IL-11在创伤性关节囊挛缩过程中的特异性致纤维化作用及相关机制研究

Recently, there have been major breakthroughs in studies on cardiac fibrosis. Interleukin (IL)-11 was identified as a specific fibrogenic factor acting downstream of transforming growth factor (TGF)-β1. It has a key role in cardiac fibrosis and is self-enhanced by extracellular signal-related kinase (ERK) activity. We hypothesize that IL-11 also plays an important role in traumatic capsular contracture. To test this hypothesis, we will inhibit IL-11 receptor expression by intra-articular injection of a lentivirus-IL-11 receptor siRNA in rat, and examine whether capsular contracture formation is significantly inhibited to determine the involvement of IL-11 in this process. Similarly, we will inhibit TGF-β1 receptor expression by intra-articular injection of a lentivirus-TGF-β1 receptor siRNA, and evaluate whether it significantly inhibit IL-11 gene expression to clarify the induction of IL-11 expression by TGF-β1. Finally, we will inhibit ERK1/2 expression by intra-articular injection of a lentivirus-ERK1/2 siRNA, and examine whether it directly reduce the IL-11 protein level to determine whether IL-11 self-enhancement is dependent on ERK1/2. These experiments will provide the foundations to develop specific treatment strategies for traumatic joint capsule contracture with fewer side effects and better therapeutic efficacy.

最近心脏纤维化的研究取得重大突破，Nature报道IL11是TGF-β1下游特异性的致纤维化因子，在心脏纤维化过程中扮演着关键角色，并通过ERK自我强化。我们假设IL11在创伤性关节囊挛缩中扮演着关键角色。通过大鼠关节腔内注射慢病毒-IL11受体siRNA而抑制IL11受体的表达，检测是否能显著抑制关节囊挛缩的形成，从而确定IL11是否也在关节囊挛缩过程中也扮演着关键角色。同样，通过关节腔内注射慢病毒-TGF-β1受体siRNA而抑制TGF-β1受体的表达，检测是否能显著抑制IL11的mRNA水平，从而确定IL11的转录表达是否由TGF-β1诱导。此外，通过关节腔内注射慢病毒-ERK1/2siRNA而抑制ERK1/2的表达，检测是否能直接抑制IL11的蛋白水平，从而确定IL11的自我强化是否依赖于ERK1/2。为创伤性关节囊挛缩找到一种特异性更强、副作用更小、疗效更佳的治疗方法奠定基础。

创伤后关节囊挛缩是关节损伤和手术后的常见并发症，其本质是一种以肌成纤维细胞过度分化增殖和细胞外基质异常分泌堆积为特点的纤维化疾病。我们采用NIH3T3细胞系设计体外实验，证明TGFβ1/IL11/ERK 1/2轴是成纤维细胞向肌成纤维细胞分化的重要通路。采用IL11、IL11R eKo基因工程小鼠构建创伤后关节囊挛缩模型，实验结果表明在创伤后关节囊挛缩中，抑制IL11能够减少关节囊内胶原蛋白分泌，抑制肌成纤维细胞过度分化增殖，从而缓解关节囊挛缩，以获得更好的关节活动度。我们的研究结果表明，在创伤性关节囊挛缩中，IL11通过激活ERK1/2通路发挥致纤维化作用，抑制IL11能够显著缓解关节囊挛缩。因此抗IL11治疗可被认为早期预防创和阻止伤性关节囊挛缩的有效手段。