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A genome-wide association study of adults with community-acquired pneumonia. 社区获得性肺炎成人全基因组关联研究。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-16 DOI: 10.1186/s12931-024-03009-4
Eva Suarez-Pajes, Itahisa Marcelino-Rodriguez, Elisa Hernández Brito, Silvia Gonzalez-Barbuzano, Melody Ramirez-Falcon, Eva Tosco-Herrera, Luis A Rubio-Rodríguez, María Luisa Briones, Olga Rajas, Luis Borderías, Jose Ferreres, Antoni Payeras, Leonardo Lorente, Javier Aspa, Jose M Lorenzo Salazar, José Manuel Valencia-Gallardo, Nieves Carbonell, Jorge L Freixinet, Felipe Rodríguez de Castro, Jordi Solé Violán, Carlos Flores, Carlos Rodríguez-Gallego

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).

Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.

Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.

Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

背景:社区获得性肺炎(CAP)的发病率和住院率都很高。在传染病中,宿主遗传学在易感性和免疫反应中起着关键作用,所涉及的免疫途径高度依赖于微生物及其感染途径。在此,我们旨在通过病例对照全基因组关联研究(GWAS)确定 CAP 的遗传风险位点:我们对 3,765 名西班牙人进行了 GWAS 研究,其中包括 257 名住院治疗的 CAP 成年患者和 3,508 名人群对照。有 30% 的患者被证实患有肺炎球菌性 CAP,其余 70% 的患者是在微生物病因不明的患者中挑选出来的。我们使用逻辑回归法测试了 760 万个估算基因型。英国生物库细菌性肺炎 GWAS 用于结果验证。随后,我们根据贝叶斯精细图谱和功能证据对基因和可能的因果变异进行了优先排序。我们还对经典的HLA等位基因和氨基酸进行了推算和关联分析:六个独立的哨点变异达到了全基因组显著性(p -8),其中三个位于染色体 6p21.32,4q28.2、11p12 和 20q11.22 各一个。只有 6p21.32 上的一个变异在细菌性肺炎和肺炎球菌性肺炎的独立 GWAS 中得到了验证。我们的分析优先考虑了 4q28.2 上的 C4orf33、6p21.32 上的 TAPBP 和 20q11.22 上的 ZNF341。有趣的是,TAPBP 和 ZNF341 的遗传缺陷是以前已知的易患细菌性肺炎(包括肺炎球菌和流感嗜血杆菌)的先天性免疫错误。经典的 HLA 等位基因的相关性均不显著:我们完成了一项关于 CAP 的基因组学分析,发现了四个与 CAP 易感性有关的新风险位点。
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引用次数: 0
Development and evaluation of a questionnaire to capture environmental and occupational inhalational exposures in adults with fibrotic interstitial lung disease. 开发和评估调查问卷,以收集患有纤维化间质性肺病的成人的环境和职业吸入暴露情况。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-15 DOI: 10.1186/s12931-024-03000-z
Aparna C Swaminathan, Molly McFatrich, Laura Mkumba, Lauren Wright, Carrie A Redlich, Laurie D Snyder, Bryce B Reeve, Divya Patel, Mridu Gulati

Background: Identification of exposures in patients with interstitial lung diseases (ILDs) is essential for diagnosis and management and can be facilitated through the use of exposure questionnaires. However, for most ILDs, a patient-focused questionnaire is lacking. Cognitive interviewing is a methodology used to evaluate sources of understanding and misunderstanding in a questionnaire and to provide evidence of content validity. We developed and refined a new exposure questionnaire for patients with fibrotic ILDs by using cognitive interviewing to establish its understandability and content validity.

Methods: An exposure assessment questionnaire was developed by a multidisciplinary team. Cognitive interviews with 24 patients with fibrosing ILDs were conducted by trained interviewers over the phone or Zoom using a semi-structured interview guide. The questionnaire was amended based on the interviewers' interpretation of sources of misunderstanding. The revised questionnaire was tested in a second round of cognitive interviews with a different group of 24 patients.

