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CXCR4+ cells are increased in lung tissue of patients with idiopathic pulmonary fibrosis.

ABSTRACT: BACKGROUND:CXCR4, a transmembrane-receptor located on epithelial cells that is activated by CXCL12, may have a role in IPF via migration of CXCR4+ fibrocytes to the lung. However, its expression has not been fully characterised in idiopathic pulmonary fibrosis (IPF) or other fibrotic interstitial lung diseases (ILDs). CXCL12 is constitutively expressed in the bone marrow, and levels of CXCR4 regulate control of this signalling pathway. The aim of this study was to profile the expression of CXCR4 in lung tissue and peripheral circulation of patients with IPF and other fibrotic ILDs. METHODS:Expression of CXCR4 on peripheral blood mononuclear cells (PBMCs) was examined by flow cytometry in 20 patients with IPF and 10 age-matched non-disease control (NDC) donors. Levels of CXCL12 in human plasma were measured by ELISA. Expression of CXCR4, CXCL12, CD45, and e-cadherin was assessed in IPF (n?=?10), other fibrotic ILD (n?=?8) and NDC (n?=?10) lung tissue by multiplex immunohistochemistry (OPAL) and slides were scanned using a Vectra 3 scanner. Cells were quantified with computer automated histological analysis software (HALO). RESULTS:In blood, the number of CXCR4+ cells was lower but the level of CXCL12 was higher in patients with IPF compared to NDC donors. Elevated CXCR4 expression was detected in lung tissue from patients with IPF and other fibrotic ILDs compared to NDC. There were higher levels of CXCR4+/e-cadherin+/CXCL12+ (epithelial) cells in IPF lung tissue compared to NDC, but there was no difference in the numbers of CXCR4+/CD45+/CXCL12+ (myeloid) cells between the two groups. CONCLUSIONS:This report demonstrates that CXCR4 is overexpressed not only in IPF but also in other ILDs and expression is particularly prominent within both honeycomb cysts and distal airway epithelium. This observation supports the hypothesis that CXCR4 may drive tissue fibrosis through binding its specific ligand CXCL12. Although CXCR4 expressing cells could be either of epithelial or myeloid origin it appears that the former is more prominent in IPF lung tissue. Further characterization of the cells of the honeycomb cyst may lead to a better understanding of the fibrogenic processes in IPF and other end-stage fibrotic ILDs.

SUBMITTER: Jaffar J

PROVIDER: S-EPMC7449054 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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CXCR4<sup>+</sup> cells are increased in lung tissue of patients with idiopathic pulmonary fibrosis.

Jaffar Jade J Griffiths Kate K Oveissi Sara S Duan Mubing M Foley Michael M Glaspole Ian I Symons Karen K Organ Louise L Westall Glen G

Respiratory research 20200826 1

<h4>Background</h4>CXCR4, a transmembrane-receptor located on epithelial cells that is activated by CXCL12, may have a role in IPF via migration of CXCR4<sup>+</sup> fibrocytes to the lung. However, its expression has not been fully characterised in idiopathic pulmonary fibrosis (IPF) or other fibrotic interstitial lung diseases (ILDs). CXCL12 is constitutively expressed in the bone marrow, and levels of CXCR4 regulate control of this signalling pathway. The aim of this study was to profile the ...[more]

PMID: 32843095

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, eventually fatal disease. IPF is characterized by excessive accumulation of the extracellular matrix (ECM) in the alveolar parenchyma and progressive lung scarring. The pathogenesis of IPF and whether the ECM involved in the process remain unknown.MethodsTo identify potential treatment target and ECM associated proteins that may be involved in the development of IPF, we employed isobaric tag for relative and absolute quantitation (iTRAQ) combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to examine protein expression in lung tissues from IPF patients.ResultsA total of 662 proteins with altered expression (455 upregulated proteins and 207 downregulated proteins) were identified in lung tissue of IPF patients compared with control. KEGG pathway enrichment analysis showed that the altered proteins in lung tissue mainly belonged to the PI3K-Akt signaling, focal adhesion, ECM-receptor interaction, and carbon metabolism pathways. According to the bioinformatic definition of the matrisome, 229 matrisome proteins were identified in lung tissue. These proteins comprised the ECM of lung, of which 104 were core matrisome proteins, and 125 were matrisome-associated proteins. Of the 229 ECM quantified proteins, 56 significantly differentially expressed proteins (19 upregulated proteins and 37 downregulated proteins) were detected in IPF lung tissue samples. In addition to proteins with well-known functions such as COL1A1, SCGB1A1, TAGLN, PSEN2, TSPAN1, CTSB, AGR2, CSPG2, and SERPINB3, we identified several novel ECM proteins with unknown function deposited in IPF lung tissue including LGALS7, ASPN, HSP90AA1 and HSP90AB1. Some of these differentially expressed proteins were further verified using Western blot analysis and immunohistochemical staining.ConclusionsThis study provides a list of proteomes that were detected in IPF lung tissue by iTRAQ technology combined with LC-MS/MS. The findings of this study will contribute better understanding to the pathogenesis of IPF and facilitate the development of therapeutic targets.

