scholarly journals Topographic heterogeneity of lung microbiota in end-stage idiopathic pulmonary fibrosis: the Microbiome in Lung Explants-2 (MiLEs-2) study

Thorax ◽  
2020 ◽  
pp. thoraxjnl-2020-214770
Author(s):  
Eleanor Valenzi ◽  
Haopu Yang ◽  
John C Sembrat ◽  
Libing Yang ◽  
Spencer Winters ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Personalised Medicine ◽  
Bacterial Load ◽  
Rrna Gene ◽  
Distinct Subgroup ◽  
Targeted Interventions ◽  
Parenchymal Tissue ◽  
Chronic Lung Diseases ◽  
Topographic Heterogeneity

BackgroundLung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.MethodsWe performed a retrospective, case-control study of explanted lung tissue obtained at the time of lung transplantation or rapid autopsy from patients with IPF and other chronic lung diseases (connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), COPD and donor lungs unsuitable for transplant from Center for Organ Recovery and Education (CORE)). We sampled subpleural tissue and airway-based specimens (bronchial washings and airway tissue) and quantified bacterial load and profiled communities by amplification and sequencing of the 16S rRNA gene.FindingsExplants from 62 patients with IPF, 15 patients with CTD-ILD, 20 patients with CF, 20 patients with COPD and 20 CORE patients were included. Airway-based samples had higher bacterial load compared with distal parenchymal tissue. IPF basilar tissue had much lower bacterial load compared with CF and CORE lungs (p<0.001). No microbial community differences were found between parenchymal tissue samples from different IPF lobes. Dirichlet multinomial models revealed an IPF cluster (29%) with distinct composition, high bacterial load and low alpha diversity, exhibiting higher odds for acute exacerbation or death.InterpretationIPF explants had low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of patients with IPF with higher bacterial load and worse clinical outcomes supports investigation of personalised medicine approaches for microbiome-targeted interventions.

scholarly journals Topographic Heterogeneity of Lung Microbiota in End-Stage Idiopathic Pulmonary Fibrosis: The Microbiome in Lung Explants-2 (MiLEs-2) Study

2020 ◽  
Author(s):  
Eleanor B Valenzi ◽  
Haopu Yang ◽  
John C Sembrat ◽  
Libing Yang ◽  
Spencer Winters ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Disease Progression ◽  
Clinical Outcomes ◽  
Bacterial Load ◽  
Patient Specific ◽  
Targeted Interventions ◽  
Parenchymal Tissue ◽  
End Stage ◽  
Topographic Heterogeneity

AbstractBackgroundLung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.MethodsWe sampled subpleural tissue from up to three lobes as well as airway-based specimens (bronchial washings and airway tissue) in patients with IPF, connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) and donor lungs deemed unsuitable for transplant (controls). We quantified bacterial load and profiled communities by polymerase chain reaction (PCR) amplification and sequencing of the 16S rRNA gene.FindingsExplants from 62 IPF, 15 CTD-ILD, 20 CF, 20 COPD and 20 control patients were included. Airway-based samples had higher bacterial load compared to distal parenchymal tissue across all patient groups. IPF basilar tissue had much lower bacterial load compared to CF and control lungs (p<0.001). Among patients with IPF, no differences in microbial community profiles were found between parenchymal tissue samples from different lobes. With Dirichlet multinomial models, a cluster of IPF patients (29%) with distinct composition, high bacterial load and low alpha diversity was identified, exhibiting higher odds for acute exacerbation of IPF or death.InterpretationIPF explants exhibited low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of IPF patients with higher bacterial load and worse clinical outcomes supports investigation of personalized medicine approaches for microbiome-targeted interventions.Key MessagesWhat is the key question?Bronchoalveolar lavage microbiome profiles in early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression, but the regional heterogeneity of resident microbiota in end-stage IPF has not been defined.What is the bottom line?IPF explants demonstrate higher bacterial load in airway compared to parenchymal samples, but no differences in between apical or basilar parenchymal samples. A subgroup of patients with higher bacterial load and respiratory pathogen abundance was associated with worse clinical outcomes.Why read on?Patient-specific heterogeneity in the lung microbiome of IPF supports the need for personalized microbiome-targeted interventions in IPF.

