Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection.
Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection.
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DOI：
10.1111/j.1600-6143.2009.02826.x
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Bishop DK
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文献类型：
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作者：
Booth AJ;Csencsits-Smith K;Wood SC;Lu G;Lipson KE;Bishop DK
心脏移植是治疗多种类型心力衰竭的有效方法。虽然免疫抑制治疗提高了移植后第一年的存活率，但慢性排斥反应(CR)仍然是移植物长期存活的重要障碍。CR的指标包括斑片状间质纤维化、血管闭塞和移植物功能进行性丧失。多种因素参与了CR的发生和发展，包括转化生长因子β、IL-6和结缔组织生长因子。虽然与CR有关，但CTGF在CR中的作用以及在体内诱导CTGF所需的因素尚不清楚。为此，我们使用了强制表达和中和抗体的方法。尽管转化生长因子β转导没有观察到的水平，但转导CTGF的同种异体移植物显著增加了纤维化组织的发展。此外，IL-6中和抑制了移植物内CTGF的表达，而转化生长因子β的表达没有变化，提示IL-6的作用可能增强了转化生长因子β介导的CTGF的诱导。最后，中和结缔组织生长因子显著减少移植物纤维化，而不降低转化生长因子β和IL-6的表达水平。这些发现表明，CTGF在CR中作为纤维化的下游介质发挥作用，CTGF中和可能减轻与CR相关的纤维化和肥厚。
Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year post-transplant, chronic rejection (CR) remains a significant barrier to long term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion, and progressive loss of graft function. Multiple factors have been implicated in the onset and progression of CR, including TGFβ, IL-6, and connective tissue growth factor (CTGF). While associated with CR, the role of CTGF in CR and the factors necessary for CTGF induction in vivo are not understood. To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGFβ transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization while TGFβ expression remained unchanged, indicating that IL-6 effects may potentiate TGFβ-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGFβ and IL-6 expression levels. These findings indicate that CTGF functions as a downstream mediator of fibrosis in CR, and that CTGF neutralization may ameliorate fibrosis and hypertrophy associated with CR.