Results: Among the 48 patients who completed interviews, mean age was 61 years, 58.3% were male and 75.0% were white. Based on the first round of cognitive interviews, the multidisciplinary team modified the questions, organization, and instructions of the questionnaire to facilitate recall, adjust for exposures that were frequently misunderstood or required clarification, and focus on clinically relevant exposures. The revised questionnaire performed well in the second round of interviews.

Conclusion: An exposure questionnaire, developed with input from patients, can be used to assess clinically relevant exposures in adults with fibrosing ILDs. This is the first questionnaire for all types of fibrosing ILD to have undergone content validation.

背景:间质性肺病(ILDs)患者的暴露识别对于诊断和管理至关重要,可通过使用暴露调查问卷来实现。然而,对于大多数 ILD 而言,缺乏以患者为中心的调查问卷。认知访谈是一种用于评估问卷中理解和误解来源并提供内容有效性证据的方法。我们采用认知访谈法为纤维化 ILD 患者开发并改进了一份新的暴露评估问卷,以确定其可理解性和内容有效性:方法:一个多学科团队开发了一份暴露评估问卷。由经过培训的访谈者通过电话或 Zoom 使用半结构化访谈指南对 24 名纤维化 ILD 患者进行认知访谈。根据访谈者对误解来源的解释,对问卷进行了修订。修订后的问卷在对另一组 24 名患者进行的第二轮认知访谈中进行了测试:在完成访谈的 48 名患者中,平均年龄为 61 岁,58.3% 为男性,75.0% 为白人。在第一轮认知访谈的基础上,多学科团队修改了问卷的问题、组织和说明,以方便回忆,调整经常被误解或需要澄清的暴露,并将重点放在与临床相关的暴露上。修订后的问卷在第二轮访谈中表现良好:结论:根据患者意见开发的暴露调查问卷可用于评估成人纤维性 ILD 患者的临床相关暴露。这是第一份经过内容验证的适用于所有类型纤维性 ILD 的问卷。
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引用次数: 0
Correction to: G12/13 signaling in asthma. 更正为哮喘中的 G12/13 信号传导。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1186/s12931-024-02985-x
Elizabeth L McDuffie, Reynold A Panettieri, Charles P Scott
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引用次数: 0
Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells. 鱼腥草素能防止气道平滑肌细胞的表型转换,从而减少卵清蛋白引发的气道重塑。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1186/s12931-024-03005-8
Yuanyuan Liu, Qiling Yin, Bin Liu, Zheng Lu, Meijun Liu, Ling Meng, Chao He, Jin Chang

Background: The transformation of airway smooth muscle cells (ASMCs) from a quiescent phenotype to a hypersecretory and hypercontractile phenotype is a defining feature of asthmatic airway remodeling. Fisetin, a flavonoid compound, possesses anti-inflammatory characteristics in asthma; yet, its impact on airway remodeling and ASMCs phenotype transition has not been investigated.

Objectives: This research seeked to assess the impact of fisetin on ovalbumin (OVA) induced asthmatic airway remodeling and ASMCs phenotype transition, and clarify the mechanisms through network pharmacology predictions as well as in vivo and in vitro validation.

Methods: First, a fisetin-asthma-ASMCs network was constructed to identify potential targets. Subsequently, cellular and animal studies were carried out to examine the inhibitory effects of fisetin on airway remodeling in asthmatic mice, and to detemine how fisetin impacts the phenotypic transition of ASMCs.

Results: Network analysis indicated that fisetin might affect asthma via mediating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway. Intraperitoneal administration of fisetin in vivo reduced airway inflammation and remodeling, as shown by reduced inflammatory cells, decreased T helper type 2 (Th2) cytokine release, diminished collagen accumulation, mitigated airway smooth muscle thickening, and decreased expression of osteopontin (OPN), collagen-I and α-smooth muscle actin (α-SMA). Moreover, fisetin suppressed the PI3K/AKT pathway in asthmatic lung tissue. According to the in vitro data, fisetin downregulated the expression of the synthetic phenotypic proteins OPN and collagen-I, contractile protein α-SMA, and inhibited cellular migration, potentially through the PI3K/AKT pathway.

