Department of Medicine, UCSF, San Francisco, California, USA.
School of Pharmacy, University of Texas, El Paso, El Paso, Texas, USA.
J Clin Invest. 2020 Apr 1;130(4):2041-2053. doi: 10.1172/JCI129635.
Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance 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.
囊性纤维化（CF）肺部疾病的特征是炎症反应，可导致终末期呼吸衰竭。囊性纤维化跨膜电导调节因子（CFTR）在 CF 中发生突变，我们假设血小板中功能失调的 CFTR（血小板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，血小板中 CFTR 的缺失会导致气管内 LPS 或铜绿假单胞菌挑战后急性肺炎症和血小板活化加剧。在小鼠或人类血小板中 CFTR 功能丧失会导致激动剂诱导的过度激活和血小板内钙离子内流增加。瞬时受体电位阳离子通道 6（TRPC6）的抑制可减少 CF 小鼠气管内 LPS 或铜绿假单胞菌挑战后的血小板活化和钙通量，并减少肺损伤。接受 CFTR 调节剂治疗的 CF 患者表现出血小板中 CFTR 功能的部分恢复，这可能是监测 CFTR 调节剂生物学反应的一种便捷方法。我们得出结论，血小板中 CFTR 功能障碍会导致异常的 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。血小板和 TRPC6 是我们认为在治疗 CF 肺部疾病方面的新的治疗靶点。
