CELLS AND EXTRACELLULAR MATRIX IN PULMONARY HYPERTENSION

人类肺纤维化疾病是一组异质性疾病 以肺泡支持组织的变化为特征。 许多人的最后阶段 这种疾病的多种原因是肺纤维化。 由于胶原蛋白具有 在纤维化中的核心作用，我们已经使用了阻断胶原蛋白合成或 增强其作为实验性肺动脉高压潜在抑制剂的降解 纤维化 各种各样的实验模型提供了有关机制的见解 在纤维化的过程中。 这里使用的两种模型是博来霉素诱导的纤维化， 仓鼠和大鼠的氧中毒。 两种模型都增加了胶原蛋白 虽然它们在结构和肺力学上不同，但它们的肺内容物是相同的。 我们有 在这些模型中测试了两种药物：顺式-4-羟基-L-脯氨酸 （顺式羟脯氨酸），一种脯氨酸类似物，特异性抑制胶原蛋白 合成，以及β-氨基-丙腈，胶原交联抑制剂， 弹性蛋白 我们的工作表明，这两种药物都能防止结构，功能， 初步纤维化的生化变化，而不会引起毒副作用 方面的影响. 考虑到这些药物在动物模型中的有效性， 合理的，他们可能会用于人体试验的疾病，其特征是 结缔组织的快速合成。 这种疾病可能是成年人 呼吸窘迫综合征，博莱霉素肺纤维化，放射 纤维化和氧中毒

The human fibrotic lung disorders are a heterogeneous group of diseases characterized by changes in alveolar supporting tissue. The end stage of many diverse causes of this disorder is the fibrotic lung. Since collagen has a central role in fibrosis, we have used agents which block collagen synthesis or enhance its degradation as potential inhibitors of experimental pulmonary fibrosis. A variety of experimetnal models is providing insights into mechanisms involved in the fibrotic process. Two models used here are bleomycin-induced fibrosis in the hamster and oxygen toxicity in the rat. Both models have increased collagen content of lungs although they differ in structure and lung mechanics. We have tested two agents in these models: cis-4-hydroxy-L-proline (cis-hydroxyproline), a proline analogue which specifically inhibits collagen synthesis, and beta-amino-propionitrile, a crosslink inhibitor of collagen and elastin. Our wor has shown that both agents prevent the structural, functional, and biochemical changes of preliminary fibrosis without causing toxic side effects. Considering the effectiveness of these agents in animal models, it seems reasonable that they might be used in human trials of disorders characterized by rapid synthesis of connective tissue. Such disorders might be the adult respiratory distress syndrome, bleomycin-induced pulmonary fibrosis, radiation fibrosis, and oxygen toxicity.