Conclusion: These results suggest that fisetin inhibits airway remodeling in asthma by regulating ASMCs phenotypic shift, emphasizing that fisetin is a promising candidate for the treatment of airway smooth muscle remodeling.

背景:气道平滑肌细胞(ASMC)从静止表型转变为高分泌和高收缩表型是哮喘气道重塑的一个决定性特征。黄酮类化合物鱼腥草素在哮喘中具有抗炎特性,但其对气道重塑和 ASMC 表型转变的影响尚未得到研究:本研究旨在评估鱼腥草素对卵清蛋白(OVA)诱导的哮喘气道重塑和ASMCs表型转换的影响,并通过网络药理学预测以及体内、体外验证阐明其机制:方法:首先,构建了鱼腥草素-哮喘-ASMCs网络,以确定潜在靶点。方法:首先构建了鱼腥草素-哮喘-ASMCs网络,确定潜在靶点,然后进行细胞和动物实验,研究鱼腥草素对哮喘小鼠气道重塑的抑制作用,并确定鱼腥草素如何影响ASMCs的表型转变:结果:网络分析表明,鱼腥草素可能通过介导磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)通路影响哮喘。腹腔注射菲赛汀可减少气道炎症和重塑,具体表现为炎症细胞减少、T辅助2型细胞因子(Th2)释放减少、胶原堆积减少、气道平滑肌增厚减轻,以及骨生成素(OPN)、胶原蛋白-I和α-平滑肌肌动蛋白(α-SMA)表达减少。此外,鱼腥草素还能抑制哮喘肺组织中的 PI3K/AKT 通路。根据体外数据,鱼腥草素可能通过 PI3K/AKT 通路下调了合成表型蛋白 OPN 和胶原蛋白-I、收缩蛋白 α-SMA 的表达,并抑制了细胞迁移:这些结果表明,鱼腥草素通过调节 ASMCs 表型转变抑制了哮喘的气道重塑,强调了鱼腥草素是治疗气道平滑肌重塑的一种有前途的候选药物。
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引用次数: 0
Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo. 人肺组织外植体在病毒和细菌感染早期的宿主转录组反应差异。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-12 DOI: 10.1186/s12931-024-02988-8
Aaqib Sohail, Fakhar H Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, Frank Pessler

Background: The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.

Results: Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77-82%; lncRNA 15-17%; pseudogenes 4-5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.

