Karasek Marvin Arthur
Stanford University, Dermatology, 269 Campus Dr, CCSR Bldg, Rm 2115, Stanford, CA 94305, United States.
Med Hypotheses. 2007;68(3):650-5. doi: 10.1016/j.mehy.2006.07.053. Epub 2006 Oct 12.
Fibrosis is a major cause of human death and disability. It has been hypothesized widely that activation of resident tissue fibroblasts is responsible for the increase in matrix protein synthesis present in fibrotic tissue. More recent studies in vitro of the physiology of human dermal microvascular endothelial cells and their transformation into spindle-shaped cells by proinflammatory cytokines may provide a new explanation for the increase in myofibroblasts in fibrotic diseases. In cell culture human dermal microvascular endothelial cells transform reversibly into 2 distinct cell phenotypes observed in the endothelium in vivo: an epithelioid phenotype present in a homeostatic microvasculature and a more spindle-shaped phenotype present in an inflammed and a reactive microvasculature. When epithelioid endothelial cell cultures are exposed to proinflammatory cytokines typically increased in fibrosis in vivo (e.g. TNF-alpha and IL-beta) for sustained periods, epithelioid dermal microvascular endothelial cells transform into a spindle-shaped morphology. Many of the transformed cells are identified as myofibroblast-like cells by electron microscopy (cytoplasmic microfilaments with attachment plaques), matrix protein synthesis (type I collagen, alpha smooth muscle actin, calponin) and by RT-PCR analysis of matrix protein mRNA. Following injury to an endothelial cell culture a similar (but reversible) transformation into myofibroblast-like cells also is induced. Drugs known to slow the clinical progression to fibrosis in vivo (e.g. phosphodiesterase inhibitors, antibodies to inflammatory cytokines) are the the same drug types capable of inhibiting endothelial cell tranformation in vitro. The in vivo and in vitro observations made on blood vessel physiology and pathology following sustained inflammation support a hypothesis that endothelial cell transformation into myofibroblast-like cells may begin to explain the increase in matrix proteins and myofibroblasts pathognomonic of fibrotic disease. The experimental and clinical evidence leading to and supporting this hypothesis is presented and discussed in this report.
纤维化是人类死亡和残疾的主要原因。人们普遍推测，驻留组织成纤维细胞的激活是纤维化组织中基质蛋白合成增加的原因。最近对人真皮微血管内皮细胞生理学及其被促炎细胞因子转化为纺锤形细胞的体外研究，可能为纤维化疾病中肌成纤维细胞增加提供新的解释。在细胞培养中，人真皮微血管内皮细胞可逆地转化为在体内内皮中观察到的两种不同细胞表型：存在于稳态微血管中的上皮样表型，以及存在于炎症和反应性微血管中的更纺锤形表型。当上皮样内皮细胞培养物长时间暴露于体内纤维化时通常增加的促炎细胞因子（如肿瘤坏死因子-α和白细胞介素-β）时，上皮样真皮微血管内皮细胞会转化为纺锤形形态。通过电子显微镜（带有附着斑的细胞质微丝）、基质蛋白合成（I型胶原、α平滑肌肌动蛋白、钙调蛋白）以及基质蛋白mRNA的逆转录聚合酶链反应分析，许多转化细胞被鉴定为肌成纤维细胞样细胞。内皮细胞培养物损伤后，也会诱导类似（但可逆）的向肌成纤维细胞样细胞的转化。已知能减缓体内纤维化临床进展的药物（如磷酸二酯酶抑制剂、炎性细胞因子抗体）与能够在体外抑制内皮细胞转化的药物类型相同。对持续炎症后血管生理和病理的体内和体外观察支持一种假说，即内皮细胞向肌成纤维细胞样细胞的转化可能开始解释纤维化疾病中特征性的基质蛋白和肌成纤维细胞的增加。本报告介绍并讨论了导致并支持这一假说的实验和临床证据。
