Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing Escherichia coli pneumonia. Injury level was then assessed at 48 h. In vitro, expression was observed as early as 4 h in lung epithelial cells. IκBα-SR and wild-type IκBα mRNAs attenuated inflammatory markers, while SOD3 mRNA induced protective and antioxidant effects. In rat E. coli pneumonia, IκBα-SR mRNA reduced arterial carbon dioxide (pCO2) and reduced lung wet/dry ratio. SOD3 mRNA improved static lung compliance and alveolar-arterial oxygen gradient (AaDO2) and decreased bronchoalveolar lavage (BAL) bacteria load. White cell infiltration and inflammatory cytokine concentrations in BAL and serum were reduced by both mRNA treatments compared to scrambled mRNA controls. These findings indicate nebulized mRNA therapeutics are a promising approach to ARDS therapy, with rapid expression of protein and observable amelioration of pneumonia symptoms.

中文翻译：

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mRNA 构建体的雾化肺递送减轻了大鼠大肠杆菌肺炎的严重程度。

急性呼吸窘迫综合征 (ARDS) 是一种快速发作的炎症性肺病，没有有效的特异性治疗，通常具有称为肺炎的致病病因。在之前的研究中，核因子-κB (NF-κB) 抑制剂 α 超级阻遏物 (IκBα-SR) 和细胞外超氧化物歧化酶 3 (SOD3) 在通过病毒载体预防性递送时可降低肺炎的严重程度。在这项研究中，编码绿色荧光蛋白、IκBα-SR 或 SOD3 的 mRNA 与阳离子脂质复合，通过振动筛网雾化器，并输送到细胞培养物或直接输送到经历大肠杆菌肺炎的大鼠。然后在 48 小时评估损伤水平。在体外，早在 4 小时就在肺上皮细胞中观察到表达。IκBα-SR 和野生型 IκBα mRNA 减弱了炎症标志物，而 SOD3 mRNA 诱导保护和抗氧化作用。在大鼠大肠杆菌肺炎中，IκBα-SR mRNA 降低了动脉二氧化碳 (pCO2) 并降低了肺湿/干比。SOD3 mRNA 改善静态肺顺应性和肺泡-动脉氧梯度 (AaDO2) 并降低支气管肺泡灌洗 (BAL) 细菌负荷。与乱序 mRNA 对照相比，两种 mRNA 处理均降低了 BAL 和血清中的白细胞浸润和炎性细胞因子浓度。这些发现表明雾化 mRNA 疗法是治疗 ARDS 的一种有前途的方法，具有蛋白质的快速表达和肺炎症状的明显改善。SOD3 mRNA 改善静态肺顺应性和肺泡-动脉氧梯度 (AaDO2) 并降低支气管肺泡灌洗 (BAL) 细菌负荷。与乱序 mRNA 对照相比，两种 mRNA 处理均降低了 BAL 和血清中的白细胞浸润和炎性细胞因子浓度。这些发现表明雾化 mRNA 疗法是治疗 ARDS 的一种有前途的方法，具有蛋白质的快速表达和肺炎症状的明显改善。SOD3 mRNA 改善静态肺顺应性和肺泡-动脉氧梯度 (AaDO2) 并降低支气管肺泡灌洗 (BAL) 细菌负荷。与乱序 mRNA 对照相比，两种 mRNA 处理均降低了 BAL 和血清中的白细胞浸润和炎性细胞因子浓度。这些发现表明雾化 mRNA 疗法是治疗 ARDS 的一种有前途的方法，具有蛋白质的快速表达和肺炎症状的明显改善。