Conclusions: Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

背景:感染的头 24 小时是病原体与宿主组织相互作用的关键时间窗口。然而,由于临床上无法获得感染早期的组织,因此无法研究人体肺部自然感染的早期事件。因此,我们对肺气肿患者的体外培养人肺组织外植体(HLTE)进行了RNA测序,以研究在感染甲型流感病毒(IAV)、牛分枝杆菌卡介苗(BCG)和铜绿假单胞菌的最初24小时内,小非编码RNA、mRNA和长非编码RNA(lncRNA、lincRNA)种群的整体变化:结果:铜绿假单胞菌引起的表达变化最强,是唯一明显影响微RNA和PIWI相关RNA表达的病原体。在感染三种病原体后出现差异表达的RNA中,主要长RNA类别(> 100 nt)的代表性相似(mRNA 77-82%;lncRNA 15-17%;假基因 4-5%),但lnc-DDX60-1、RP11-202G18.1和lnc-THOC3-2是与IAV感染特别相关的RNA特征的一部分(此外还包括SNX10和SLC8A1)。IAV 感染诱导了快速的干扰素反应,CCL8 是上调最强烈的 mRNA。单细胞 RNA 测序确定气道上皮细胞和巨噬细胞是主要的 IAV 宿主细胞,但在表达很少或没有 IAV 转录本的细胞类型中也检测到了炎症反应。对大量和单细胞 RNAseq 数据的综合分析确定了一组 6 个 mRNA(IFI6、IFI44L、IRF7、ISG15、MX1、MX2)是对 IAV 感染的核心转录组反应。两种细菌病原体诱导的 mRNA 表达和预测的信号通路发生了非常相似的定性变化,但铜绿假单胞菌感染的变化幅度更大。GJB2、VNN1、DUSP4、SerpinB7和IL10的上调以及PKMYT1、S100A4、GGTA1P和SLC22A31的下调与细菌感染的关系最为密切:结论:人类肺组织对 IAV 感染的转录组反应与对卡介苗和铜绿假单胞菌感染的反应大不相同,而对这两种不同细菌病原体的反应却惊人地相似。在感染的早期阶段,这种 HLTE 模型应能在组织和单细胞水平上用于 RNA 引导的发病机制研究和组织生物标记物的发现。
{"title":"Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo.","authors":"Aaqib Sohail, Fakhar H Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, Frank Pessler","doi":"10.1186/s12931-024-02988-8","DOIUrl":"https://doi.org/10.1186/s12931-024-02988-8","url":null,"abstract":"<p><strong>Background: </strong>The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.</p><p><strong>Results: </strong>Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77-82%; lncRNA 15-17%; pseudogenes 4-5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.</p><p><strong>Conclusions: </strong>Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"369"},"PeriodicalIF":5.8,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478723","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
Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro. Aggregatibacter 与慢性气道疾病患者痰液中的炎症介质成反比,并能在体外减轻炎症。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-12 DOI: 10.1186/s12931-024-02983-z
Ellen Goeteyn, Steven L Taylor, Alison Dicker, Laura Bollé, Merel Wauters, Marie Joossens, Eva Van Braeckel, Jodie L Simpson, Lucy Burr, James D Chalmers, Geraint B Rogers, Aurélie Crabbé

Background: Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD.

Methods: Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients.

Results: We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability.

Conclusions: These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.

背景:慢性气道疾病(CAD)的特征是慢性气道炎症和促炎症病原体在肺部的定植。然而,虽然下气道中存在各种其他细菌种类,但人们对它们如何影响炎症尚未完全了解。我们的目的是鉴定存在于 CAD 患者下气道样本中的新型抗炎菌种:我们使用线性判别分析效应大小(LEfSE)和斯皮尔曼相关性分析法分析了三个独立队列(澳大利亚哮喘和支气管扩张症、苏格兰支气管扩张症)中成人 CAD 患者的配对痰微生物组和炎症标志物数据,以确定与患者低炎症特征相关的物种:结果:我们发现,在两个 CAD 队列(澳大利亚哮喘和支气管扩张)中,气道炎症标志物水平较低的患者中,Aggregatibacter 属的数量较多。此外,Aggregatibacter 的相对丰度与痰中 IL-8(澳大利亚支气管扩张症)和 IL-1β 水平(澳大利亚哮喘和支气管扩张症)成反比。随后使用生理相关的三维肺上皮细胞模型进行的体外测试表明,Aggregatibacter 菌属(即放线菌属(A. actinomycetemcomitans)和嗜水气单胞菌属(A. aphrophilus))及其无细胞上清液具有抗炎活性,且不会影响宿主细胞的活力:这些研究结果表明,Aggregatibacter 菌属可减轻 CAD 患者的气道炎症。
{"title":"Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro.","authors":"Ellen Goeteyn, Steven L Taylor, Alison Dicker, Laura Bollé, Merel Wauters, Marie Joossens, Eva Van Braeckel, Jodie L Simpson, Lucy Burr, James D Chalmers, Geraint B Rogers, Aurélie Crabbé","doi":"10.1186/s12931-024-02983-z","DOIUrl":"https://doi.org/10.1186/s12931-024-02983-z","url":null,"abstract":"<p><strong>Background: </strong>Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD.</p><p><strong>Methods: </strong>Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients.</p><p><strong>Results: </strong>We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability.</p><p><strong>Conclusions: </strong>These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"368"},"PeriodicalIF":5.8,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478717","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
Treatment patterns and patient journey in progressive pulmonary fibrosis: a cross-sectional survey. 进行性肺纤维化的治疗模式和患者历程:横断面调查。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-09 DOI: 10.1186/s12931-024-02995-9
Nazia Chaudhuri, Paolo Spagnolo, Claudia Valenzuela, Valeria C Amatto, Oliver-Thomas Carter, Lauren Lee, Mark Small, Michael Kreuter

Background: For patients with interstitial lung diseases (ILDs) presenting with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of disease characteristics at diagnosis, patient journey, and treatment is limited. This study aimed to describe demographics and clinical experiences of patients presenting with PPF in a European real-world setting.

