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

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.

Joint association of serum urate and healthy diet with chronic obstructive pulmonary disease incidence: results from the UK Biobank study

“…Previous studies have explored the role of SU in COPD and lung function; however, the results were contradictory. [6][7][8]12,13,[29][30][31][32] Several cross-sectional studies have suggested a correlation between elevated levels of SU or hyperuricemia and reduced pulmonary function. [6][7][8]32 A cross-sectional study of 1966 participants suggested that urate is positively associated with the prevalence of COPD.…”

Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study

“…For example, urate can activate NLRP3 inflammasome to induce the activation of leucocytes that cause damage to endothelial cells,30 while as demonstrated by some studies, pulmonary endothelial dysfunction is involved in the pathogenesis of COPD 34 35. In addition, Liu et al found that extracellular vesicles isolated from patients with hyperuricaemia might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway 36…”

“…34 35 In addition, Liu et al found that extracellular vesicles isolated from patients with hyperuricaemia might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway. 36 From a public health perspective, we would like to identify whether the population with hyperuricaemia is at high risk of COPD. Some studies have reported findings that are consistent with our own.…”