Wilder R L, Case J P, Crofford L J, Kumkumian G K, Lafyatis R, Remmers E F, Sano H, Sternberg E M, Yocum D E
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Cell Biochem. 1991 Feb;45(2):162-6. doi: 10.1002/jcb.240450207.
Endothelial cells play a fundamental role in the pathogenesis of chronic inflammatory arthritis in humans such as rheumatoid arthritis (RA), as well as experimental animal models such as streptococcal cell wall (SCW) arthritis in Lewis (LEW/N) rats. This review summarizes data in support of this concept. The earliest apparent abnormalities in synovial tissues of patients with RA and Lewis rats with SCW arthritis appear to reflect microvascular endothelial cell activation or injury. At the molecular level, the abnormalities include enhanced expression by endothelial cells of activation markers such as class II major histocompatibility complex antigens, phosphotyrosine, leukocyte adhesion molecules, oncoproteins such as c-Fos and c-Myc, and metalloproteinases such as collagenase and transin/stromelysin. The development of severe, chronic, destructive arthritis is dependent upon thymic-derived lymphocytes and is accompanied by tumorlike proliferation of cells in the synovial connective tissue stroma (blood vessels and fibroblastlike cells), which results in resorptive destruction of bone and cartilage. Multiple criteria support the analogy to a neoplastic process. Paracrine and autocrine factors such as interleukin-1 (IL-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and heparin-binding fibroblast growth factors (HBGF, FGF) appear to play important roles in the generation of these lesions. Finally, in addition to the autocrine and paracrine regulatory factors, neuroendocrine factors, particularly the hypothalamic-pituitary-adrenal axis, appear to be involved in the counterregulation of the inflammatory process. The counterregulatory effects are mediated, in part, by inhibition of endothelial cell activation by corticosteroids.
内皮细胞在人类慢性炎症性关节炎（如类风湿关节炎，RA）以及实验动物模型（如Lewis（LEW/N）大鼠的链球菌细胞壁（SCW）关节炎）的发病机制中发挥着重要作用。本综述总结了支持这一概念的数据。RA患者和患有SCW关节炎的Lewis大鼠滑膜组织中最早出现的明显异常似乎反映了微血管内皮细胞的激活或损伤。在分子水平上，这些异常包括内皮细胞激活标志物的表达增强，如II类主要组织相容性复合体抗原、磷酸酪氨酸、白细胞粘附分子、癌蛋白如c-Fos和c-Myc，以及金属蛋白酶如胶原酶和转胶酶/基质溶解素。严重、慢性、破坏性关节炎的发展依赖于胸腺来源的淋巴细胞，并伴有滑膜结缔组织基质（血管和成纤维样细胞）中细胞的肿瘤样增殖，这导致骨和软骨的吸收性破坏。多项标准支持将其类比为肿瘤形成过程。旁分泌和自分泌因子，如白细胞介素-1（IL-1）、血小板衍生生长因子（PDGF）、转化生长因子-β（TGF-β）和肝素结合成纤维细胞生长因子（HBGF，FGF）似乎在这些病变的产生中起重要作用。最后，除了自分泌和旁分泌调节因子外，神经内分泌因子，特别是下丘脑-垂体-肾上腺轴，似乎参与了炎症过程的反向调节。这种反向调节作用部分是由皮质类固醇对内皮细胞激活的抑制介导的。