Methods: Data were analysed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey of pulmonologists and rheumatologists in five European countries (France, Germany, Italy, Spain, United Kingdom) and internal medicine specialists (France) from April to October 2022. Physicians provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype other than idiopathic pulmonary fibrosis. Analyses were descriptive.

Results: Overall, 265 physicians reported on 1,335 patients. Mean (standard deviation) age at survey date was 60.4 (11.6) years, 91.2% were white, 58.1% female, 44.0% non-smokers. Most patients (63.3%) first consulted a primary care physician. There was a mean delay of 7.8 (22.7) months between first ILD symptom and healthcare professional visit, and another 7.7 (12.8) months to ILD diagnosis. At survey date, 47.7% of patients had physician-reported moderate ILD, 42.3% had mild ILD and 10.0% had severe ILD. Disease progression was reported in the 12 months prior to the survey for 19.5% of patients; of these, progression was based on worsening symptom in 27.3% and lung function decline in 25.8%. For patients experiencing symptoms prior to ILD diagnosis (72.8%), the most common symptoms were dyspnoea on exertion (80.5%) and cough (57.8%). Overall, 17.4% of patients were misdiagnosed prior to ILD diagnosis, with chronic obstructive pulmonary disease suspected in 39.2% of them. The most frequent comorbidities were anxiety (16.9%) and gastroesophageal reflux (15.5%). Although 77.8% of patients were receiving treatment for ILD at survey date, 15.6% of patients had never been prescribed treatment for ILD.

Conclusions: This real-world study expands our understanding of patients, diagnostic delays and treatment gaps experienced by patients diagnosed with PPF in Europe. There was a mean delay of 15.5 months between first ILD symptoms and ILD diagnosis. Given the progressive nature of PPF, diagnostic delay may lead to poor outcomes, including shorter survival.

Trial registration: N/a.

背景:对于表现为进行性肺纤维化(PPF)表型的间质性肺疾病(ILDs)患者,目前对其诊断时的疾病特征、患者历程和治疗方法的了解十分有限。本研究旨在描述欧洲真实世界中出现进行性肺纤维化的患者的人口统计学特征和临床经验:阿德尔菲真实世界 PPF-ILD 疾病专项计划™(Adelphi Real World PPF-ILD Disease Specific Programme™)于 2022 年 4 月至 10 月期间对欧洲五国(法国、德国、意大利、西班牙、英国)的肺病专家和风湿病专家以及内科专家(法国)进行了横断面调查,对调查数据进行了分析。医生们提供了最多 12 名经医生确诊的连续性 ILD 患者的数据,这些患者具有除特发性肺纤维化以外的进行性表型。分析为描述性分析:共有 265 名医生报告了 1,335 名患者的情况。调查时的平均年龄(标准差)为 60.4 (11.6) 岁,91.2% 为白人,58.1% 为女性,44.0% 不吸烟。大多数患者(63.3%)首先咨询的是初级保健医生。从首次出现 ILD 症状到就诊,平均延迟了 7.8 (22.7) 个月,到确诊 ILD 又延迟了 7.7 (12.8) 个月。在调查日期,47.7% 的患者由医生报告为中度 ILD,42.3% 为轻度 ILD,10.0% 为重度 ILD。据报告,19.5% 的患者在调查前的 12 个月内病情恶化;其中 27.3% 的患者病情恶化是因为症状恶化,25.8% 的患者是因为肺功能下降。在确诊 ILD 之前出现症状的患者(72.8%)中,最常见的症状是用力时呼吸困难(80.5%)和咳嗽(57.8%)。总体而言,有 17.4% 的患者在确诊 ILD 之前被误诊,其中 39.2% 的患者被怀疑患有慢性阻塞性肺病。最常见的合并症是焦虑(16.9%)和胃食管反流(15.5%)。尽管在调查日期,77.8% 的患者正在接受 ILD 治疗,但 15.6% 的患者从未接受过 ILD 治疗:这项真实世界的研究加深了我们对欧洲 PPF 患者、诊断延误和治疗差距的了解。从首次出现 ILD 症状到确诊 ILD,平均延迟了 15.5 个月。鉴于PPF的进展性,诊断延误可能导致不良后果,包括生存期缩短:未注册。
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引用次数: 0
Transmission electron microscopy of transbronchial lung cryobiopsy samples in a cohort of fibrotic interstitial lung disease patients - feasibility and implications of endothelial alterations. 对一组纤维化间质性肺病患者的经支气管肺冷冻生物切片样本进行透射电子显微镜观察--内皮改变的可行性及其影响。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-09 DOI: 10.1186/s12931-024-02981-1
David Lang, Walter Stoiber, Sylvia Lohfink-Schumm, Astrid Obermayer, Guangyu Shao, Bernhard Kaiser, Rupert Langer, Bernd Lamprecht

