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Impaired Myofibroblast Dedifferentiation Contributes to Non-Resolving Fibrosis in Aging.

受损的肌成纤维细胞去分化有助于衰老中的非分辨纤维化。

  • 影响因子:3.37
  • DOI:10.1165/rcmb.2019-0092OC
  • 作者列表:"Kato K","Logsdon NJ","Shin YJ","Palumbo S","Knox A","Irish JD","Rounseville SP","Rummel SR","Mohamed M","Ahmad K","Trinh JM","Kurundkar D","Knox KS","Thannickal VJ","Hecker L
  • 发表时间:2020-01-21
Abstract

:Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease with no cure. Although IPF is widely regarded as a disease of aging, the cellular mechanisms that contribute to this age-associated predilection remain elusive. In this study, we sought to evaluate the consequences of senescence on myofibroblast cell fate and fibrotic responses to lung injury, in the context of aging. We demonstrate that non-senescent lung myofibroblasts maintain the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation. We have previously demonstrated that the transcription factor, MyoD, acts as a critical switch in the differentiation and dedifferentiation of myofibroblasts. Here we demonstrate that decreased levels of MyoD preceded myofibroblast dedifferentiation and apoptosis susceptibility in non-senescent cells, whereas MyoD expression remained elevated in senescent/IPF myofibroblasts which failed to undergo dedifferentiation and demonstrated resistance to apoptosis. Genetic strategies to silence MyoD restored susceptibility of IPF myofibroblasts to undergo apoptosis, and led to a partial reversal of age-associated persistent fibrosis in vivo. The capacity for myofibroblast dedifferentiation and subsequent apoptosis may be critical to normal physiologic responses to tissue injury, whereas restricted dedifferentiation and apoptosis-resistance in senescent cells may underlie the progressive nature of age-associated human fibrotic disorders. These studies support the concept that senescence may promote pro-fibrotic effects via impaired myofibroblast dedifferentiation and apoptosis-resistance, which contributes to myofibroblast accumulation and ultimately persistent fibrosis in aging.

摘要

特发性肺纤维化 (IPF) 是一种致命的年龄相关疾病,无法治愈。尽管 IPF 被广泛认为是一种衰老疾病,但导致这种年龄相关倾向的细胞机制仍然难以捉摸。在这项研究中,我们试图评估在衰老的背景下,衰老对肌成纤维细胞命运和对肺损伤的纤维化反应的影响。我们证明非衰老肺肌成纤维细胞保持去分化能力,而衰老/IPF 肌成纤维细胞表现出去分化能力受损。我们之前已经证明转录因子 MyoD 在肌成纤维细胞的分化和去分化中起着关键的开关作用。在这里,我们证明了在非衰老细胞中,MyoD 水平的降低早于肌成纤维细胞去分化和凋亡敏感性, 而 MyoD 表达在衰老/IPF 肌成纤维细胞中仍然升高,其未能进行去分化并表现出对凋亡的抗性。沉默 MyoD 的遗传策略恢复了 IPF 肌成纤维细胞发生凋亡的易感性,并导致体内年龄相关性持续性纤维化的部分逆转。肌成纤维细胞去分化和随后的凋亡能力可能对组织损伤的正常生理反应至关重要, 而衰老细胞中限制性去分化和凋亡抵抗可能是年龄相关人类纤维化疾病的进行性本质的基础。这些研究支持衰老可能通过受损的肌成纤维细胞去分化和细胞凋亡抵抗促进促纤维化作用的概念,这有助于肌成纤维细胞积累并最终导致衰老中的持续性纤维化。

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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
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"]

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
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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