Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH-neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM-pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the upregulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.

中文翻译：

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Sonic hedgehog 在过敏性气道上皮细胞中的高表达有助于杯状细胞化生。

Sonic hedgehog (SHH) 大量表达，对胚胎肺的形态发生至关重要；然而，从 E17.5 开始，SHH 表达在小鼠和第 21 个妊娠周的人类中下降到更低的水平。我们发现 SHH 表达在患有哮喘的儿童或患有过敏性气道疾病的小鼠模型的气道上皮细胞中被强烈上调。具体而言，气道特异性 SMO 功能丧失显着抑制过敏原诱导的杯状细胞表型，而气道特异性 SMO 功能获得显着增强过敏性气道疾病小鼠模型中的杯状细胞表型。值得注意的是，气管内给予 SHH 中和抗体或环巴胺可显着减弱患有过敏性气道疾病的小鼠模型中的杯状细胞表型。最后，我们确定编码 MUC5AC 粘蛋白的 Muc5AC 基因作为响应 SHH 的 GLI 转录因子的直接靶标，而含有 SAM 指向结构域的 ETS 转录因子和 Forkhead box A2（杯状细胞表型的关键转录因子）均作为GLI 的效应器响应 SHH 刺激。总之，过敏性支气管上皮细胞中 SHH 表达的上调有助于杯状细胞化生；因此，阻断 SHH 信号传导是慢性气道疾病上皮重塑治疗干预的合理方法。两者都作为响应 SHH 刺激的 GLI 效应器发挥作用。总之，过敏性支气管上皮细胞中 SHH 表达的上调有助于杯状细胞化生；因此，阻断 SHH 信号传导是慢性气道疾病上皮重塑治疗干预的合理方法。两者都作为响应 SHH 刺激的 GLI 效应器发挥作用。总之，过敏性支气管上皮细胞中 SHH 表达的上调有助于杯状细胞化生；因此，阻断 SHH 信号传导是慢性气道疾病上皮重塑治疗干预的合理方法。