Pub Date : 2024-10-16DOI: 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.
{"title":"A genome-wide association study of adults with community-acquired pneumonia.","authors":"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","doi":"10.1186/s12931-024-03009-4","DOIUrl":"https://doi.org/10.1186/s12931-024-03009-4","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Six independent sentinel variants reached the genome-wide significance (p < 5 × 10<sup>-8</sup>), 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.</p><p><strong>Conclusions: </strong>We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"374"},"PeriodicalIF":5.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478707","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}
Pub Date : 2024-10-15DOI: 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.
{"title":"Development and evaluation of a questionnaire to capture environmental and occupational inhalational exposures in adults with fibrotic interstitial lung disease.","authors":"Aparna C Swaminathan, Molly McFatrich, Laura Mkumba, Lauren Wright, Carrie A Redlich, Laurie D Snyder, Bryce B Reeve, Divya Patel, Mridu Gulati","doi":"10.1186/s12931-024-03000-z","DOIUrl":"10.1186/s12931-024-03000-z","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"372"},"PeriodicalIF":5.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478722","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}
Pub Date : 2024-10-14DOI: 10.1186/s12931-024-02985-x
Elizabeth L McDuffie, Reynold A Panettieri, Charles P Scott
{"title":"Correction to: G<sub>12/13</sub> signaling in asthma.","authors":"Elizabeth L McDuffie, Reynold A Panettieri, Charles P Scott","doi":"10.1186/s12931-024-02985-x","DOIUrl":"https://doi.org/10.1186/s12931-024-02985-x","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"371"},"PeriodicalIF":5.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478721","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}
Pub Date : 2024-10-14DOI: 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.
{"title":"Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells.","authors":"Yuanyuan Liu, Qiling Yin, Bin Liu, Zheng Lu, Meijun Liu, Ling Meng, Chao He, Jin Chang","doi":"10.1186/s12931-024-03005-8","DOIUrl":"https://doi.org/10.1186/s12931-024-03005-8","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"370"},"PeriodicalIF":5.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478736","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}
Pub Date : 2024-10-12DOI: 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.
{"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}
Pub Date : 2024-10-12DOI: 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.
{"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}
Pub Date : 2024-10-09DOI: 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.
{"title":"Treatment patterns and patient journey in progressive pulmonary fibrosis: a cross-sectional survey.","authors":"Nazia Chaudhuri, Paolo Spagnolo, Claudia Valenzuela, Valeria C Amatto, Oliver-Thomas Carter, Lauren Lee, Mark Small, Michael Kreuter","doi":"10.1186/s12931-024-02995-9","DOIUrl":"10.1186/s12931-024-02995-9","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>N/a.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"364"},"PeriodicalIF":5.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394610","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}
Pub Date : 2024-10-09DOI: 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。
{"title":"Transmission electron microscopy of transbronchial lung cryobiopsy samples in a cohort of fibrotic interstitial lung disease patients - feasibility and implications of endothelial alterations.","authors":"David Lang, Walter Stoiber, Sylvia Lohfink-Schumm, Astrid Obermayer, Guangyu Shao, Bernhard Kaiser, Rupert Langer, Bernd Lamprecht","doi":"10.1186/s12931-024-02981-1","DOIUrl":"10.1186/s12931-024-02981-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"366"},"PeriodicalIF":5.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394609","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}
Pub Date : 2024-10-09DOI: 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.
{"title":"Tezepelumab for severe asthma: elevating current practice to recognize epithelial driven profiles.","authors":"Marco Caminati, A Vatrella, P Rogliani, E Carpagnano, A Spanevello, G Senna","doi":"10.1186/s12931-024-02998-6","DOIUrl":"10.1186/s12931-024-02998-6","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Main body: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"367"},"PeriodicalIF":5.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394608","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}
Pub Date : 2024-10-09DOI: 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.
{"title":"Exploring the diagnostic and immune infiltration roles of disulfidptosis related genes in pulmonary hypertension.","authors":"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","doi":"10.1186/s12931-024-02978-w","DOIUrl":"10.1186/s12931-024-02978-w","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"365"},"PeriodicalIF":5.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394607","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}