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Distinct enterotypes and dysbiosis: unraveling gut microbiota in pulmonary and critical care medicine inpatients. 不同的肠型和菌群失调:揭开肺病和重症医学住院病人肠道微生物群的神秘面纱。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-10 DOI: 10.1186/s12931-024-02943-7
Naijian Li, Guiyan Tan, Zhiling Xie, Weixin Chen, Zhaowei Yang, Zhang Wang, Sha Liu, Mengzhang He

Background: The gut-lung axis, pivotal for respiratory health, is inadequately explored in pulmonary and critical care medicine (PCCM) inpatients.

Methods: Examining PCCM inpatients from three medical university-affiliated hospitals, we conducted 16S ribosomal RNA sequencing on stool samples (inpatients, n = 374; healthy controls, n = 105). We conducted statistical analyses to examine the gut microbiota composition in PCCM inpatients, comparing it to that of healthy controls. Additionally, we explored the associations between gut microbiota composition and various clinical factors, including age, white blood cell count, neutrophil count, platelet count, albumin level, hemoglobin level, length of hospital stay, and medical costs.

Results: PCCM inpatients exhibited lower gut microbiota diversity than healthy controls. Principal Coordinates Analysis revealed marked overall microbiota structure differences. Four enterotypes, including the exclusive Enterococcaceae enterotype in inpatients, were identified. Although no distinctions were found at the phylum level, 15 bacterial families exhibited varying abundances. Specifically, the inpatient population from PCCM showed a significantly higher abundance of Enterococcaceae, Lactobacillaceae, Erysipelatoclostridiaceae, Clostridiaceae, and Tannerellaceae. Using random forest analyses, we calculated the areas under the receiver operating characteristic curves (AUCs) to be 0.75 (95% CIs 0.69-0.80) for distinguishing healthy individuals from inpatients. The four most abundant genera retained in the classifier were Blautia, Subdoligranulum, Enterococcus, and Klebsiella.

Conclusions: Evidence of gut microbiota dysbiosis in PCCM inpatients underscores the gut-lung axis's significance, promising further avenues in respiratory health research.

背景:肠道-肺轴对呼吸系统健康至关重要,但对肺部和重症监护医学(PCCM)住院患者的肠道-肺轴研究不足:方法:我们对三所医科大学附属医院的 PCCM 住院患者的粪便样本(住院患者,n = 374;健康对照组,n = 105)进行了 16S 核糖体 RNA 测序。我们对 PCCM 住院患者的肠道微生物群组成进行了统计分析,并与健康对照组进行了比较。此外,我们还探讨了肠道微生物群组成与各种临床因素(包括年龄、白细胞计数、中性粒细胞计数、血小板计数、白蛋白水平、血红蛋白水平、住院时间和医疗费用)之间的关联:与健康对照组相比,PCCM 住院患者的肠道微生物群多样性较低。主坐标分析显示,微生物群的整体结构存在明显差异。确定了四种肠型,包括住院患者独有的肠球菌肠型。虽然在门一级没有发现差异,但有 15 个细菌科表现出不同的丰度。具体而言,来自 PCCM 的住院病人中肠球菌科、乳酸菌科、鞘氨醇梭菌科、梭菌科和丹拿菌科细菌的数量明显较多。通过随机森林分析,我们计算出区分健康人和住院病人的接收者操作特征曲线下面积(AUC)为 0.75(95% CIs 0.69-0.80)。分类器中保留最多的四个菌属是布劳氏菌、亚多利格兰菌、肠球菌和克雷伯氏菌:结论:PCCM 住院患者肠道微生物群失调的证据凸显了肠道-肺轴的重要性,有望为呼吸健康研究提供新的途径。
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引用次数: 0
Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension. 关于 TEF 和昼夜节律与肺动脉高压因果关系的孟德尔随机研究。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02934-8
Dandan Chen, Qi Jin, Lifan Yang, Xiaochun Zhang, Mingfei Li, Lei Zhang, Wenzhi Pan, Daxin Zhou, Junbo Ge, Lihua Guan

Background: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS).

Methods: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH.

Results: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, β = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, β = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines.

