BAL Is Safe and Well Tolerated in Individuals with Idiopathic Pulmonary Fibrosis: An Analysis of the PROFILE Study.
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SUBMITTER: Molyneaux PL
PROVIDER: S-EPMC7781115 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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BAL Is Safe and Well Tolerated in Individuals with Idiopathic Pulmonary Fibrosis: An Analysis of the PROFILE Study.
Molyneaux Philip L PL Smith Jonathan J JJ Saunders Peter P Chua Felix F Wells Athol U AU Renzoni Elisabetta A EA Nicholson Andrew G AG Fahy William A WA Jenkins R Gisli RG Maher Toby M TM
American journal of respiratory and critical care medicine 20210101 1
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Project description:BackgroundGiven the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another.Research questionDo IPF endotypes exist and are they associated with outcome?Study design and methodsUsing a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples.ResultsOne hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes.InterpretationGene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.
| S-EPMC9424328 | biostudies-literature
Project description:RationaleDNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).ObjectivesTo determine the DNA methylation changes in IPF and their effects on gene expression.MethodsTotal DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.Measurements and main resultsDNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.ConclusionsChanges in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
| S-EPMC3480526 | biostudies-literature
Project description:RationaleIdiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course.ObjectivesTo determine whether BAL cell gene expression is predictive of survival in IPF.MethodsThis retrospective study analyzed the BAL transcriptome of three independent IPF cohorts: Freiburg (Germany), Siena (Italy), and Leuven (Belgium) including 212 patients. BAL cells from 20 healthy volunteers, 26 patients with sarcoidosis stage III and IV, and 29 patients with chronic obstructive pulmonary disease were used as control subjects. Survival analysis was performed by Cox models and component-wise boosting. Presence of airway basal cells was tested by immunohistochemistry and flow cytometry.Measurements and main resultsA total of 1,582 genes were predictive of mortality in the IPF derivation cohort in univariate analyses adjusted for age and sex at false discovery rate less than 0.05. A nine-gene signature, derived from the discovery cohort (Freiburg), performed well in both replication cohorts, Siena (P < 0.0032) and Leuven (P = 0.0033). nCounter expression analysis confirmed the array results (P < 0.0001). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal cells. Further analyses by gene expression, flow cytometry, and immunohistochemistry showed an increase in airway basal cells in BAL and tissues of IPF compared with control subjects, but not in chronic obstructive pulmonary disease or sarcoidosis.ConclusionsOur results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role for airway basal cells in IPF.
| S-EPMC6396865 | biostudies-literature
Project description: Not available
| S-EPMC6396860 | biostudies-literature
Project description:BackgroundIt is known severe influenza infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other. Till now, no associated mechanism has been reported.MethodWe collected the genetic pattern of expression of severe influenza (GSE111368) and IPF (GSE70866) from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (C-DEGs) were identified from the two datasets, and using this data, we conducted three forms of analyses, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.ResultsIn all, 174 C-DEGs were selected for additional analyses. Based on our functional analysis, these C-DEGs mediated inflammatory response and cell differentiation. Furthermore, using cytoHubba, we identified 15 genes, namely, MELK, HJURP, BIRC5, TPX2, TK1, CDT1, UBE2C, UHRF1, CCNA2, TYMS, CDCA5, CDCA8, RAD54L, CCNB2, and ITGAM, which served as hub genes to possibly contribute to severe influenza patients with IPF disease as comorbidity. The hub gene expressions were further confirmed using two stand-alone datasets (GSE101702 for severe influenza and GSE10667 for IPF).ConclusionHerein, we demonstrated the significance of common pathways and critical genes in severe influenza and IPF etiologies. The identified pathways and genes may be employed as possible therapeutic targets for future therapy against severe influenza patients with IPF.
| S-EPMC11488079 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-06-30 | GSE35147 | GEO
Project description:ObjectiveThe objective of this study is to define the real-life clinical profile and therapeutic management of patients with idiopathic pulmonary fibrosis using artificial intelligence.MethodsWe have conducted an observational, retrospective, non-interventional study using data from the Castilla-La Mancha Regional Healthcare Service (SESCAM) in Spain between January 2012 and December 2020. The Savana Manager 3.0 artificial intelligence platform was used to collect information from electronic medical records by applying natural language processing.ResultsOur study includes 897 subjects whose diagnosis was compatible with idiopathic pulmonary fibrosis; 64.8% were men, with a mean age of 72.9 years (95% CI 71.9-73.8), and 35.2% were women, with a mean age of 76.8 years (95% CI 75.5-78). Patients who had a family history of IPF (98 patients; 12%) were younger and predominantly female (53.1%). Regarding treatment, 45% of patients received antifibrotic therapy. Patients who had undergone lung biopsy, chest CT, or bronchoscopy were younger than the patient population in whom these studies were not completed.ConclusionsThis study has used artificial intelligence techniques to analyze a large population over a 9-year period and determine the situation of IPF in standard clinical practice by identifying the patient clinical profile, use of diagnostic tests and therapeutic management.
