It's Complicated: Lung Dendritic Cells in Chronic Obstructive Pulmonary Disease.
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ABSTRACT:
SUBMITTER: Freeman CM
PROVIDER: S-EPMC7427380 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
It's Complicated: Lung Dendritic Cells in Chronic Obstructive Pulmonary Disease.
Freeman Christine M CM Curtis Jeffrey L JL
American journal of respiratory and critical care medicine 20200801 4
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Project description:Rationale: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined.Objectives: To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD.Methods: Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR+ cells sorted from human lungs. We measured the in vitro capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21+CXCL13+ (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. In situ imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs.Measurements and Main Results: Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-21+CXCL13+ Tfh-like cells. Importantly, the capacity to induce IL-21+ Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s.Conclusions: In COPD lungs, we found lung EBI2+ (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-21+ Tfh-like cells, suggesting an involvement of these cells in TLO formation.
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Project description:Identifying protein biomarkers for chronic obstructive pulmonary disease (COPD) has been challenging. Most previous studies have utilized individual proteins or pre-selected protein panels measured in blood samples. To identify COPD protein biomarkers by applying comprehensive mass spectrometry proteomics in lung tissue samples. We utilized mass spectrometry proteomic approaches to identify protein biomarkers from 152 lung tissue samples representing COPD cases and controls.
2022-01-07 | PXD024124 | Pride
Project description:Diaphragm muscles in Chronic Obstructive Pulmonary Disease (COPD) patients undergo an adaptive fast to slow transformation that includes cellular adaptations. This project studies the signaling mechanisms responsible for this transformation. Keywords: other
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Project description:BackgroundLung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD.MethodsA panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients.ResultsThe 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD.ConclusionsThe consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.
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Project description:RationaleDendritic cells (DCs) have not been well studied in chronic obstructive pulmonary disease (COPD), yet their integral role in activating and differentiating T cells makes them potential participants in COPD pathogenesis.ObjectivesTo determine the expression of maturation molecules by individual DC subsets in relationship to COPD stage and to expression of the acute activation marker CD69 by lung CD4(+) T cells.MethodsWe nonenzymatically released lung leukocytes from human surgical specimens (n = 42) and used flow cytometry to identify three DC subsets (mDC1, mDC2, and pDC) and to measure their expression of three costimulatory molecules (CD40, CD80 and CD86) and of CD83, the definitive marker of DC maturation. Spearman nonparametric correlation analysis was used to identify significant correlations between expression of DC maturation molecules and COPD severity.Measurements and main resultsExpression of CD40 by mDC1 and mDC2 and of CD86 by mDC2 was high regardless of GOLD stage, but CD80 and CD83 on these two DC subsets increased with disease progression. pDC also showed significant increases in expression of CD40 and CD80. Expression of all but one of the DC molecules that increased with COPD severity also correlated with CD69 expression on lung CD4(+) T cells from the same patients, with the exception of CD83 on mDC2.ConclusionsThis cross-sectional study implies that COPD progression is associated with significant increases in costimulatory molecule expression by multiple lung DC subsets. Interactions with lung DCs may contribute to the immunophenotype of CD4(+) T cells in advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00281229).
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Project description:Investigation of whole genome gene expression level changes of the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10, compared to the normal people and stable COPD patients. A five chip study using total RNA recovered from Peripheral Blood Mononuclear Cell of Peripheral Blood.Evaluating the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10 after the hospital admission, to compared with healthy controls or patients with stable COPD. Slides were scanned at 5 μm/pixel resolution using an Axon GenePix 4000B scanner (Molecular Devices Corporation) piloted by GenePix Pro 6.0 software (Axon). Scanned images (TIFF format) were then imported into NimbleScan software (version 2.5) for grid alignment and expression data analysis. Expression data were normalized through quantile normalization and the Robust Multichip Average (RMA) algorithm included in the NimbleScan software. The Probe level (*_norm_RMA.pair) files and Gene level (*_RMA.calls) files were generated after normalization.
