BACKGROUND ALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI. METHODS We examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, and FGF-10 with LPS via western blot and qRT-PCR. Western blot and chromatin immunoprecipitation assay detected the effects of liraglutide on GLP-1R, SPC, Ang-1, and FGF-10 through PKAc/β-catenin pathway and cAMP pathway. In the ALI animal model, we detected the effects of MSC and liraglutide combination on ALI symptoms by H&E staining, western blot, ELISA assays, calculating wet-to-dry ratio of the lung tissue, and counting neutrophils, leukocytes, and macrophages in mouse bronchoalveolar lavage fluid (BALF). RESULTS The data demonstrated that LPS reduced hCMSC proliferation and GLP-1R, SPC, Ang-1, and FGF-10 levels in a dose- and time-dependent manner. Liraglutide significantly dampened the reduction of GLP-1R, SPC, Ang-1, and FGF-10 and reversed the effect of LPS on hCMSCs, which could be regulated by GLP-1R and its downstream cAMP/PKAc/β-catenin-TCF4 signaling. Combination of hCMSCs with liraglutide showed more therapeutic efficacy than liraglutide alone in reducing LPS-induced ALI in the animal model. CONCLUSIONS These results reveal that the combination of hCMSCs and liraglutide might be an effective strategy for ALI treatment.

中文翻译：

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hCMSCs 和利拉鲁肽组合通过 cAMP/PKAc/β-catenin 信号通路对 ALI 的影响。

背景ALI/ARDS是危重患者急性呼吸衰竭的主要原因。由于人绒毛膜绒毛来源的间充质干细胞（hCMSCs）可以减轻气道损伤模型中的ALI，而利拉鲁肽，胰高血糖素样肽1（GLP-1）激动剂，具有抗炎和促进增殖的功能，我们建议探索潜在的组合hCMSCs 和利拉鲁肽对 ALI 的影响。方法 我们通过蛋白质印迹和 qRT-PCR 检查了 GLP-1R、SPC、Ang-1 和 FGF-10 与 LPS 的时间和剂量依赖性方式。Western blot和染色质免疫沉淀法检测利拉鲁肽通过PKAc/β-catenin途径和cAMP途径对GLP-1R、SPC、Ang-1和FGF-10的影响。在ALI动物模型中，我们通过H&E染色、蛋白质印迹、ELISA测定、计算肺组织湿干比以及计数小鼠中性粒细胞、白细胞和巨噬细胞，检测MSC和利拉鲁肽组合对ALI症状的影响支气管肺泡灌洗液（BALF）。结果数据表明，LPS 以剂量和时间依赖性方式降低 hCMSC 增殖以及 GLP-1R、SPC、Ang-1 和 FGF-10 水平。利拉鲁肽显着抑制 GLP-1R、SPC、Ang-1 和 FGF-10 的减少，并逆转 LPS 对 hCMSC 的影响，这可能受到 GLP-1R 及其下游 cAMP/PKAc/β-catenin-TCF4 信号传导的调节。在动物模型中，hCMSC 与利拉鲁肽的组合在减少 LPS 诱导的 ALI 方面比单独使用利拉鲁肽显示出更好的治疗效果。结论 这些结果表明，hCMSC 和利拉鲁肽联合使用可能是治疗 ALI 的有效策略。