Beyer Christian, Schett Georg, Gay Steffen, Distler Oliver, Distler Jörg H W
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Arthritis Res Ther. 2009;11(2):220. doi: 10.1186/ar2598. Epub 2009 Apr 21.
Autoimmunity, microangiopathy and tissue fibrosis are hallmarks of systemic sclerosis (SSc). Vascular alterations and reduced capillary density decrease blood flow and impair tissue oxygenation in SSc. Oxygen supply is further reduced by accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Therefore, severe hypoxia is a characteristic feature of SSc and might contribute directly to the progression of the disease. Hypoxia stimulates the production of ECM proteins by SSc fibroblasts in a transforming growth factor-beta-dependent manner. The induction of ECM proteins by hypoxia is mediated via hypoxia-inducible factor-1alpha-dependent and -independent pathways. Hypoxia may also aggravate vascular disease in SSc by perturbing vascular endothelial growth factor (VEGF) receptor signalling. Hypoxia is a potent inducer of VEGF and may cause chronic VEGF over-expression in SSc. Uncontrolled over-expression of VEGF has been shown to have deleterious effects on angiogenesis because it leads to the formation of chaotic vessels with decreased blood flow. Altogether, hypoxia might play a central role in pathogenesis of SSc by augmenting vascular disease and tissue fibrosis.
自身免疫、微血管病变和组织纤维化是系统性硬化症（SSc）的特征。血管改变和毛细血管密度降低会减少血流量并损害SSc中的组织氧合。细胞外基质（ECM）的积累进一步减少了氧气供应，这增加了从血管到细胞的扩散距离。因此，严重缺氧是SSc的一个特征，可能直接导致疾病进展。缺氧以转化生长因子-β依赖的方式刺激SSc成纤维细胞产生ECM蛋白。缺氧对ECM蛋白的诱导通过缺氧诱导因子-1α依赖和非依赖途径介导。缺氧还可能通过干扰血管内皮生长因子（VEGF）受体信号传导加重SSc中的血管疾病。缺氧是VEGF的强效诱导剂，可能导致SSc中VEGF的慢性过度表达。VEGF的不受控制的过度表达已被证明对血管生成有有害影响，因为它会导致形成血流量减少的混乱血管。总之，缺氧可能通过加剧血管疾病和组织纤维化在SSc的发病机制中起核心作用。
