Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation
Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation
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DOI：
10.1172/jci129635
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发表时间：
2020-04-01
影响因子：
15.9
通讯作者：
Looney, Mark R.
中科院分区：
文献类型：
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作者：
Ortiz-Munoz, Guadalupe;Yu, Michelle A.;Looney, Mark R.
囊性纤维化（CF）肺部疾病的特点是炎症反应，可导致终末期呼吸衰竭。囊性纤维化跨膜传导调节因子（CFTR）在CF中发生突变，我们假设血小板CFTR功能失调是CF炎症的主要决定因素，血小板是免疫反应的关键参与者。我们发现，在气管内LPS或铜绿假单胞菌攻击后，血小板中CFTR的缺失会导致急性肺部炎症和血小板活化的加剧。小鼠或人血小板CFTR功能丧失导致激动剂诱导的过度活化和血小板钙进入增加。抑制瞬时受体电位阳离子通道6 （TRPC6）可降低血小板活化和钙通量，减轻气管内LPS或铜绿假单胞菌攻击后CF小鼠的肺损伤。CF患者接受CFTR调节剂治疗后，血小板中CFTR功能部分恢复，这可能是监测CFTR调节剂生物反应的一种方便方法。我们得出结论，血小板中CFTR功能障碍产生异常的trpc6依赖性血小板激活，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肺病的新靶点。
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.