| S-EPMC9959732 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and fatal disease characterized by progressive interstitial lung fibrosis. Given its insidious onset and poor outcome, there is an urgent need to elucidate the molecular mechanisms underlying IPF and identify effective therapeutic targets and diagnosis and prognosis biomarkers. Ferroptosis is an iron-dependent form of programmed cell death that occurs as lipid peroxides accumulate. Growing evidence suggests that ferroptosis is important in IPF.MethodsHuman ferroptosis PCR array was performed on IPF and control lung tissue. The differentially expressed ferroptosis-related genes (DE-FRGs) were identified, underwent functional enrichment analyses, protein-protein interaction network construction, and potential drug target prediction. The DE-FRGs were validated and their value as diagnostic and prognostic blood biomarkers were evaluated using the Gene Expression Omnibus dataset GSE28042.ResultsThe array identified 13 DE-FRGs. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the DE-FRGs were mainly related to iron ion transport, blood microparticles, and oxidoreductase activity, and were involved in porphyrin metabolism, necroptosis, and the p53 signaling pathway in addition to ferroptosis. The 13 DE-FRGs were analyzed using the Drug-Gene Interaction Database to explore novel IPF therapeutic agents, yielding 42 potential drugs. Four DE-FRGs (BBC3, STEAP3, EPRS, SLC39A8) in the peripheral blood of IPF patients from the GSE28042 dataset demonstrated the same expression pattern as that observed in the lung tissue array. The receiver operating characteristic analysis demonstrated that the area under the curve of STEAP3 and EPRS were > 0.75. The survival analysis demonstrated that STEAP3 and EPRS were significantly different between the IPF and control groups.ConclusionsThe FRG expression profiles in IPF and control lung tissue were characterized. The findings provided valuable ideas to elucidate the role of ferroptosis in IPF and aided the identification of novel IPF therapeutic targets and biomarkers.
| S-EPMC11869717 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the complex interaction of cells involved in chronic inflammation and fibrosis. Global gene expression of a homogenous cell population will identify novel candidate genes.MethodsGene expression of fibroblasts derived from lung tissues (8 IPF and 4 controls) was profiled, and ontology and functional pathway were analyzed in the genes exhibiting >2 absolute fold changes with p-values < 0.05. CCL8 mRNA and protein levels were quantified using real-time PCR and ELISA. CCL8 localization was evaluated by immunofluorescence staining.ResultsOne hundred seventy eight genes differentially expressed and 15 genes exhibited >10-fold change. Among them, 13 were novel in relation with IPF. CCL8 expression was 22.8-fold higher in IPF fibroblasts. The levels of CCL8 mRNA and protein were 3 and 9-fold higher in 14 IPF fibroblasts than those in 10 control fibroblasts by real-time PCR and ELISA (p = 0.022 and p = 0.026, respectively). The CCL8 concentrations in BAL fluid was significantly higher in 86 patients with IPF than those in 41 controls, and other interstitial lung diseases including non-specific interstitial pneumonia (n = 22), hypersensitivity pneumonitis (n = 20) and sarcoidosis (n = 19) (p < 0.005, respectively). Cut-off values of 2.29 pg/mL and 0.43 pg/mL possessed 80.2 and 70.7% accuracy for the discrimination of IPF from NC and the other lung diseases, respectively. IPF subjects with CCL8 levels >28.61 pg/mL showed shorter survival compared to those with lower levels (p = 0.012). CCL8 was expressed by α-SMA-positive cells in the interstitium of IPF.ConclusionsTranscriptome analysis identified several novel IPF-related genes. Among them, CCL8 is a candidate molecule for the differential diagnosis and prediction of survival.
| S-EPMC5216573 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a disease related to AT2 cell. We used flow cytometry to analyze the epithelial component of donor and IPF lungs. From the live cells, we first excluded the CD31PosCD45Pos and then selected the EPCAMPos cells for further analysis using the human AT2 cell marker HTll-280 and the surface marker PD-L1. Our data indicate that, the bona fide differentiated AT2 cells (HTll-280High PD-L1Neg), were drastically reduced in the context of IPF. More interestingly, the number of HTll-280Low/Neg PD-L1High was drastically increased, suggesting that HTll-280Low PD-L1High epithelial cells could represent a pool of progenitors linked to the deficient AT2 lineage. The aim of this experiment is further characterization of AT2 and PDL1+ cells in donor and IPF.
2023-01-01 | GSE195770 | GEO