PREVENTION OF LUNG INJURY BY A PROLINE ANALOGUE

脯氨酸类似物预防肺损伤

• 批准号: 3337563
• 负责人: David Joseph Riley
• 金额: $ 14.94万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 1987-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3337563
• 关键词: DNA; aminoacid analog; disease /disorder model; dosage; emphysema; genetic manipulation; histopathology; hyperoxia; lung disorder; proline; pulmonary fibrosis /granuloma; respiratory airway pressure; respiratory airway volume; respiratory insufficiency /failure; respiratory pharmacology

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.

人类纤维性肺病是一组不同种类的疾病 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。因为胶原蛋白有一种 在纤维化中的核心作用，我们已经使用了阻止胶原合成或 增强其作为实验性肺损伤潜在抑制剂的降解作用 纤维化症。 各种实验模型提供了对相关机制的洞察 在纤维化过程中。本文使用的两种模型是博莱霉素性肝纤维化。 仓鼠和大鼠体内的氧气中毒。这两种模式都增加了胶原蛋白 虽然它们在结构和肺力学上有所不同，但它们的内容物是相同的。我们有 在这些模型中测试了两种试剂：顺-4-羟基-L-脯氨酸 (顺-羟基脯氨酸)，一种能特异性抑制胶原蛋白的脯氨酸类似物 合成，以及胶原和胶原的交联剂β-氨基丙腈 弹性蛋白。我们的WOR表明，这两种药物都能防止结构性、功能性、 和生化变化的初步纤维化，没有引起毒副作用 效果。 考虑到这些药物在动物模型中的有效性，似乎 合理的是它们可以用于以以下特征为特征的疾病的人体试验 结缔组织的快速合成。这样的障碍可能是成年人 呼吸窘迫综合征，博莱霉素性肺纤维化，放射 纤维化和氧气中毒。