scholarly journals High Bacterial Load Predicts Poor Outcomes in Patients with Idiopathic Pulmonary Fibrosis

2014 ◽  
Author(s):  
Philip Molyneaux ◽  
Michael Cox ◽  
Saffron Willis-Owen ◽  
Kirsty Russell ◽  
Patrick Mallia ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
16S Rrna ◽  
16S Rrna Gene ◽  
Bacterial Load ◽  
Chronic Obstructive ◽  
Rrna Gene ◽  
Bacterial Burden ◽  
Obstructive Pulmonary Disease ◽  
Poor Outcomes

Background: Repetitive alveolar damage and aberrant repair may be important in the development of the fatal condition Idiopathic Pulmonary Fibrosis (IPF). The role played by microorganisms in this cycle is unknown. Methods: We consecutively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, non-smokers and subjects with moderate Chronic Obstructive Pulmonary Disease (COPD) as controls. Subjects underwent bronchoalveolar lavage (BAL) from which genomic DNA was isolated. The V3-V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA qPCR and pyrosequencing. Results: Our 65 IPF patients had 3.9x109 copies of the 16S rRNA gene per ml of BAL, two-fold more than the 1.8x109 copies in 44 sex- and smoking-matched controls (P<0.0001). Baseline BAL bacterial burden predicted Forced Vital Capacity (FVC) decline (P=0.02). Patients in the highest tertile of bacterial burden were at a higher risk of mortality compared to subjects in the lowest tertile (hazard ratio 4.59 (95% CI, 1.05-20); P=0.04). Sequencing yielded 912,883 high quality reads from all subjects. Operational Taxonomic Units (OTUs) representing Haemophilus, Streptococcus, Neisseria and Veillonella were 1.5 to 3.5 fold more abundant in cases than controls (P<0.05). Regression analyses indicated that these specific OTUs as well as bacterial burden associated independently with IPF. Conclusions: IPF is characterised by an increased bacterial burden in BAL that predicts decline in lung function and death. Clinical trials of antimicrobial therapy may determine if microbial burden is causal or not in IPF progression.

scholarly journals Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension

2016 ◽  
Vol 311 (2) ◽  
pp. L238-L254 ◽  
Author(s):  
Ning-Yuan Chen ◽  
Scott D. Collum ◽  
Fayong Luo ◽  
Tingting Weng ◽  
Thuy-Trahn Le ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Diseases ◽  
Vascular Lesions ◽  
Unknown Etiology ◽  
Group Iii ◽  
Chronic Lung Diseases ◽  
Protein Receptor ◽  
Stat3 Phosphorylation

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.

scholarly journals Hallmarks of the ageing lung

2015 ◽  
Vol 45 (3) ◽  
pp. 807-827 ◽  
Author(s):  
Silke Meiners ◽  
Oliver Eickelberg ◽  
Melanie Königshoff
Keyword(s):  
Lung Cancer ◽  
Chronic Obstructive Pulmonary Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pulmonary Disease ◽  
Lung Diseases ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Specific Effects ◽  
Chronic Lung Diseases

Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, “dysregulation of the extracellular matrix”, which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases.

scholarly journals There is detectable variation in the lipidomic profile between stable and progressive patients with idiopathic pulmonary fibrosis (IPF)

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shabarinath Nambiar ◽  
Britt Clynick ◽  
Bong S. How ◽  
Adam King ◽  
E. Haydn Walters ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Lipid Metabolism ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Statistical Modelling ◽  
Ultra Performance Liquid Chromatography ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Flight Mass Spectrometry ◽  
Chronic Lung Diseases

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear. Methods In this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification. Results Statistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue. Conclusion This is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

scholarly journals Cluster analysis of transcriptomic datasets to identify endotypes of Idiopathic Pulmonary Fibrosis