Conclusion: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

背景:以往的研究揭示了昼夜节律对肺部疾病的潜在影响;然而,昼夜节律相关的甲状腺胚胎因子(TEF)与肺动脉高压(PAH)之间的联系仍不清楚。我们旨在利用两组遗传工具变量(IV)和公开的肺动脉高压全基因组关联研究(GWAS)来评估TEF与PAH之间的遗传因果关系:在这项双样本 MR 研究中,使用了最近 MR 报告和 PAH GWAS(包括 162 962 名欧洲个体)中的 23 个独立 TEF 遗传 IV。结果:我们的分析表明,随着 TEF 水平的升高,PAH 中的 TEF 基因水平也随之升高:我们的分析表明,随着 TEF 水平的遗传增加,PAH 的风险也相应增加,IVW(OR = 1.233,95% CI:1.054-1.441;P = 0.00871)和加权中位数(OR = 1.292,95% CI 为 OR:1.064-1.568;P = 0.00964)方法证明了这一点。此外,TEF表达的上调与昼夜节律异常的可能性显著增加有关(IVW:P = 0.0024733,β = 0.05239)。然而,我们并未观察到昼夜节律与 PAH 之间存在明显的正相关性(IVW:P = 0.3454942,β = 1.4980398)。此外,我们的体外实验表明,TEF 在肺动脉平滑肌细胞(PASMCs)中明显过表达。结论:我们的分析表明,TEF 在肺动脉平滑肌细胞(PASMC)中的过度表达与肺动脉平滑肌细胞的活力和迁移能力有关:我们的分析表明,遗传性 TEF 水平升高与 PAH 和昼夜节律异常风险升高之间存在因果关系。因此,较高的 TEF 水平可能是 PAH 患者的一个风险因素。
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引用次数: 0
Effects of increasing tidal volume and end-expiratory lung volume on induced bronchoconstriction in healthy humans. 增加潮气量和呼气末肺活量对健康人诱发支气管收缩的影响。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02909-9
Alessandro Gobbi, Andrea Antonelli, Raffaele Dellaca, Giulia M Pellegrino, Riccardo Pellegrino, Jeffrey J Fredberg, Julian Solway, Vito Brusasco

Background: Increasing functional residual capacity (FRC) or tidal volume (VT) reduces airway resistance and attenuates the response to bronchoconstrictor stimuli in animals and humans. What is unknown is which one of the above mechanisms is more effective in modulating airway caliber and whether their combination yields additive or synergistic effects. To address this question, we investigated the effects of increased FRC and increased VT in attenuating the bronchoconstriction induced by inhaled methacholine (MCh) in healthy humans.

Methods: Nineteen healthy volunteers were challenged with a single-dose of MCh and forced oscillation was used to measure inspiratory resistance at 5 and 19 Hz (R5 and R19), their difference (R5-19), and reactance at 5 Hz (X5) during spontaneous breathing and during imposed breathing patterns with increased FRC, or VT, or both. Importantly, in our experimental design we held the product of VT and breathing frequency (BF), i.e, minute ventilation (VE) fixed so as to better isolate the effects of changes in VT alone.

Results: Tripling VT from baseline FRC significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Doubling VT while halving BF had insignificant effects. Increasing FRC by either one or two VT significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Increasing both VT and FRC had additive effects on R5, R19, R5-19 and X5, but the effect of increasing FRC was more consistent than increasing VT thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when VT was three times larger than during spontaneous breathing.

Conclusions: These data show that increasing FRC and VT can attenuate induced bronchoconstriction in healthy humans by additive effects that are mainly related to an increase of mean operational lung volume. We suggest that static stretching as with increasing FRC is more effective than tidal stretching at constant VE, possibly through a combination of effects on airway geometry and airway smooth muscle dynamics.