2014-08-14 | E-GEOD-60399 | biostudies-arrayexpress
Project description:This experiment was carried out to see if there were any miRNA expression differences in pulmonary endothelial cells between patients with and without COPD. COPD is an inflammatory condition and although much work has previously been performed to investigate the inflammatory cells in COPD there has not been as much research looking at the endothelium through which inflammatory cells must pass through to reach the lung tissue. In this experiment pulmonary endothelial cells were extracted from whole lung tissue removed at the time of cardiothoracic surgery. This was performed for patients with and without COPD. RNA was extracted using the Qiagen microRNeasy kits prior to transferring to the University of Birmingham Biosciences department who performed RNA labelling and ran the microarrays. Once the microarrays were performed quality was checked using ArrayQualityMetrics and the COPD group was compared to the non-COPD group using SAM. The experiment was then repeated using another patient group. MiRNAs of interest were validated with qPCR initially before moving on to functional work.
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Project description:Although chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) have distinct clinical features, both diseases may coexist in a patient because they share similar risk factors such as smoking, male sex, and old age. Patients with both emphysema in upper lung fields and diffuse ILD are diagnosed with combined pulmonary fibrosis and emphysema (CPFE), which causes substantial clinical deterioration. Patients with CPFE have higher mortality compared with patients who have COPD alone, but results have been inconclusive compared with patients who have idiopathic pulmonary fibrosis (IPF). Poor prognostic factors for CPFE include exacerbation, lung cancer, and pulmonary hypertension. The presence of interstitial lung abnormalities, which may be an early or mild form of ILD, is notable among patients with COPD, and is associated with poor prognosis. Various theories have been proposed regarding the pathophysiology of CPFE. Biomarker analyses have implied that this pathophysiology may be more closely associated with IPF development, rather than COPD or emphysema. Patients with CPFE should be advised to quit smoking and undergo routine lung function tests, and pulmonary rehabilitation may be helpful. Various pharmacologic agents and surgical approaches may be beneficial in patients with CPFE, but further studies are needed.
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Project description:UnlabelledCD56+ natural killer (NK) and CD56+ T cells, from sputum or bronchoalveolar lavage of subjects with chronic obstructive pulmonary disease (COPD) are more cytotoxic to highly susceptible NK targets than those from control subjects. Whether the same is true in lung parenchyma, and if NK activity actually contributes to emphysema progression are unknown. To address these questions, we performed two types of experiments on lung tissue from clinically-indicated resections (n = 60). First, we used flow cytometry on fresh single-cell suspension to measure expression of cell-surface molecules (CD56, CD16, CD8, NKG2D and NKp44) on lung lymphocytes and of the 6D4 epitope common to MICA and MICB on lung epithelial (CD326+) cells. Second, we sequentially isolated CD56+, CD8+ and CD4+ lung lymphocytes, co-cultured each with autologous lung target cells, then determined apoptosis of individual target cells using Annexin-V and 7-AAD staining. Lung NK cells (CD56+ CD3-) and CD56+ T cells (CD56+ CD3+) were present in a range of frequencies that did not differ significantly between smokers without COPD and subjects with COPD. Lung NK cells had a predominantly "cytotoxic" CD56+ CD16+ phenotype; their co-expression of CD8 was common, but the percentage expressing CD8 fell as FEV1 % predicted decreased. Greater expression by autologous lung epithelial cells of the NKG2D ligands, MICA/MICB, but not expression by lung CD56+ cells of the activating receptor NKG2D, correlated inversely with FEV1 % predicted. Lung CD56+ lymphocytes, but not CD4+ or CD8+ conventional lung T cells, rapidly killed autologous lung cells without additional stimulation. Such natural cytotoxicity was increased in subjects with severe COPD and was unexplained in multiple regression analysis by age or cancer as indication for surgery. These data show that as spirometry worsens in COPD, CD56+ lung lymphocytes exhibit spontaneous cytotoxicity of autologous structural lung cells, supporting their potential role in emphysema progression.Trial registrationClinicalTrials.gov NCT00281229.
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