2021 ◽  
Author(s):  
Luke Michael Kraven ◽  
Adam R Taylor ◽  
Phil Michael Molyneaux ◽  
Toby M Maher ◽  
John E McDonough ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Personalised Medicine ◽  
Enrichment Analysis ◽  
Innate And Adaptive Immunity ◽  
Blood Gene Expression ◽  
Mitochondrial Homeostasis ◽  
Gene Enrichment Analysis ◽  
Gene Enrichment ◽  
Distinct Disease

Rationale: Considerable clinical heterogeneity in Idiopathic Pulmonary Fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes could allow for a biomarker-driven personalised medicine approach in IPF. Objectives: To improve our understanding of the pathogenesis of IPF by identifying clinically distinct groups of patients with IPF that could represent distinct disease endotypes. Methods: We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases). Measurements and main results: We identified three clusters of IPF patients with statistically significant differences in lung function (P=0.009) and mortality (P=0.009) between groups. Gene enrichment analysis implicated dysregulation of mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: hazard ratio= 4.25, 95% confidence interval= [2.14, 8.46], P=3.7×10-5). Conclusions: We have identified blood gene expression signatures capable of discerning groups of IPF patients with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

scholarly journals Recent advances in understanding idiopathic pulmonary fibrosis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1046 ◽  
Author(s):  
Cécile Daccord ◽  
Toby M. Maher
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Clinical Care ◽  
Personalised Medicine ◽  
New Drugs ◽  
Rapid Progression ◽  
Recent Advances ◽  
Prediction Of Mortality ◽  
Dismal Prognosis ◽  
Disease Stratification

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.

scholarly journals Platelets: a potential role in chronic respiratory diseases?

2021 ◽  
Vol 30 (161) ◽  
pp. 210062
Author(s):  
Mohamad Chebbo ◽  
Catherine Duez ◽  
Marie C. Alessi ◽  
Pascal Chanez ◽  
Delphine Gras
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Immune Responses ◽  
Immune Cells ◽  
Lung Diseases ◽  
Respiratory Diseases ◽  
Potential Role ◽  
Inflammatory Disorders ◽  
Chronic Respiratory Diseases ◽  
Chronic Lung Diseases

Platelets are small anucleate cells known for their role in haemostasis and thrombosis. In recent years, an increasing number of observations have suggested that platelets are also immune cells and key modulators of immunity. They express different receptors and molecules that allow them to respond to pathogens, and to interact with other immune cells. Platelets were linked to the pathogenesis of some inflammatory disorders including respiratory diseases such as asthma and idiopathic pulmonary fibrosis. Here, we discuss the involvement of platelets in different immune responses, and we focus on their potential role in various chronic lung diseases.

scholarly journals Microbiome in lung explants of idiopathic pulmonary fibrosis: a case–control study in patients with end-stage fibrosis

Thorax ◽  
2017 ◽  
Vol 73 (5) ◽  
pp. 481-484 ◽  
Author(s):  
Georgios D Kitsios ◽  
Mauricio Rojas ◽  
Daniel J Kass ◽  
Adam Fitch ◽  
John C Sembrat ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Case Control Study ◽  
16S Rrna Gene Sequencing ◽  
Case Control ◽  
Rrna Gene ◽  
Tissue Samples ◽  
Rrna Gene Sequencing ◽  
End Stage ◽  
Control Study

The microbiome has been proposed to play a role in the progression of idiopathic pulmonary fibrosis (IPF) based on bronchoalveolar lavage analyses, but the microbiome of lung tissue in IPF has not been explored. In a case–control study of lung explants analysed by 16S rRNA gene sequencing, we could not reliably detect bacterial DNA in basilar tissue samples from patients with either chronic or acute exacerbations of IPF, in contrast to control candidate-donor lungs or cystic fibrosis explants. Thus, our data do not indicate microbiome alterations in regions of IPF lung with advanced fibrosis.

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