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Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

血小板中的囊性纤维化跨膜传导调节因子功能障碍驱动肺部过度炎症。

  • 影响因子:10.49
  • DOI:10.1172/JCI129635
  • 作者列表:"Ortiz-Munoz G","Yu MA","Lefrançais E","Mallavia B","Valet C","Tian JJ","Ranucci S","Wang KM","Liu Z","Kwaan N","Dawson D","Kleinhenz ME","Khasawneh FT","Haggie PM","Verkman AS","Looney MR
  • 发表时间:2020-01-21
Abstract

: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.

摘要

: 囊性纤维化 (CF) 肺病的特征是炎症反应可导致终末呼吸衰竭。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 CF 炎症的中心决定因素,血小板是免疫反应的关键参与者。我们发现血小板中 CFTR 的缺失在气管内 LPS 或铜绿假单胞菌激发后产生夸大的急性肺部炎症和血小板活化。小鼠或人血小板的 CFTR 功能丧失导致激动剂诱导的过度激活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) 可降低 CF 小鼠气管内 LPS 或铜绿假单胞菌激发后的血小板活化和钙通量,并降低肺损伤。接受 CFTR 调节剂治疗的 CF 受试者显示血小板中 CFTR 功能部分恢复,这可能是监测 CFTR 调节剂生物学反应的方便方法。我们得出结论,血小板 CFTR 功能障碍产生异常 TRPC6-dependent 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 是我们认为治疗 CF 肺病的新治疗靶点。

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作者列表:["Vadillo C","Nieto MA","Romero-Bueno F","Leon L","Sanchez-Pernaute O","Rodriguez-Nieto MJ","Freites D","Jover JA","Álvarez-Sala JL","Abasolo L"]

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翻译标题与摘要 下载文献
影响因子:4.40
发表时间:2020-01-01
DOI:10.1007/s00262-019-02431-8
作者列表:["Shibaki, Ryota","Murakami, Shuji","Matsumoto, Yuji","Yoshida, Tatsuya","Goto, Yasushi","Kanda, Shintaro","Horinouchi, Hidehito","Fujiwara, Yutaka","Yamamoto, Nobuyuki","Kusumoto, Masahiko","Yamamoto, Noboru","Ohe, Yuichiro"]

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翻译标题与摘要 下载文献
影响因子:4.04
发表时间:2020-01-25
来源期刊:New biotechnology
DOI:10.1016/j.nbt.2019.08.006
作者列表:["Sousa SA","Soares-Castro P","Seixas AMM","Feliciano JR","Balugas B","Barreto C","Pereira L","Santos PM","Leitão JH"]

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