Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane regulator (CFTR) is mutated in CF and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets, and TRPC6, are what we believe to be novel therapeutic targets in the treatment of CF lung disease.

中文翻译：

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血小板中的囊性纤维化跨膜电导调节器功能障碍导致肺过度炎症。

囊性纤维化 (CF) 肺病的特征在于可导致终末呼吸衰竭的炎症反应。囊性纤维化跨膜调节因子 (CFTR) 在 CF 中发生突变，我们假设血小板中功能失调的 CFTR 是免疫反应的关键参与者，是 CF 炎症的核心决定因素。我们发现，在气管内 LPS 或铜绿假单胞菌攻击后，血小板中 CFTR 的缺失会导致严重的急性肺部炎症和血小板活化。CFTR 在小鼠或人血小板中的功能丧失导致激动剂诱导的过度活化和钙进入血小板的增加。抑制瞬时受体电位阳离子通道 6 (TRPC6) 会降低血小板活化和钙通量，在气管内 LPS 或铜绿假单胞菌攻击后减少 CF 小鼠的肺损伤。接受 CFTR 调节剂治疗的 CF 受试者显示血小板中 CFTR 功能的部分恢复，这可能是监测对 CFTR 调节剂的生物反应的便捷方法。我们得出结论，血小板中的 CFTR 功能障碍会产生异常的 TRPC6 依赖性血小板活化，这是 CF 肺部炎症和细菌清除受损的主要驱动因素。我们认为血小板和 TRPC6 是治疗 CF 肺病的新治疗靶点。我们得出结论，血小板中的 CFTR 功能障碍会产生异常的 TRPC6 依赖性血小板活化，这是 CF 肺部炎症和细菌清除受损的主要驱动因素。我们认为血小板和 TRPC6 是治疗 CF 肺病的新治疗靶点。我们得出结论，血小板中的 CFTR 功能障碍会产生异常的 TRPC6 依赖性血小板活化，这是 CF 肺部炎症和细菌清除受损的主要驱动因素。我们认为血小板和 TRPC6 是治疗 CF 肺病的新治疗靶点。