跨界RNA干扰在声带纤维化失调介导网络中的作用：致病假说与分子干预靶点

文献信息

中文摘要

声带纤维化是顽固性嗓音疾病的主要病理基础。以往的病因学模型将声带瘢痕 solely 归因于机械创伤和化学刺激，而声带局部黏膜微生物群及其对宿主基因表达的跨界调控长期未受重视。整合跨学科进展，本综述提出一个跨界致病假说：发声创伤诱导喉部菌群失调和声带上皮紧密连接解体，应激条件下的机会性病原体释放富含细菌小RNA（bsRNAs）的外膜囊泡（OMVs）。这些纳米级载体穿过受损的黏膜屏障并浸润声带固有层；其携带的bsRNAs通过序列互补被宿主Argonaute蛋白识别并装载到RNA诱导沉默复合体（RISC）中，在声带成纤维细胞中转录后沉默Smad7——转化生长因子-β（TGF-β）信号通路的关键负调控因子。Smad7的转录后沉默解除了TGF-β/Smad3促纤维化信号轴的负反馈抑制，驱动成纤维细胞向肌成纤维细胞转化，并诱导致密胶原的过度沉积。同时，OMV表面的脂多糖等病原体相关分子模式激活固有层驻留巨噬细胞中的Toll样受体4（TLR4）/NF-κB通路；释放的促炎细胞因子与成纤维细胞内的跨界RNA干扰相互增强，推动组织修复走向终末纤维化状态。由此形成的“机械创伤-菌群失调-跨界RNA干扰-免疫激活”网络可能解释在起始机械损伤消退后，持续性喉部菌群失调所维持的纤维化进展，并为基于微生物群调节和RNA靶向的抗纤维化策略指明新方向。

英文摘要

Vocal fold fibrosis is the principal pathological basis of intractable voice disorders. Previous etiological models have attributed vocal fold scarring solely to mechanical trauma and chemical irritation, whereas the local mucosal microbiota of the vocal folds and its cross-kingdom regulation of host gene expression have long received little attention. Integrating interdisciplinary advances, this review proposes a cross-kingdom pathogenic hypothesis: phonotrauma induces laryngeal dysbiosis and disassembly of the vocal fold epithelial tight junctions, and opportunistic pathogens under stress release outer membrane vesicles (OMVs) enriched in bacterial small RNAs (bsRNAs). These nanoscale carriers traverse the damaged mucosal barrier and infiltrate the vocal fold lamina propria; the bsRNAs they carry are recognized through sequence complementarity by host Argonaute proteins and loaded into the RNA-induced silencing complex (RISC), post-transcriptionally silencing Smad7, a key negative regulator of the transforming growth factor-β (TGF-β) signaling pathway, in vocal fold fibroblasts. Post-transcriptional silencing of Smad7 releases the TGF-β/Smad3 pro-fibrotic signaling axis from negative-feedback inhibition, driving the transition of fibroblasts into myofibroblasts and inducing excessive deposition of dense collagen. In parallel, pathogen-associated molecular patterns such as lipopolysaccharide on the OMV surface activate the Toll-like receptor 4 (TLR4)/NF-κB pathway in resident macrophages of the lamina propria; the released pro-inflammatory cytokines and the cross-kingdom RNA interference within fibroblasts reinforce each other, propelling tissue repair toward a terminal fibrotic state. The resulting "mechanical trauma-dysbiosis-cross-kingdom RNA interference-immune activation" network may explain fibrotic progression maintained by persistent laryngeal dysbiosis after the initiating mechanical injury has resolved, and points to new directions for anti-fibrotic strategies based on microbiota modulation and RNA targeting.