Dataset Information

Comparison of the inflammatory niches of CF and COPD and the differences to healthy controls

ABSTRACT: This study aimed to compare – at a multi-omics level, inflammation, protease abundance and activity, microbiome, and proteome in sputum samples from patients with cystic fibrosis (CF, n=38) or chronic obstructive pulmonary disease (COPD, n=18) and healthy controls (n=10) to identify shared and unique pathways between these respiratory conditions. Sputum analysis revealed elevated inflammatory cell counts in both CF and COPD patients, with neutrophils being the dominant cell type. Key inflammatory markers, including IL-1β, TNF-α, TGF-β1, IL-8, and LTB4, were increased in both disease groups, with the highest levels observed in CF. Conversely, COPD patients exhibited higher levels of IL-5, IL-6, and IL-10. Microbiome analysis showed distinct clusters for each group, with CF patients often characterized by a preponderance of Pseudomonas. Hierarchical clustering unveiled robust interdependencies between microbiome parameters and inflammation, a richer and more diverse microbiome was associated with a healthier microbial community. This study uncovered significant disparities in inflammation, microbiome composition, and proteome profiles among CF, COPD, and healthy control cohorts. Neutrophilic inflammation and protease activity emerged as common factors in both diseases highlighting proteases as good targets for both indications, while distinct microbial signatures were identified. These findings offer valuable insights into the underlying mechanisms of CF and COPD and may inform future clinical strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Saliva

SUBMITTER: Marcel Schilling

LAB HEAD: Prof. Dr. Ursula Klingmüller

PROVIDER: PXD048388 | Pride | 2025-09-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20220615_220706_20220615_Lung_Human_Sputum_COPD_CF_OTEX2_SN15.5.csv	Csv
	OTEX2_220429_21-054_FG_DF_02_24_HC_SK10_SPUTUM.raw	Raw
	OTEX2_220429_21-054_FG_DF_04_2_CF_A062_SPUTUM.raw	Raw
	OTEX2_220429_21-054_FG_DF_06_12_CF_B086_SPUTUM.raw	Raw
	OTEX2_220429_21-054_FG_DF_08_27_HC_SK20_SPUTUM.raw	Raw

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Project description:Cystic Fibrosis lung disease progresses by a combination of accelerated airways inflammation and bacterial colonization and infection. Airways inflammation in CF is predominantly neutrophilic and complicates airway clearance therapies through cellular debris, excessive DNA, excessive and viscous mucous, and high concentrations of neutrophils,Il-8 and related cytokines liberated along the NFkB signaling pathway. We conducted a single site, randomized, double blind, placebo-controlled, proof-of-concept trial in which we evaluated the effects of 28 days of two dose levels (0.05 mg and 0.10 mg daily) of an older cardiac glycoside, digitoxin, as compared with placebo, on inflammatory markers in induced sputum obtained from 24 subjects with mild to moderate CF lung disease. Nasal epithelial cells from 23 subjects were analyzed for microarray analysis. CF patients 18 to 45 years old, any genotype combination, were eligible. The primary objective was to measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum. Secondary objectives were to measure: 1) the pharmacokinetics of digitoxin in serum in stable CF patients, 2) safety indices, including ECG changes and sputum microbiology, in stable CF patients, 3) the effect of digitoxin on gene expression in nasal epithelial cells of stable CF patients and 4) quality of life scores using the CFQ-R©. As expected, it took several weeks to achieve a detectable serum level of digitoxin in CF. Digitoxin showed a trend towards reduction in sputum free neutrophil elastase and neutrophil counts, but was not associated with a reduction in sputum Il-8. Digitoxin did not dampen sputum inflammation as measured by primary and secondary outcome measures over the 28 day study period. However the patient groups receiving placebo and 50 micro gram digitoxin daily fell into similar patterns which were distinctly different from the patient group taking 100 micro gram digitoxin. The mRNAs encoding chemokine/cytokine or cell surface receptors in immune cells were decreased in nasal epithelial cells at the higher dose, leading to pathway mediated reductions in Il-8, Il-6, lung epithelial inflammation, neutrophil recruitment and mucus hypersecretion. It is possible that a longer treatment period would be necessary to detect a meaningful, dose- dependent change in sputum indices of inflammation in CF. Importantly, there were no safety issues over the course of the study