背景:在动物和人类中,增加功能残余容量(FRC)或潮气量(VT)可降低气道阻力,减轻对支气管收缩刺激物的反应。目前尚不清楚的是,上述机制中哪一种在调节气道口径方面更有效,以及两者结合是否会产生相加或协同效应。为了解决这个问题,我们研究了增加 FRC 和增加 VT 对减轻健康人吸入甲氧胆碱(MCh)引起的支气管收缩的影响:19 名健康志愿者接受了单剂量 MCh 的挑战,并使用强迫振荡法测量了自主呼吸时的 5 赫兹和 19 赫兹吸气阻力(R5 和 R19)、它们的差值(R5-19)以及 5 赫兹的电抗(X5),还测量了强加的 FRC 或 VT 增加或两者同时增加的呼吸模式。重要的是,在我们的实验设计中,我们将 VT 与呼吸频率(BF)的乘积(即分钟通气量(VE))保持不变,以便更好地隔离 VT 单独变化的影响:结果:将 VT 在基线 FRC 的基础上增加三倍,可明显减弱 MCh 对 R5、R19、R5-19 和 X5 的影响。将 VT 增加一倍,同时将 BF 减半的效果不明显。增加一个或两个 VT 的 FRC 可明显减弱 MCh 对 R5、R19、R5-19 和 X5 的影响。增加 VT 和 FRC 对 R5、R19、R5-19 和 X5 有叠加效应,但增加 FRC 的效应比增加 VT 更一致,这表明支气管扩张作用更大。在等容积条件下进行比较时,除了 VT 比自主呼吸时大三倍外,其他呼吸模式之间没有差异:这些数据表明,增加 FRC 和 VT 可通过相加效应减轻健康人的诱导性支气管收缩,而这种效应主要与平均肺活量的增加有关。我们认为,在 VE 保持不变的情况下,静态拉伸和增加 FRC 比潮汐拉伸更有效,这可能是通过对气道几何形状和气道平滑肌动力学的综合影响实现的。
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引用次数: 0
Therapeutic effect of long-acting muscarinic antagonist for treating uncontrolled asthma assessed using impulse oscillometry. 使用脉冲振荡仪评估长效毒蕈碱拮抗剂治疗不受控制的哮喘的疗效。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02921-z
Hiroyuki Sugawara, Atsushi Saito, Saori Yokoyama, Hirofumi Chiba

Background: In recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS.

Methods: Of a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV1 or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA.

Results: Of the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV1 or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV1, %MMEF, %PEF, and all IOS parameters.

Conclusion: ICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases.

背景:近年来,将 LAMAs 纳入哮喘治疗有望加强症状控制。然而,仍有大量哮喘患者的症状控制不佳。在采用 IOS 治疗哮喘的过程中,有关 LAMA 引起的气道改变的研究十分有限。在这项研究中,我们对控制不佳的哮喘患者施用了一种 LAMA,评估了临床反应和呼吸功能,并使用 IOS 调查了 LAMA 治疗促进的气道变化:在总共 1282 名连续哮喘患者中,118 人的症状未得到控制。其中,42 人转为接受大剂量糠酸氟替卡松/优甲乐/维兰特罗(FF/UMEC/VI)(ICS/LABA/LAMA)治疗。然后使用 AHQ-33 或 LCQ 和 ACT 对患者进行评估。测量肺活量参数(如 FEV1 或 MMEF)和 IOS 参数(如 R20 或 AX),并在病情加重和添加 LAMA 前后进行比较:在 42 名患者中,17 名因呼吸困难而改用 FF/UMEC/VI 的患者在第一阶段和基线之间的肺功能有所下降,随后在基线和第二阶段之间的肺功能有所上升。在第一阶段与基线之间以及基线与第二阶段之间,观察到 R20、R5-R20、Fres 或 AX 等 IOS 参数存在显著差异。在因咳嗽而改用吸入器的患者中,有 25 人根据治疗结果被分为有反应者(17 人)和无反应者(8 人)。在无应答者中,肺活量参数(如 FEV1 或 PEF)和 IOS 参数(如 R20 或 AX)在第一阶段和基线之间没有显著差异。然而,在有反应者中,虽然大多数肺活量参数在第一阶段和基线之间没有明显差异,但所有 IOS 参数都有明显差异。此外,在 FEV1、%MMEF、%PEF 和所有 IOS 参数方面,基线和第 2 期之间也存在明显差异:结论:ICS/LABA/LAMA 在改善症状和肺功能方面优于 ICS/LABA,这主要归功于 LAMA 的加入。此外,IOS 显示 LAMA 在所有气道段都有效,尤其是在外周。因此,LAMA 可以有效治疗以气道炎症为特征的各种哮喘表型,即使在真实世界的病例中也是如此。
{"title":"Therapeutic effect of long-acting muscarinic antagonist for treating uncontrolled asthma assessed using impulse oscillometry.","authors":"Hiroyuki Sugawara, Atsushi Saito, Saori Yokoyama, Hirofumi Chiba","doi":"10.1186/s12931-024-02921-z","DOIUrl":"10.1186/s12931-024-02921-z","url":null,"abstract":"<p><strong>Background: </strong>In recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS.</p><p><strong>Methods: </strong>Of a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV<sub>1</sub> or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA.</p><p><strong>Results: </strong>Of the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV<sub>1</sub> or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV<sub>1</sub>, %MMEF, %PEF, and all IOS parameters.</p><p><strong>Conclusion: </strong>ICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation. TNKS1BP1 通过抑制 EEF2 降解介导 AECII 衰老和辐射诱导的肺损伤。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02914-y
Jiaojiao Zhu, Xingkun Ao, Yuhao Liu, Shenghui Zhou, Yifan Hou, Ziyan Yan, Lin Zhou, Huixi Chen, Ping Wang, Xinxin Liang, Dafei Xie, Shanshan Gao, Ping-Kun Zhou, Yongqing Gu