We evaluated the utility of transmission electron microscopy (TEM) in transbronchial lung cryobiopsy (TBLC) samples from 16 consecutive patients undergoing routine evaluation of fibrotic interstitial lung disease (ILD). Next to routine pathology examination, 1 to 2 TBLC samples were prepared for TEM analysis and evaluated using a Zeiss LEO EM 910. Subpleural cryobiopsies and unfrozen excision biopsies from fresh lobectomy tissue of non-ILD lung cancer patients served as controls. TEM provided high-quality images with only minor cryoartifacts as compared to controls. Furthermore, in several ILD patients we found marked microvascular endothelial abnormalities like luminal pseudopodia-like protrusions and inner surface defects. These were extensively present in four (25%), moderately present in seven (43.8%), and largely absent in five (31.3%) patients. A higher degree of TEM endothelial abnormalities was associated with younger age, non-specific interstitial pneumonia pattern, higher broncho-alveolar lavage lymphocyte count, positive autoantibodies, and lower spirometry, diffusion capacity and oxygenation biomarkers. We conclude that TEM evaluation of TBLC samples from ILD patients is feasible, while the observed microvascular alterations warrant further evaluation.

我们评估了透射电子显微镜(TEM)在经支气管肺冷冻活检(TBLC)样本中的应用,这些样本来自16名接受纤维化间质性肺病(ILD)常规评估的连续患者。除常规病理检查外,还准备了 1 到 2 份 TBLC 样品用于 TEM 分析,并使用蔡司 LEO EM 910 进行评估。非 ILD 肺癌患者的胸膜下冷冻活检组织和新鲜肺叶切除组织的解冻切除活检组织作为对照。与对照组相比,TEM 可提供高质量的图像,仅有轻微的低温伪影。此外,在几名 ILD 患者身上,我们发现了明显的微血管内皮异常,如管腔伪足样突起和内表面缺损。这些异常在四名患者(25%)中广泛存在,在七名患者(43.8%)中中度存在,在五名患者(31.3%)中基本不存在。TEM 内皮异常程度较高与年龄较小、非特异性间质性肺炎模式、支气管肺泡灌洗液淋巴细胞计数较高、自身抗体阳性以及肺活量、扩散能力和氧合生物标志物较低有关。我们的结论是,对 ILD 患者的 TBLC 样本进行 TEM 评估是可行的,而观察到的微血管改变值得进一步评估。
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引用次数: 0
Tezepelumab for severe asthma: elevating current practice to recognize epithelial driven profiles. 治疗重症哮喘的替塞普鲁单抗:提升现有实践,识别上皮驱动的特征。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-09 DOI: 10.1186/s12931-024-02998-6
Marco Caminati, A Vatrella, P Rogliani, E Carpagnano, A Spanevello, G Senna

Background: An increasing amount of evidence supports the relevance of epithelium across the wide spectrum of asthma pathobiology. On a clinical ground tezepelumab, selectively binding TSLP, a major epithelial cytokine, has demonstrated to be effective in asthma patients regardless their specific phenotype. In order to avoid the risk of considering tezepelumab as a not-specific option, the present perspective aims to sketch the tezepelumab best eligible patient profile and to propose some hallmarks of epithelial-driven disease by reviewing the published evidence on the drug mechanism of action and efficacy data.