Project description:Background: Assessments of airways inflammation in patients with chronic obstructive pulmonary diseases (COPD) require semi-invasive procedures and specialized sample processing know-how. In this study we aimed to set up and validate a novel non-invasive processing-free method for RNA sequencing (RNAseq) of spontaneous sputum samples collected from COPD patients. Methods: Spontaneous sputum samples were collected and stabilized, with or without selection of plugs and with or without the use of a stabilizer specifically formulated for downstream diagnostic testing (PrimeStore® Molecular Transport Medium). After 8-day storage at ambient temperature RNA was isolated according to an optimized RNAzol® method. An average percentage of fragments longer than 200 nucleotides (DV200) >30% and an individual yield >50ng were required for progression of samples to sequencing. Finally, to assess if the transcriptome generated would reflect a true endotype of COPD inflammation, the outcome of single-sample gene-set enrichment analysis (ssGSEA) was validated using an independent set of processed induced sputum samples Results: RNA extracted from spontaneous sputum using a stabilizer showed an average DV200 higher than 30%. 70% of the samples had a yield >50ng and were submitted to downstream analysis. There was a straightforward correlation in terms of gene expression between samples handled with or without separation of plugs. This was also confirmed by principal component analysis and ssGSEA. The top ten enriched pathways resulting from spontaneous sputum ssGSEA were associated to features of COPD, namely, inflammation, immune responses and oxidative stress; up to 70% of these were in common within the top ten enriched pathways resulting from induced sputum ssGSEA. Conclusion: This analysis confirmed that the typical COPD endotype was represented within spontaneous sputum and supported the current method as a non-invasive processing-free procedure to assess the level of sputum cell inflammation in COPD patients by RNAseq analysis.

Project description:The mechanistic role of the airway microbiome in chronic obstructive pulmonary disease (COPD) remains largely unexplored. We present a landscape of airway microbe-host interactions in COPD by an in-depth profiling of sputum metagenome, metabolome, host transcriptome and proteome from 99 COPD patients and 36 healthy individuals. Multi-omic data were integrated using a sequential mediation analysis, to assess in silico associations of the microbiome with neutrophilic or eosinophilic inflammation, two primary COPD inflammatory endotypes, mediated through microbial metabolic interaction with host gene expression. Mechanistic links of microbiome-metabolite-host interaction were identified leveraging microbial genetic information and established metabolite-human gene pairs. The strongest link for neutrophil-predominant COPD was altered tryptophan metabolism driven by airway lactobacilli resulting in reduced indole-3-acetic acid (IAA), which was in turn linked to perturbed host IL-22 signaling and epithelial cell apoptosis pathways. In vivo and in vitro studies showed that airway microbiome-derived IAA mitigates neutrophilic inflammation, apoptosis, emphysema, and lung function decline, via IL-22-mediated macrophage-epithelial cell crosstalk. Intranasal inoculation of two airway lactobacilli restored IAA and recapitulated its protective effects in mice. These findings provide the rationale for therapeutically targeting microbe-host interaction in COPD. Linked studies:UPLC-MS/MS assays of original cohort human samples are reported in this study.UPLC-MS/MS assays of more recent cohort human samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS5423' rel='noopener noreferrer' target='_blank'>MTBLS5423</a>.UPLC-MS/MS assays of more recent murine samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6894' rel='noopener noreferrer' target='_blank'>MTBLS6894</a>.

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Comparison of the inflammatory niches of CF and COPD and the differences to healthy controls

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