Background: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI.

Results: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI.

Conclusions: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

背景:尽管最近的研究对辐射诱导肺损伤(RILI)的发病机制有了机理上的了解,但很少有治疗方法显示出治疗这种疾病的确切前景。II型肺泡上皮细胞(AECII)以各种方式损伤,导致炎症反应,从而引发RILI:结果:我们在此报告了辐射(IR)上调 TNKS1BP1,通过上调 EEF2 导致 RILI 小鼠肺泡上皮细胞和肺组织中的细胞衰老逐渐累积。衰老的AECII诱导衰老相关分泌表型(SASP),从而激活成纤维细胞和巨噬细胞,促进RILI的发展。在对红外的反应中,TNKS1BP1的升高与CNOT4相互作用并降低了CNOT4,从而抑制了EEF2的降解。EEF2的异位表达加速了AECII的衰老。利用 TNKS1BP1 基因敲除(KO)小鼠模型系统,我们证明 TNKS1BP1 基因敲除可预防 IR 诱导的肺组织衰老和 RILI:值得注意的是,这项研究表明 TNKS1BP1/CNOT4/EEF2 轴在 AECII 衰老中的调控机制可能是治疗 RILI 的潜在策略。
{"title":"TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.","authors":"Jiaojiao Zhu, Xingkun Ao, Yuhao Liu, Shenghui Zhou, Yifan Hou, Ziyan Yan, Lin Zhou, Huixi Chen, Ping Wang, Xinxin Liang, Dafei Xie, Shanshan Gao, Ping-Kun Zhou, Yongqing Gu","doi":"10.1186/s12931-024-02914-y","DOIUrl":"10.1186/s12931-024-02914-y","url":null,"abstract":"<p><strong>Background: </strong>Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI.</p><p><strong>Results: </strong>Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI.</p><p><strong>Conclusions: </strong>Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic efficacy of thrombin-preconditioned mesenchymal stromal cell-derived extracellular vesicles on Escherichia coli-induced acute lung injury in mice. 凝血酶预处理间充质基质细胞衍生细胞外囊泡对大肠杆菌诱发的小鼠急性肺损伤的疗效。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02908-w
Yuna Bang, Sein Hwang, Young Eun Kim, Dong Kyung Sung, Misun Yang, So Yoon Ahn, Se In Sung, Kyeung Min Joo, Yun Sil Chang

Background: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model.

Methods: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically.

Results: In vitro, IL-1β, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group.

Conclusion: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.

背景:肺炎后的急性肺损伤(ALI)包括不受控制的炎症和组织损伤,导致很高的死亡率。我们之前证实,与未激活和其他预处理方法相比,凝血酶预处理的人间充质基质细胞(thMSCs)中的货物含量和细胞外囊泡(EV)生成明显增加。本研究旨在探讨间充质干细胞产生的EVs在大肠杆菌(E. coli)诱导的ALI小鼠模型中防止炎症和组织损伤的疗效:在体外,用 0.1 µg/mL 脂多糖(LPS)刺激 RAW 264.7 细胞 1 小时,然后用 PBS(LPS Ctrl)或 5 × 107 粒 thMSC-EVs(LPS + thMSC-EVs)处理 24 小时。在体内,对 ICR 小鼠进行麻醉、插管、注射 2 × 107 CFU/100 µl 大肠杆菌。50 分钟后,给小鼠注射 50 µL 生理盐水(ECS)或 1 × 109 粒子/50 µL thMSC-EVs(EME)。三天后,使用提取的肺组织、支气管肺泡灌洗液(BALF)和活体计算机断层扫描评估 thMSC-EVs 的疗效。采用单因素方差分析和事后 TUKEY 检验对实验组进行统计比较:结果:在体外,LPS + thMSC-EVs 组的 IL-1β、CCL-2 和 MMP-9 水平明显低于 LPS Ctrl 组。正常对照组、LPS Ctrl 组和 LPS + thMSC-EV 组的 M1 巨噬细胞百分比分别为 12.5%、98.4% 和 65.9%。在体内,EME 组的肺泡充血、出血、肺壁增厚和白细胞浸润的组织学评分明显低于 ECS 组。EME组的肺干湿比明显低于ECS组。EME组BALF中的CCL2、TNF-a和IL-6水平明显低于ECS组。体内 CT 分析显示,EME 组受损肺的比例明显低于 ECS 组:结论:气管内注射 thMSC-EVs 能明显减轻大肠杆菌诱发的炎症和肺组织损伤。总之,这些结果表明,经治疗增强的thMSC-EVs是一种治疗ARDS/ALI的新型疗法,前景广阔。
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引用次数: 0
The cGAS-STING pathway in COPD: targeting its role and therapeutic potential. 慢性阻塞性肺病中的 cGAS-STING 通路:针对其作用和治疗潜力。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-07 DOI: 10.1186/s12931-024-02915-x
Kexin Liao, Fengshuo Wang, Chenhao Xia, Ze Xu, Sen Zhong, Wenqi Bi, Jingjing Ruan

