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


  • 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

: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.


: 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。



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"]

METHODS:OBJECTIVES:To asses the clinical course in RA-related interstitial lung disease (RA-ILD) patients with and without rituximab (RTX). The influence of other variables was also evaluated. METHODS:A longitudinal multicentre study was conducted in RA diagnosed with ILD from 2007 until 2018 in Madrid. Patients were included in a registry [pNEumology RhEumatology Autoinmune diseases (NEREA)] from the time of ILD diagnosis. The main endpoint was functional respiratory impairment (FI), when there was a decline ≥5% in the predicted forced vital capacity compared with the previous one. Pulmonary function was measured at baseline and in follow-up visits every 6-12 months. The independent variable was therapy with RTX. Covariables included sociodemographic, clinical, radiological and other therapies. Survival techniques were used to estimate the incidence rate (IR) and 95% CI of functional impairment, expressed per 100 patient-semesters. Cox multivariate regression models were run to examine the influence of RTX and other covariates on FI. Results were expressed as the hazard ratio (HR) and CI. RESULTS:A total of 68 patients were included. FI occurred in 42 patients [IR 23.5 (95% CI 19, 29.1)] and 50% of them had FI within 1.75 years of an ILD diagnosis. A multivariate analysis showed that RTX exposure resulted in a lower risk of FI compared with non-exposure [HR 0.51 (95% CI 0.31, 0.85)]. Interstitial pneumonia, glucocorticoids, disease activity and duration also influenced FI. CONCLUSION:RA-ILD patients deteriorate over time, with the median time free of impairment being <2 years. Patients exposed to RTX had a higher probability of remaining free of FI compared with other therapies. Other factors have also been identified. Key words: rheumatoid arthritis, interstitial lung disease, observational study, rituximab and prognosis

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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"]

METHODS:The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P  = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.

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来源期刊:New biotechnology
作者列表:["Sousa SA","Soares-Castro P","Seixas AMM","Feliciano JR","Balugas B","Barreto C","Pereira L","Santos PM","Leitão JH"]

METHODS::Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous multidrug resistant organisms and opportunistic pathogens capable of causing life threatening lung infections among cystic fibrosis (CF) patients. No effective therapies are currently available to eradicate Bcc bacteria from CF patients, as these organisms are inherently resistant to the majority of clinically available antimicrobials. An immunoproteomics approach was used to identify Bcc proteins that stimulate the humoral immune response of the CF host, using bacterial cells grown under conditions mimicking the CF lung environment and serum samples from CF patients with a clinical record of Bcc infection. 24 proteins of the Bcc strain B. cenocepacia J2315 were identified as immunoreactive, 19 here reported as immunogenic for the first time. Ten proteins were predicted as extracytoplasmic, 9 of them being conserved in Bcc genomes. The immunogenic Bcc extracytoplasmic proteins are potential targets for development of novel therapeutic strategies and diagnostic tools to protect patients against the onset of chronic Bcc lung infections.