Perspectives for the use of collagen synthesis inhibitors as antifibrotic agents.
Perspectives for the use of collagen synthesis inhibitors as antifibrotic agents.
复制标题
使用胶原蛋白合成抑制剂作为抗纤维化药物的前景。
DOI：
10.1021/jm00138a001
复制
发表时间：
1981
影响因子：
7.3
通讯作者：
G. Fuller
中科院分区：
文献类型：
--
作者：
G. Fuller
简介 纤维化疾病是一类获得性结缔组织疾病，其特征是细胞外基质中纤维成分过度积累。尽管这些疾病中的终末纤维化病变被一致认为是细胞损伤的后遗症，但受损的细胞群和负责损伤后纤维化反应的内源性介质因器官而异。实质器官中纤维化反应的最终结果是实质结构的扭曲或破坏，导致功能丧失。在心血管系统中，纤维化血管结构紊乱导致血管壁弹性和与血小板相容的表面丧失。所有这些情况下的纤维化通常都未被发现，直到其完全形成并发展为终末期器官衰竭。这些因素，加上基质胶原蛋白的缓慢更新，导致了出厂前的结论：纤维化是一种无法治疗和不可逆转的病变。最近使用脯氨酸类似物或胶原蛋白交联抑制剂的示范项目表明，这种观点是不正确的，通过抑制胶原蛋白合成或加工来药理学控制纤维化是一个可以实现的目标。考虑到西方社会纤维化病变的高发率以及各种器官（肝、肺、肾、心血管）终末期纤维化导致的死亡率不断上升，抗纤维化药物开发的重要性就显而易见了。这些严重的医学问题已成为最近临床文献的编辑主题。 1, 2哺乳动物的细胞外基质由两种纤维蛋白（弹性蛋白和胶原蛋白）组成，周围环绕着蛋白聚糖。每个器官的结构发育和功能受到胶原蛋白和蛋白聚糖的异质性以及所有三种基质成分的相对比例的影响并依赖于它们。因此，基质成分的化学紊乱将导致器官的结构改变和功能受损。当化学紊乱是胶原蛋白过度积累时，通常会发生纤维化，但在某些形式的肺纤维化中，器官中胶原蛋白的几何分布发生变化，但没有过度积累。
Introduction The fibrotic diseases are a family of acquired connective tissue diseases characterized by the overaccumulation of fibrous components in the extracellular matrix. Although the terminalfibrotic lesion in these diseases is uniformly considered to be a sequela of cellular injury, the cell populations injured and the endogenous mediators re-sponsible for the postinjury fibrotic response varyfrom organ to organ. The end result of a fibrogenic response in a parenchymatous organ is distortion or destruction of the parenchymal architecture resulting in loss of function. In thecardiovascular system the fibrotic vascular archi-tectural derangement results in the loss of vessel wall elasticity and surfaces that are compatible with platelets. Fibrosis in all of these situations usually remains undetected until it is well established and has progressed toward end-stage organ failure. These factors, combined with the slow turnover of matrix collagen, contributed to thepre-factory conclusion that fibrosis was an untreatable and irreversible lesion. Recent demonstration projects using proline analogues or inhibitors of collagen cross-linking now indicate that this view is incorrect and that pharmacological control of fibrosis through inhibition of collagen synthesis or processing is an achievable objective. The importance of antifibrotic drug development is evident when one considers the high frequency of occurrence of the fibrotic lesion in Western society and the increasing death rate resulting from end-stage fibrosis of various organs (liver, lung, kidney, cardiovascular). These serious medical problems havebeen editorial topics inrecent clinical literature. 1, 2The extracellular matrix of the mammal is composed of two fibrous proteins, elastin and collagen, surrounded by proteoglycans. The architectural development and func-tion of each organ is influenced by and dependent upon the heterogeneity of collagen and proteoglycan, as well as the relative ratio of all three matrix components. Accordingly, chemical derangement of the matrix components will result in altered structure and compromised function of the organ. Fibrosisusually occurs when the chemical derangement is an overaccumulation of collagen, but in some forms of lung fibrosis changes in the geometricdis-tribution of collagen in the organ without overaccumula-