Strutz Frank, Neilson Eric G
Department of Nephrology and Rheumatology, Georg-August-University Göttingen, Robert-Koch-Str. 40, Göttingen, Germany.
Springer Semin Immunopathol. 2003 May;24(4):459-76. doi: 10.1007/s00281-003-0123-5.
. Renal fibrosis is the final common pathway for many kidney lesions that lead to chronic progressive organ failure. The tubulointerstitial space occupies up to 90% of kidney volume, indicating that pathological changes in that space can not be without functional significance. By analogy to wound healing, renal fibrogenesis can be divided arbitrarily into three phases: induction, inflammatory, and post-inflammatory phases. The latter phase is of particular importance, since its length often exceeds what would be required for healing. The induction phase is characterized by the infiltration of the tubulointerstitial space by mononuclear inflammatory cells. This influx is mediated by proinflammatory cytokines and chemokines often secreted by activated tubular epithelial cells. Subsequently, these infiltrating mononuclear cells stimulate a heterogeneous group of resident fibroblasts and tubular epithelial cells to undergo phenotypic conversion into activated fibroblasts that secrete abundant extracellular matrix. Tubular epithelial cells contribute to this process through epithelial-mesenchymal transition. During the inflammatory phase these activated fibroblasts are stimulated to produce collagenous matrix mainly by cytokines, such as TGF-beta1, EGF, ET-1, and FGF-2, which are secreted by inflammatory and injured somatic cells. Occasionally however, when inflammation subsides, the matrix synthesis in the post-inflammatory phase of renal fibrogenesis continues and may be more dependent on autocrine stimulation from resident renal cells such as remaining tubular epithelium. Eventually, the collagenous matrix of fibrogenesis destroys blood supply and the perimeter of viability for fibroblasts regresses to the point where scars become acellular.
肾纤维化是许多导致慢性进行性器官衰竭的肾脏病变的最终共同途径。肾小管间质空间占肾脏体积的90%，这表明该空间的病理变化具有功能意义。类比伤口愈合，肾纤维化可任意分为三个阶段：诱导期、炎症期和炎症后期。后一阶段尤为重要，因为其持续时间常常超过愈合所需时间。诱导期的特征是单核炎性细胞浸润肾小管间质空间。这种浸润由通常由活化的肾小管上皮细胞分泌的促炎细胞因子和趋化因子介导。随后，这些浸润的单核细胞刺激一群异质性的驻留成纤维细胞和肾小管上皮细胞发生表型转化，成为分泌大量细胞外基质的活化成纤维细胞。肾小管上皮细胞通过上皮-间质转化参与这一过程。在炎症期，这些活化的成纤维细胞主要受到细胞因子如TGF-β1、EGF、ET-1和FGF-2的刺激而产生胶原基质，这些细胞因子由炎症和受损的体细胞分泌。然而，偶尔在炎症消退时，肾纤维化炎症后期的基质合成仍会继续，并且可能更依赖于驻留肾细胞如剩余肾小管上皮细胞的自分泌刺激。最终，纤维化形成的胶原基质破坏血液供应，成纤维细胞的存活边界退缩到瘢痕变成无细胞状态的程度。