Main body: Although it cannot rely on standardised or exclusive "markers", the relationship between environment and poor asthma control might suggest a major relevance of the epithelial barrier dysfunction. In that light, allergy and asthma exacerbations concomitant with specific exposures (pathogens, pollutants, chemicals), as well as increased susceptibility to infections can be considered as the hallmark of an impaired epithelial immune response. Tezepelumab is effective in allergic patients, being able to reduce asthma exacerbations precipitated by the exposure to seasonal or perennial aeroallergens, including fungi. In addition, tezepelumab reduced the incidence of co-occurring respiratory illness and asthma exacerbations. In terms of inflammation, epithelial immune response has been related to an impaired mucus hypersecretion and plugging. A placebo-controlled trial demonstrated a significant reduction of mucus plugging in treated patient. Airways hyperreactivity (AHR), airways obstruction and remodelling have been described as an expression of epithelial orchestrated immunological activation. Of note, a significantly higher incidence of mannitol negative test in patients treated with tezepelumab when compared to placebo group has been observed. In addition, A 130 mL improvement in pre-BD FEV1 has been described in patients assuming Tezepelumab. The above-mentioned data suggest that bronchial reversibility and AHR can be considered "functional biomarkers" supporting patients' phenotyping and the identification of tezepelumab best responders.

Conclusion: Integrating "functional biomarkers" to the inflammatory ones and a better characterization of asthma exacerbations might pave the way to a different and more transversal phenotyping, which overcomes the "restrictive" labels including T2 high, allergic/atopic or T2 low asthma. Precisely defining the disease characteristics and potential targets for a better control even in tezepelumab eligible subjects is essential to avoid the block buster temptation and optimize the personalized medicine approach according to each patient's individuality.

背景:越来越多的证据表明,上皮细胞与哮喘的病理生物学有着广泛的关联。在临床上,选择性结合主要上皮细胞因子 TSLP 的替塞普鲁单抗已被证明对哮喘患者有效,而无需考虑其具体表型。为了避免将替塞普鲁单抗视为非特异性选择的风险,本观点旨在通过回顾已发表的有关药物作用机制和疗效数据的证据,勾勒出替塞普鲁单抗的最佳合格患者特征,并提出上皮细胞驱动疾病的一些特征:虽然不能依靠标准化或排他性的 "标志物",但环境与哮喘控制不佳之间的关系可能表明上皮屏障功能障碍具有重要的相关性。因此,与特定暴露(病原体、污染物、化学物质)同时出现的过敏和哮喘加重,以及感染易感性的增加,可被视为上皮免疫反应受损的标志。Tezepelumab 对过敏性患者有效,能够减少因接触季节性或常年性过敏原(包括真菌)而导致的哮喘恶化。此外,替塞单抗还能降低呼吸道疾病和哮喘恶化并发症的发病率。在炎症方面,上皮免疫反应与粘液分泌过多和堵塞受损有关。一项安慰剂对照试验显示,接受治疗的患者粘液堵塞现象明显减少。气道高反应性(AHR)、气道阻塞和重塑被描述为上皮协调免疫激活的一种表现形式。值得注意的是,与安慰剂组相比,接受替塞泊单抗治疗的患者甘露醇试验阴性的发生率明显更高。此外,在使用替塞泊单抗的患者中,BD 前 FEV1 提高了 130 毫升。上述数据表明,支气管可逆性和AHR可被视为 "功能性生物标志物",有助于对患者进行表型分析,并确定特珠单抗的最佳应答者:结论:将 "功能性生物标志物 "与炎症性生物标志物相结合,并更好地描述哮喘恶化的特征,可能会为不同的、更具横向性的表型分析铺平道路,从而克服包括 T2 高、过敏性/变应性或 T2 低哮喘在内的 "限制性 "标签。精确定义疾病特征和潜在靶点,即使是符合替塞单抗治疗条件的受试者也能更好地控制病情,这对于避免 "阻断 "诱惑和根据每位患者的个体差异优化个性化医疗方法至关重要。
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引用次数: 0
Exploring the diagnostic and immune infiltration roles of disulfidptosis related genes in pulmonary hypertension. 探索二硫化相关基因在肺动脉高压中的诊断和免疫渗透作用。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-09 DOI: 10.1186/s12931-024-02978-w
Xin Tan, Ningning Zhang, Ge Zhang, Shuai Xu, Yiyao Zeng, Fenlan Bian, Bi Tang, Hongju Wang, Jili Fan, Xiaohong Bo, Yangjun Fu, Huimin Fan, Yafeng Zhou, Pinfang Kang

