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Subacute TGFβ Exposure Drives Airway Hyperresponsiveness in CF Mice through the PI3K Pathway.

亚急性 tgf β 暴露通过 PI3K 通路驱动 CF 小鼠气道高反应性。

  • 影响因子:3.37
  • DOI:10.1165/rcmb.2019-0158OC
  • 作者列表:"Kramer EL","Madala SK","Hudock KM","Davidson C","Clancy JP
  • 发表时间:2020-01-10

:Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CFTR expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is Transforming Growth Factor beta 1 (TGFβ), a genetic modifier of CF lung disease. Prior studies demonstrated that TGFβ exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFβ, with elevated PI3K signaling and greater increases in lung resistance compared to controls. Here, we show that TGFβ drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared to non-CF mice. Further, therapeutic inhibition of PI3K signaling mitigated the TGFβ-induced AHR, as well as goblet cell hyperplasia, in CF mice. These results highlight a latent airway hyperresponsiveness phenotype in CFTR deficiency that is enhanced through TGFβ-induced PI3K signaling.


: 囊性纤维化 (CF) 是一种致死性遗传性疾病,以进行性肺损伤和气道阻塞为特征。大多数患者表现出气道高反应性 (AHR),这与更快速的肺功能下降有关。最近在新生 CF 猪中的研究证实了气道平滑肌 (ASM) 功能障碍。这些发现,结合观察到的 ASM 中的 CFTR 表达,提示 ASM 功能的基本缺陷导致 CF 的肺功能下降。AHR 和 ASM 功能障碍的一个既定驱动因素是转化生长因子 β 1 (tgf β),CF 肺病的遗传修饰因子。既往研究表明,CF 小鼠的 tgf β 暴露驱动 CF 肺病的特征,包括杯状细胞增生和肺力学异常。CF 小鼠对肺 tgf β 表现出异常反应,与对照组相比,PI3K 信号增加,肺阻力增加更大。在此,我们发现 tgf β 通过 PI3K 信号驱动 CF ASM 结构和功能的异常,该信号在 CFTR 缺陷肺中增强。CF 和非 CF 小鼠气管内暴露于含有 tgf β 1 cDNA 、空载体或仅 PBS 的腺病毒载体。我们在对照组和 CF 小鼠中评估了乙酰甲胆碱诱导的 AHR 、支气管扩张剂反应和 ASM 面积。值得注意的是,与非 CF 小鼠相比,CF 小鼠表现出 AHR 和支气管扩张反应增强,ASM 面积增加更大。此外,PI3K 信号的治疗性抑制减轻了 CF 小鼠中 tgf β 诱导的 AHR 以及杯状细胞增生。这些结果突出了 CFTR 缺陷中潜在的气道高反应性表型,通过 tgf β 诱导的 PI3K 信号增强。



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

翻译标题与摘要 下载文献
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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翻译标题与摘要 下载文献
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.