Chronic obstructive pulmonary disease(COPD) is a gradually worsening and fatal heterogeneous lung disease characterized by airflow limitation and increasingly decline in lung function. Currently, it is one of the leading causes of death worldwide. The consistent feature of COPD is airway inflammation. Several inflammatory factors are known to be involved in COPD pathogenesis; however, anti-inflammatory therapy is not the first-line treatment for COPD. Although bronchodilators, corticosteroids and roflumilast could improve airflow and control symptoms, they could not reverse the disease. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway plays an important novel role in the immune system and has been confirmed to be a key mediator of inflammation during infection, cellular stress, and tissue damage. Recent studies have emphasized that abnormal activation of cGAS-STING contributes to COPD, providing a direction for new treatments that we urgently need to develop. Here, we focused on the cGAS-STING pathway, providing insight into its molecular mechanism and summarizing the current knowledge on the role of the cGAS-STING pathway in COPD. Moreover, we explored antagonists of cGAS and STING to identify potential therapeutic strategies for COPD that target the cGAS-STING pathway.

慢性阻塞性肺疾病(COPD)是一种逐渐恶化的致命性异质性肺部疾病,以气流受限和肺功能日益下降为特征。目前,它是导致全球死亡的主要原因之一。慢性阻塞性肺病的共同特征是气道炎症。已知有几种炎症因素与慢性阻塞性肺病的发病机制有关,但抗炎治疗并不是慢性阻塞性肺病的一线治疗方法。尽管支气管扩张剂、皮质类固醇和罗氟司特可以改善气流和控制症状,但它们无法逆转疾病。环GMP-AMP合成酶-干扰素基因刺激器(cGAS-STING)信号通路在免疫系统中扮演着重要的新角色,已被证实是感染、细胞应激和组织损伤时炎症的关键介质。最近的研究强调,cGAS-STING 的异常激活是慢性阻塞性肺病的诱因,这为我们急需开发的新疗法提供了方向。在此,我们聚焦于 cGAS-STING 通路,深入探讨其分子机制,并总结了目前关于 cGAS-STING 通路在慢性阻塞性肺病中作用的知识。此外,我们还探讨了 cGAS 和 STING 的拮抗剂,以确定针对 cGAS-STING 通路的慢性阻塞性肺病潜在治疗策略。
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引用次数: 0
Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history. 布地奈德/甘草酸铵/富马酸福莫特罗二水合物对慢性阻塞性肺病肺功能和病情加重的益处:根据血液嗜酸性粒细胞水平和病情加重病史对 KRONOS 研究进行的事后分析。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-05 DOI: 10.1186/s12931-024-02918-8
Shigeo Muro, Tomotaka Kawayama, Hisatoshi Sugiura, Munehiro Seki, Elizabeth A Duncan, Karin Bowen, Jonathan Marshall, Ayman Megally, Mehul Patel

Background: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity.

Methods: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses.

Results: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD.

Conclusions: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations.

