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Project description:Background: We got interested whether genes of airway basal cells are enriched in COPD. Methods: Bronchoscopy with bronchial brushes and bronchoalveolar lavage was performed in 28 patients with COPD and 29 healthy donors and isolated BAL cells.Transcriptome of BAL cells were studied by using Affymetrix Human Genome U133 Plus 2.0 array on an Affymetrix platform. Microarray data were normalized data were imported, log2-transformed and quantile normalized using robust multi-array average (RMA). We tested enrichment for airway basal cells by ROMER enrichment analysis. Results: we did not find enrichment of airway basal cell genes in COPD compared to healthy volunteers.
2018-12-31 | GSE73395 | GEO
Project description:Background: We got interested whether genes of airway basal cells are enriched in sarcoidosis. Methods: Bronchoscopy with bronchoalveolar lavage (BAL) was performed in 26 patients with sarcoidosis, chest-x-ray type III and IV, and 20 healthy donors and isolated BAL cells.Transcriptome of BAL cells were studied by using Affymetrix Human Affymetrix Whole-Transcript Human Gene 1.0 ST array on an Affymetrix platform. Microarray data were imported, log2-transformed and quantile normalized using robust multi-array average (RMA). We tested enrichment for airway basal cells by global enrichment analysis. Results: we did not find enrichment of airway basal cell genes in sarcoidosis compared to healthy volunteers.
2018-12-31 | GSE73394 | GEO
Project description:Background: Based on previous publication and our own data we became interested in the gene expression signature of airway basal cells. Methods: Bronchoscopy with bronchial brushes and bronchoalveolar lavage was performed in healthy donors. Airway basal cells were obtained by brushing segmental bronchi of the right lower lobe and outgrowth of cells in BEGM supplemented with growth factors according to the manufacturer’s instructions. Alveolar macrophages were sorted by flow cytometry. Microarray data of 11 airway basal cell samples, 7 alveolar macrophage samples and 4 samples of bronchial epithelial cells were obtained. The transcriptome of the three different cell types was compared using univariate ANOVA resulting in 8874 genes significantly differently expressed between the three cell types (p<0.0001). The data of these 8874 transcripts were used for a clustering approach applying Cluster 3.0 software. The samples were hierarchically clustered with median normalization of the genes and centroid linkage, and the similarity metric used was Pearson correlation. Results and Conclusion: we obtained an airway basal cell type specific signature consisting out of 961 genes which was used in further studies.
2018-12-31 | GSE70864 | GEO
Project description:Background: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with variable outcome. Currently, there is little information whether changes in molecular pathways in the alveolar compartment of patients with IPF are indicative of disease progression. To address this question we analyzed gene expression signatures in cells obtained from bronchoalveolar lavage (BAL) of patients with IPF. Methods: BAL cells were harvested from 212 IPF patients and 20 healthy donors at the time of diagnosis. RNA was extracted, labeled and hybridized to Agilent gene expression arrays. Our study included a discovery cohort of 62 patients from Freiburg, Germany, and two independent validation cohorts, Siena, Italy (50 patients) and Leuven, Belgium (64 patients). Survival analysis was performed by applying Cox models and component-wise boosting. Results: We found 1582 genes predictive of mortality in the discovery cohort in univariate analyses adjusted for age and gender at FDR<0.05. A nine gene signature, developed by component-wise boosting in the Freiburg array dataset, performed well in both validation cohorts, Siena (p<0.0032) and Leuven (p=0.0033). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal epithelial cells, airway progenitor cells recently implicated in fibrosis. Conclusions: Our results identify and validate a BAL cell gene expression signature that predicts mortality in IPF. This signature unmasks a potential novel role for airway basal epithelial cells in IPF.
2018-12-31 | GSE70866 | GEO
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:BAL cell gene expression is predictive of Mortality in Idiopathic Pulmonary Fibrosis and enriched for Genes of Airway Basal Cells
| PRJNA289721 | ENA
Project description: Not available
| S-EPMC6396860 | biostudies-literature
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:Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17high PTENlow dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2-/- or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNAseq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrate that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model.
| S-EPMC9513076 | biostudies-literature
Project description:Background Recent years, idiopathic pulmonary fibrosis (IPF) is thought to be a disease of alveoli as well as small airways. This study aimed to demonstrate the clinical feature, predictor, and prognosis of small airway dysfunction (SAD) in Chinese patients with IPF. Methods We enrolled 416 patients with IPF who hospitalized in Beijing Chao-Yang Hospital from 2000 to 2014 in this study, and the follow-up ended at December 2016. We collected demographic information, clinical examination results, spirometry results, HRCT results, and blood gas results during the study. Logistic regression analysis was used to identify the predictor for SAD. The COX proportional hazard model was used to analysis the prognosis effect of SAD. Results Among all the participants, 165 (39.66%) patients had SAD. FEV1 (% predicted) and FEV3/FVC were significantly associated with SAD in patients with IPF. IPF patients with lower FEV1 (% predicted, OR 30.04, 95% CI 9.61–93.90) and FEV3/FVC (OR 77.76, 95% CI 15.44–391.63) had increased risk for SAD. Patients with SAD were associated with significantly increased risk of mortality in patients with IPF (HR 1.73, 95% CI 1.02–2.92), as well as in IPF patients without other pulmonary comorbidities (COPD, emphysema, and asthma). Conclusions Spirometry-defined SAD was like 40% in patients with IPF. Lower FEV1 (% predicted) and FEV3/FVC were main predictors for SAD. IPF patients with SAD showed poorer prognosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-02089-6.
| S-EPMC9347131 | biostudies-literature