分子，该分子诱导表面活性剂胞外分泌。(3)霍乱毒素对腺苷酸环化酶相关异三聚G蛋白的adp -核糖基化意外但强烈地抑制了肺表面活性物质的分泌。这些结果表明，目前对肺表面活性物质作用途径的假设是错误的，并为肺表面活性物质生物学带来了新的认识。(4)此外，我们还研究了肺收缩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了解急性呼吸衰竭的发病机制和新的治疗策略。这些结果发表在医学期刊上，在医学会议上提出，并提交给医学书籍。特别是在美国医学期刊上发表的论文，影响因子（Journal Citation Report， ISI）共计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).