Eddy A A
Children's Hospital and Regional Medical Center, Division of Nephrology, University of Washington, CH-46, 4800 Sand Point Way, NE, Seattle, WA 98105-0371, USA.
Pediatr Nephrol. 2000 Dec;15(3-4):290-301. doi: 10.1007/s004670000461.
All progressive renal diseases are the consequence of a process of destructive fibrosis. This review will focus on tubulointerstitial fibrosis, the pathophysiology of which will be divided into four arbitrary phases. First is the cellular activation and injury phase. The tubules are activated, the peritubular capillary endothelium facilitates migration of mononuclear cells into the interstitium where they mature into macrophages, and myofibroblasts/activated fibroblasts begin to populate the interstitium. Each of these cells releases soluble products that contribute to ongoing inflammation and ultimately fibrosis. The second phase, the fibrogenic signaling phase, is characterized by the release of soluble factors that have fibrosis-promoting effects. Several growth factors and cytokines have been implicated, with primary roles suggested for transforming growth factor-beta, connective tissue growth factor, angiotensin II and endothelin-1. Additional factors may participate including platelet-derived growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and interleukin-1, while interferon-gamma and hepatocyte growth factor may elicit antifibrotic responses. Third is the fibrogenic phase when matrix proteins, both normal and novel to the renal interstitium, begin to accumulate. During this time both increased matrix protein synthesis and impaired matrix turnover are evident. The latter is due to the renal production of protease inhibitors such as the tissue inhibitors of metalloproteinases and plasminogen activator inhibitors which inactivate the renal proteases that normally regulate matrix turnover. Fourth is the phase of renal destruction, the ultimate sequel to excessive matrix accumulation. During this time the tubules and peritubular capillaries are obliterated. The number of intact nephrons progressively declines resulting in a continuous reduction in glomerular filtration.
所有进行性肾脏疾病都是破坏性纤维化过程的结果。本综述将聚焦于肾小管间质纤维化，其病理生理学可分为四个任意阶段。首先是细胞激活和损伤阶段。肾小管被激活，肾小管周围毛细血管内皮促进单核细胞迁移到间质，在那里它们成熟为巨噬细胞，肌成纤维细胞/活化的成纤维细胞开始在间质中聚集。这些细胞中的每一个都会释放可溶性产物，这些产物会导致持续的炎症并最终导致纤维化。第二阶段是促纤维化信号阶段，其特征是释放具有促纤维化作用的可溶性因子。几种生长因子和细胞因子已被牵连其中，转化生长因子-β、结缔组织生长因子、血管紧张素 II 和内皮素-1 被认为起主要作用。其他可能参与的因子包括血小板衍生生长因子、碱性成纤维细胞生长因子、肿瘤坏死因子-α 和白细胞介素-1，而干扰素-γ 和肝细胞生长因子可能引发抗纤维化反应。第三是纤维化阶段，此时正常和肾脏间质特有的基质蛋白开始积累。在此期间，基质蛋白合成增加和基质周转受损都很明显。后者是由于肾脏产生蛋白酶抑制剂，如金属蛋白酶组织抑制剂和纤溶酶原激活物抑制剂，这些抑制剂会使正常调节基质周转的肾脏蛋白酶失活。第四是肾脏破坏阶段，这是基质过度积累的最终后果。在此期间，肾小管和肾小管周围毛细血管被闭塞。完整肾单位的数量逐渐减少，导致肾小球滤过持续降低。