Trial registration: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

背景:日本指南建议,对于慢性阻塞性肺病(COPD)且未同时诊断为哮喘的患者,如果病情经常加重且血液中嗜酸性粒细胞(EOS)计数≥ 300 cells/mm3,则应采用吸入皮质类固醇(ICS)/长效毒蕈碱拮抗剂(LAMA)/长效β2-受体激动剂(LABA)三联疗法、以及在接受 ICS/LABA 双联疗法后症状仍持续/恶化的 COPD 和哮喘患者。这些KRONOS研究的事后分析以慢性阻塞性肺病患者和未确诊为哮喘的患者为对象,研究了布地奈德/甘草酸铵/富马酸福莫特罗二水合物(BGF)固定剂量三联疗法与双联疗法对肺功能和基于血液EOS计数的哮喘加重的影响--侧重于血液EOS计数100至3--作为哮喘加重史和慢性阻塞性肺病严重程度的函数:在KRONOS中,患者被随机分配接受治疗,包括BGF 320/14.4/10 µg、二水甘草酸铵/富马酸福莫特罗(GFF)14.4/10 µg或布地奈德/富马酸福莫特罗二水(BFF)320/10 µg,通过计量吸入器吸入(每日两次,每次吸入两次,共24周)。这些事后分析评估了12-24周内早晨用药前1秒内用力呼气容积(FEV1)谷值与基线相比的变化,以及24周内中度或重度慢性阻塞性肺疾病加重率。KRONOS研究没有为这些亚组分析提供前瞻性动力:在血EOS计数为100至3的患者中,过去一年无病情加重史的患者以及中度和重度慢性阻塞性肺病患者肺功能改善的最小二乘法平均治疗差异为BGF优于BFF,不同人群的观察差异从62毫升到73毫升不等。在同一血液 EOS 群体中,相对于 GFF,BGF 的中度或重度病情加重率在过去一年无病情加重史的患者中降低了 56%,在中度慢性阻塞性肺病患者中降低了 47%,在重度慢性阻塞性肺病患者中降低了 50%:KRONOS研究对中度到极重度慢性阻塞性肺病患者进行的事后分析似乎表明,对于症状持续/恶化、血EOS计数> 100 cells/mm3的患者,即使疾病严重程度为中度且近期无病情加重史,临床医生也可能需要考虑升级为三联疗法:试验注册:ClinicalTrials.gov 注册号 NCT02497001(注册日期 2015 年 7 月 13 日)。
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引用次数: 0
Exploring the mechanism of Lianhuaqingwen (LHQW) in treating chronic bronchitis based on network pharmacology and experimental validation. 基于网络药理学和实验验证,探讨连花清瘟散治疗慢性支气管炎的机制
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-02 DOI: 10.1186/s12931-024-02927-7
Shaozhang Lin, Shuan Wang, Qingping Jiang, Shaoyan Liu, Shujing Liu, Tonghui Cai

Background: Lianhuaqingwen (LHQW) has been used in the treatment of chronic bronchitis, but the precise mechanism through which LHQW exhibits its anti-inflammatory effects in this context is not yet fully understood. The aim of this study was to investigate the active ingredients and signaling pathways responsible for LHQW's effectiveness in managing chronic bronchitis.

Methods: The research leveraged the TCMSP database to determine the active compounds and drug targets of LHQW. In parallel, the GeneCards, DrugBank, and PharmGkb databases were used to uncover targets pertinent to chronic bronchitis. To discern the potential mechanisms by which LHQW's active ingredients might treat chronic bronchitis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Network pharmacology facilitated the construction of a drug-active ingredient-disease target network, aiding in forecasting the core targets for chronic bronchitis treatment by LHQW. Subsequently, molecular docking techniques alongside in vitro experiments were applied to confirm the interactions between the active ingredients and the primary targets.

Results: A total of 157 active ingredients, 225 potential drug targets, and 594 bronchitis-related targets were derived from various databases. Following this, 76 potential gene targets were pinpointed by integrating drug and related targets. GO and KEGG enrichment analyses were employed to identify key pathways involved in LHQW's mechanism for treating chronic bronchitis. By constructing a protein-protein interaction (PPI) network for the 76 potential gene targets, four core targets (TNF, IL6, IFNG, and STAT3) were identified as primarily involved in responses to lipopolysaccharide, the TNF pathway, and the JAK-STAT pathway. Molecular docking results revealed a favorable affinity between multiple active ingredients of LHQW and the four core targets, suggesting that the therapeutic effects are mediated through the inhibition of inflammatory responses and signaling pathways. Interestingly, quercetin, an active ingredient of LHQW, was observed to bind to all four core targets simultaneously. Furthermore, cell experiment and western blot analysis indicated that both LHQW and quercetin exhibit anti-inflammatory effects by targeting the four core proteins and the JAK-STAT pathways.

