Development of therapeutic ways on various pathological features in chronic obstructive pulmonary diseases

慢性阻塞性肺疾病(COPD)是世界范围内致病的主要原因。然而，目前治疗这种疾病的药物屈指可数。为了评价治疗COPD的新的药理学方法，有必要对COPD的肺生理和病理生理学有更深入的了解。这项研究的发现总结如下1.我们发现髓系Elf-1样因子(MEF)对呼吸道上皮细胞的分化有调节作用。除此之外，转MEF基因的癌细胞没有生长。因此，我们认为MEF不仅具有分化调节作用，而且还具有肿瘤抑制作用。我们发现Ets-2转录因子上调了腺癌细胞GM-CSF mRNA的表达，并且是蛋白激酶的靶点。我们发现了一些新药来控制呼吸道疾病的粘液分泌。其中，新型半胱氨酸衍生物福多司汀抑制气道杯状细胞的形成，甘草酸通过增强糖皮质激素的作用抑制粘液的产生。我们发现了新的内源性肺表面活性物质促分泌剂，肾上腺髓质素和前列腺素E_2。我们还发现，在肺泡型细胞中，蛋白激酶A和蛋白激酶C依赖的信号之间存在协同串扰。

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity in the world. However, there are only a few therapeutic drugs for the treatment of this disease. To evaluate new pharmacological approaches for COPD, it is necessary to make progress in understanding lung physiology and pathophysiology of COPD. The findings in this study were summarized below.1. We have found that myeloid Elf-1 like factor (MEF) regulated the differentiation of airway epithelial cells. In addition to this, MEF-transfected carcinoma cells did not grow. Therefore, we proposed that MEF act as not only a differentiation regulator, but also a tumor suppressor.2. We found that GM-CSF mRNA expression was upnregulated by ETS-2 transcription factor in adenocarcinoma cells, and was a target of protein kinase C.3. We have found some new drugs to control mucous secretion in airway diseases. Among them, fudosteine, a new cysteine derivative, inhibited the formation of airway goblet cells, and glycyrrhizin, inhibited mucus production by enhancing the effect of glucocorticoids.4. We have found new endogenous pulmonary surfactant secretagogues, adrenomedullin and prostaglandin E_2. We also found that there is a synergistic cross-talk between protein kinase A- and protein kinase C-dependent signalings in alveolar type II cells.