Background: Pulmonary hypertension (PH) is marked by elevated pulmonary artery pressures due to various causes, impacting right heart function and survival. Disulfidptosis, a newly recognized cell death mechanism, may play a role in PH, but its associated genes (DiGs) are not well understood in this context. This study aims to define the diagnostic relevance of DiGs in PH.

Methods: Using GSE11726 data, we analyzed DiGs and their immune characteristics to identify core genes influencing PH progression. Various machine learning models, including RF, SVM, GLM, and XGB, were compared to determine the most effective diagnostic model. Validation used datasets GSE57345 and GSE48166. Additionally, a CeRNA network was established, and a hypoxia-induced PH rat model was used for experimental validation with Western blot analysis.

Results: 12 DiGs significantly associated with PH were identified. The XGB model excelled in diagnostic accuracy (AUC = 0.958), identifying core genes DSTN, NDUFS1, RPN1, TLN1, and MYH10. Validation datasets confirmed the model's effectiveness. A CeRNA network involving these genes, 40 miRNAs, and 115 lncRNAs was constructed. Drug prediction suggested therapeutic potential for folic acid, supported by strong molecular docking results. Experimental validation in a rat model aligned with these findings.

Conclusion: We uncovered the distinct expression patterns of DiGs in PH, identified core genes utilizing an XGB machine-learning model, and established a CeRNA network. Drugs targeting the core genes were predicted and subjected to molecular docking. Experimental validation was also conducted for these core genes.

背景:肺动脉高压(PH)是由各种原因导致的肺动脉压力升高,影响右心功能和存活。二硫化血症是一种新发现的细胞死亡机制,可能在 PH 中起作用,但其相关基因(DiGs)在 PH 中的作用还不十分清楚。本研究旨在确定 DiGs 在 PH 中的诊断相关性:我们利用 GSE11726 数据分析了 DiGs 及其免疫特征,以确定影响 PH 进展的核心基因。我们比较了各种机器学习模型,包括RF、SVM、GLM和XGB,以确定最有效的诊断模型。验证使用了数据集 GSE57345 和 GSE48166。此外,还建立了一个CeRNA网络,并使用缺氧诱导的PH大鼠模型进行Western印迹分析实验验证:结果:发现了 12 个与 PH 明显相关的 DiGs。XGB模型在诊断准确性(AUC = 0.958)方面表现出色,识别出了核心基因DSTN、NDUFS1、RPN1、TLN1和MYH10。验证数据集证实了该模型的有效性。构建了一个涉及这些基因、40个miRNA和115个lncRNA的CeRNA网络。在强大的分子对接结果支持下,药物预测显示了叶酸的治疗潜力。在大鼠模型中的实验验证与这些发现一致:我们发现了 PH 中 DiGs 的独特表达模式,利用 XGB 机器学习模型确定了核心基因,并建立了 CeRNA 网络。我们预测了针对核心基因的药物,并进行了分子对接。还对这些核心基因进行了实验验证。
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引用次数: 0
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Respiratory Research
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