Conclusion: This research emphasizes the diverse active ingredients, targets, channels, and pathways of LHQW in the treatment of chronic bronchitis, providing important perspectives for the creation of novel therapeutic drugs and clinical uses.

背景:连花清瘟散(LHQW)已被用于治疗慢性支气管炎,但其抗炎作用的确切机制尚未完全清楚。本研究的目的是调查LHQW有效治疗慢性支气管炎的活性成分和信号通路:研究利用 TCMSP 数据库确定 LHQW 的活性化合物和药物靶点。同时,研究人员还利用GeneCards、DrugBank和PharmGkb数据库发现了与慢性支气管炎相关的靶点。为了确定 LHQW 活性成分治疗慢性支气管炎的潜在机制,研究人员进行了基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。网络药理学有助于构建药物-有效成分-疾病靶点网络,帮助预测 LHQW 治疗慢性支气管炎的核心靶点。随后,分子对接技术与体外实验相结合,证实了活性成分与主要靶点之间的相互作用:结果:从各种数据库中共提取出 157 种活性成分、225 个潜在药物靶点和 594 个支气管炎相关靶点。随后,通过整合药物靶点和相关靶点,确定了 76 个潜在基因靶点。通过GO和KEGG富集分析,确定了参与LHQW治疗慢性支气管炎机制的关键通路。通过为76个潜在基因靶点构建蛋白-蛋白相互作用(PPI)网络,确定了四个核心靶点(TNF、IL6、IFNG和STAT3),它们主要参与脂多糖反应、TNF通路和JAK-STAT通路。分子对接结果显示,LHQW 的多种活性成分与四个核心靶点之间具有良好的亲和力,这表明其治疗效果是通过抑制炎症反应和信号通路介导的。有趣的是,LHQW 的活性成分槲皮素可同时与所有四个核心靶点结合。此外,细胞实验和 Western 印迹分析表明,LHQW 和槲皮素都能通过靶向四个核心蛋白和 JAK-STAT 通路发挥抗炎作用:本研究强调了LHQW在治疗慢性支气管炎方面的多种有效成分、靶点、通道和途径,为新型治疗药物的开发和临床应用提供了重要的视角。
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引用次数: 0
G12/13 signaling in asthma. 哮喘中的 G12/13 信号传导
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-02 DOI: 10.1186/s12931-024-02920-0
Elizabeth L McDuffie, Reynold A Panettieri, Charles P Scott

Shortening of airway smooth muscle and bronchoconstriction are pathognomonic for asthma. Airway shortening occurs through calcium-dependent activation of myosin light chain kinase, and RhoA-dependent calcium sensitization, which inhibits myosin light chain phosphatase. The mechanism through which pro-contractile stimuli activate calcium sensitization is poorly understood. Our review of the literature suggests that pro-contractile G protein coupled receptors likely signal through G12/13 to activate RhoA and mediate calcium sensitization. This hypothesis is consistent with the effects of pro-contractile agonists on RhoA and Rho kinase activation, actin polymerization and myosin light chain phosphorylation. Recognizing the likely role of G12/13 signaling in the pathophysiology of asthma rationalizes the effects of pro-contractile stimuli on airway hyperresponsiveness, immune activation and airway remodeling, and suggests new approaches for asthma treatment.

气道平滑肌缩短和支气管收缩是哮喘的病理标志。气道缩短是通过钙依赖性激活肌球蛋白轻链激酶和 RhoA 依赖性钙敏化(抑制肌球蛋白轻链磷酸酶)发生的。人们对促收缩刺激激活钙敏化的机制还知之甚少。我们的文献综述表明,促收缩 G 蛋白偶联受体可能通过 G12/13 发出信号,激活 RhoA 并介导钙敏化。这一假设与原收缩激动剂对 RhoA 和 Rho 激酶活化、肌动蛋白聚合和肌球蛋白轻链磷酸化的影响相一致。认识到 G12/13 信号在哮喘病理生理学中可能扮演的角色,就能合理解释促收缩刺激对气道高反应性、免疫激活和气道重塑的影响,并为哮喘治疗提出新的方法。
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引用次数: 0
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Respiratory Research
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