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. 2022 Nov 2;19(1):18.
doi: 10.1186/s12950-022-00315-w.

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Xuanqi Liu #  1   2   3 , Zheng Li #  1   4 , Yang Zheng #  1 , Wenhao Wang  1   5 , Peiqing He  5 , Kangwei Guan  5 , Tao Wu  6   7 , Xiaojun Wang  8 , Xuelin Zhang  9   10
Affiliations

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Xuanqi Liu et al. J Inflamm (Lond). .

Abstract

Backgrounds: Chronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD are still challenging until now. Elevated serum uric acid(SUA) levels seem to be associated with the inflammatory level in patients with COPD. However, the underlying mechanism is not yet clearly established. In the current research, we aim to elucidate the effect of high SUA levels on airway inflammation among COPD patients.

Methods: Through bioinformatic analysis, the common potential key genes were determined in both COPD and hyperuricemia (HUA) patients. A total of 68 COPD patients aged 50-75-year were included in the study, and their clinical parameters, including baseline characteristics, lung function test, as well as blood chemistry test were recorded. These parameters were then compared between the COPD patients with and without HUA. Hematoxylin & Eosin (HE), immunofluorescence (IF), and Masson trichrome staining were performed to demonstrate the pathological changes in the lung tissues. Furthermore, we isolated extracellular vesicles (EVs) from plasma, sputum, and bronchoalveolar lavage fluid (BALF) samples and detected the expression of inflammatory factor (Interleukin-6 (IL-6), IL-8 and COPD related proteases (antitrypsin and elastase) between two groups. Additionally, we treated the human bronchial epithelial (HBE) cells with cigarette smoke extract (CSE), and EVs were derived from the plasma in vitro experiments. The critical pathway involving the relationship between COPD and HUA was eventually validated based on the results of RNA sequencing (RNA-seq) and western blot (WB).

Results: In the study, the COPD patients co-existing with HUA were found to have more loss of pulmonary function compared with those COPD patients without HUA. The lung tissue samples of patients who had co-existing COPD and HUA indicated greater inflammatory cell infiltration, more severe airway destruction and even fibrosis. Furthermore, the high SUA level could exacerbate the progress of airway inflammation in COPD through the transfer of EVs. In vitro experiments, we determined that EVs isolated from plasma, sputum, and BALF played pivotal roles in the CSE-induced inflammation of HBE. The EVs in HUA patients might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway.

Conclusion: The pulmonary function and clinical indicators of COPD patients with HUA were worse than those without HUA, which may be caused by the increased airway inflammatory response through the EVs in the patient's peripheral blood. Moreover, it might mediate the EVs via senescence-related pathways in COPD patients with HUA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
The potential targets and pathways between COPD and HUA. A The Venn diagram showing the shared genes between COPD and HUA. B The protein interaction network of 27 common genes. C The bar plot showing the GO enrichment of core common genes including CC, MP and CM. D The bar rplot showing the cellular component terms in GO enrichment. E The bubble plot showing the KEGG enrichment of common genes. F The hub-genes among the core 27 shared genes. G The Venn diagram showing the shared genes between AECOPD and HUA. H The hub-genes among the common 9 genes. Abbreviation: CC, cell component; BP, biological process; MF, molecular function; AECOPD, Acute Exacerbation of Chronic Obstructive Pulmonary Disease; HUA, hyperuricemia; COPD, chronic obstruction pulmonary disease
Fig. 2
Fig. 2
Clinical features of the included COPD patients. A Density distribution showing the difference of clinical indicators between COPD patients with or without HUA groups. B Correlation coefficient matrix indicating the correlation between clinical parameters including baseline features, blood biochemistry and lung function test among COPD patients. C-H Scatter diagram and linear regression showing the level of serum uric acid and lung function test FEV1percent (C, F), FVC percent (D, G) and FEV1-FVCpercent (E, H). Abbreviation: COPD, chronic obstruction pulmonary disease; HUA, hyperuricemia; SUA, serum uric acid; BMI, body mass index; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; CRP, C-reactive protein; ALT, alanine transaminase; AST, aspartate transaminase; ALB, albumin; EGFR, estimated Glomerular Filtration Rate; SCR, serum creatinine
Fig. 3
Fig. 3
The comparison of inflammation status in lung tissue and peripheral blood between COPD patients with or without HUA. A HE staining detected alveolar cells morphology (X20) and MASSON staining of lung tissue (X20). Scale bars, 50 μm. B Quantification of cell counts according to HE staining and fibrotic area of difference groups by MASSON staining (X20). Scale bars, 50 μm. C Expression of inflammatory factors, IL-1β, IL-6, IL-8 and MUC1 were detected in lung by multiplex immunofluorescences(X20). Scale bars, 50 μm. The immunofluorescence quantification of mean fluorescence intensity was indicated in the bar plot. D Multiplex immunofluorescences of location of Antitrypsin and Elane in lung tissues(X20). Scale bars, 50 μm. E The level of IL-6, IL-8, Antitrypsin and Elane in plasma from two groups detected by ELISA (unpaired t test, *P < 0.05 and ****P < 0.001). Abbreviation: COPD, chronic obstruction pulmonary disease; HUA, hyperuricemia; HE, Hematoxylin & Eosin; IL-6, interleukin-6; IL-8, interleukin-8; IL-1β, interleukin-1 beta; DAPI, 4’,6-Diamidino-2’-phenylindol; MUC1, mucin 1
Fig. 4
Fig. 4
Identification of plasma, sputum and bronchoalveolar lavage fluid (BALF) derived EVs from included COPD patients. A Morphology of extracellular vesicles by electron microscope and transmission electron microscope. B Exosome nanoparticle tracking analysis. The mean size of EVs in sputum is 124.4 nm; EVs in BALF is 142.1 nm; EVs in serum is 124.1 nm. C Identification of characteristic marker including TSG101 and CD63 by western blot. D Level of IL-6, IL-8, Elane, Antitrypsin and MUC1 in extracellular vesicles derived from sputum, BALF and plasma of COPD patients examined by western blot. E Heatmap indicating the results of mRNA expression of significant difference genes between two groups (HBE treated CSE and subsequent EVs isolated from patients with or without HUA). F-G KEGG enrichment (F) and GO enrichment (G) analysis of these significant differentially expressed genes. Abbreviation: BALF, bronchoalveolar lavage fluid; TSG101, tumor susceptibility gene101; CD63, lysosomal membrane-associated glycoprotein 3; MUC1, mucin 1; EVs, extracellular vesicles; COPD, chronic obstruction pulmonary disease
Fig. 5
Fig. 5
The pathology of COPD may be associated with mtDNA in EVs via a senescence related pathway. A Identification of senescence related protein including CDKN1A, CDKN2A, IL1A and 53BP1 in HBE treated with CSE and EVs from healthy controls and HUA patients was performed by western blot. B RT-PCR analysis of mtDNA content in PBMCs derived from COPD patients with or without HUA was compared using RT-PCR (unpaired t test, *P < 0.05). C IF microscopy analysis of CDKN1A and CDKN2A expression in HBE cells treated with CSE and subsequent EVs from patients with or without HUA(X20). Scale bars, 500 μm. Abbreviation: PBMC, peripheral blood mononuclear cell; CDKNI1A, cyclin-dependent kinase inhibitor 1A; CDKN2A, cyclin-dependent kinase inhibitor 2A; 53BP1, recombinant Tumor Protein p53 Binding Protein 1; IL-1A, Human IL-1 alpha protein; HBE, human bronchial epithelial; CSE, cigarette smoke extract; EVs, extracellular vesicles
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