Project description:RATIONALE:There is increasing evidence that aberrant processes occurring in the airways may precede the development of idiopathic pulmonary fibrosis (IPF); however, there has been no prior confirmatory data derived from imaging studies. OBJECTIVES:To assess quantitative measures of airway wall thickness (AWT) in populations characterized for interstitial lung abnormalities (ILA) and for IPF. METHODS:Computed tomographic imaging of the chest and measures of AWT were available for 6,073, 615, 1,167, and 38 participants from COPDGene (Genetic Epidemiology of COPD study), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study), and the Framingham Heart Study (FHS) and in patients with IPF from the Brigham and Women's Hospital Herlihy Registry, respectively. To evaluate these associations, we used multivariable linear regression to compare a standardized measure of AWT (the square root of AWT for airways with an internal perimeter of 10 mm [Pi10]) and characterizations of ILA and IPF by computed tomographic imaging of the chest. RESULTS:In COPDGene, ECLIPSE, and FHS, research participants with ILA had increased measures of Pi10 compared with those without ILA. Patients with IPF had mean measures of Pi10 that were even greater than those noted in research participants with ILA. After adjustment for important covariates (e.g., age, sex, race, body mass index, smoking behavior, and chronic obstructive pulmonary disease severity when appropriate), research participants with ILA had increased measures of Pi10 compared with those without ILA (0.03 mm in COPDGene, 95% confidence interval [CI], 0.02-0.03; P < 0.001; 0.02 mm in ECLIPSE, 95% CI, 0.005-0.04; P = 0.01; 0.07 mm in FHS, 95% CI, 0.01-0.1; P = 0.01). Compared with COPDGene participants without ILA older than 60 years of age, patients with IPF were also noted to have increased measures of Pi10 (2.0 mm, 95% CI, 2.0-2.1; P < 0.001). Among research participants with ILA, increases in Pi10 were correlated with reductions in lung volumes in some but not all populations. CONCLUSIONS:These results demonstrate that measurable increases in AWT are consistently noted in research participants with ILA and in patients with IPF. These findings suggest that abnormalities of the airways may play a role in, or be correlated with, early pathogenesis of pulmonary fibrosis.

Project description:Background: Several studies using bronchoalveolar lavage fluid (BALF) reported that lung microbial communities were associated with the development and clinical outcome of idiopathic pulmonary fibrosis (IPF). However, the microbial communities in IPF lung tissues are not well known. This study is aimed to investigate bacterial microbial communities in lung tissues and determine their impact on the clinical outcomes of patients with IPF. Methods: Genomic DNA extracted from lung tissues of patients with IPF (n = 20; 10 non-survivors) and age- and sex-matched controls (n = 20) was amplified using fusion primers targeting the V3 and V4 regions of the 16S RNA genes with indexing barcodes. Results: Mean age of IPF subjects was 63.3 yr, and 65% were male. Alpha diversity indices did not significantly differ between IPF patients and controls, or between IPF non-survivors and survivors. The relative abundance of Lactobacillus, Paracoccus, and Akkermansia was increased, whereas that of Caulobacter, Azonexus, and Undibacterium decreased in patients with IPF compared with that in the controls. A decreased relative abundance of Pelomonas (odds ratio [OR], 0.352, p = 0.027) and Azonexus (OR, 0.013, p = 0.046) was associated with a diagnosis of IPF in the multivariable logistic analysis adjusted by age and gender. Multivariable Cox analysis adjusted for age and forced vital capacity (FVC) revealed that higher relative abundance of Streptococcus (hazard ratio [HR], 1.993, p = 0.044), Sphingomonas (HR, 57.590, p = 0.024), and Clostridium (HR, 37.189, p = 0.038) was independently associated with IPF mortality. The relative abundance of Curvibacter (r = 0.590) and Thioprofundum (r = 0.373) was correlated positively, whereas that of Anoxybacillus (r = -0.509) and Enterococcus (r = -0.593) was correlated inversely with FVC. In addition, the relative abundance of the Aquabacterium (r = 0.616) and Peptoniphilus (r = 0.606) genera was positively correlated, whereas that of the Fusobacterium (r = -0.464) and Phycicoccus (r = -0.495) genera was inversely correlated with distance during the 6-min walking test. Conclusions: The composition of the microbiome in lung tissues differed between patients with IPF and controls and was associated with the diagnosis, mortality, and disease severity of IPF.

Dataset Information

CXCR4+ cells are increased in lung tissue of patients with idiopathic pulmonary fibrosis.

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CXCR4<sup>+</sup> cells are increased in lung tissue of patients with idiopathic pulmonary fibrosis.

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