The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

中文翻译：

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肺上皮细胞来源的 C3 可预防肺炎引起的肺损伤


补体成分 C3 是宿主防御的基本血浆蛋白，主要由肝脏产生。然而，最近的研究表明组织特异性 C3 表达对于细胞存活至关重要。在这里，我们分析了 C3 表达的局部与外周来源在急性细菌性肺炎模型中的影响铜绿假单胞菌。虽然整体 C3 缺乏的小鼠患有严重的肺炎引起的肺损伤，但与野生型小鼠相比，那些仅缺乏肝源性 C3 的小鼠仍受到保护。人肺转录组分析表明，分泌上皮细胞（例如俱乐部细胞）表达高水平的 C3 mRNA。尽管维持了正常的循环 C3 水平，但与接受类似治疗的对照组相比，接受他莫昔芬诱导的肺部俱乐部细胞 C3 基因消融的小鼠的肺损伤更严重。最后，在小鼠肺炎模型和培养的原代人气道上皮细胞中，我们发现与 C3 缺乏相关的应激诱导死亡与 B 因子缺乏而非 C3a 受体缺乏相似。此外，C3 介导的上皮细胞死亡减少需要替代途径成分因子 B。因此，我们的研究结果表明，依赖于局部衍生的 C3 和因子 B 的途径可以保护肺粘膜屏障。