Elucidating the role of par2 in bronchial smooth muscle in COPD
Creators: name: Black, Kimberly
Publisher: name: Zenodo
Year: 2024

description: Chronic obstructive pulmonary disease (COPD) is a multifactorial condition encompassing chronic bronchitis & emphysema. Characterised by progressive airflow limitation & chronic inflammation, COPD is currently the third leading cause of death worldwide and there is an urgent unmet clinical need for improved treatments. Proliferation, hypertrophy, and hyper-contractility of bronchial smooth muscle (BSM) are key features of COPD, and current treatments focus on bronchodilation to improve airflow. Proteinase-activated receptor-2 (PAR2) is a promising therapeutic target that plays a key role in multiple inflammatory pathologies and is associated with airway hypersensitisation and inflammation in asthma. Protective bronchodilatory roles for PAR2 have also been described, thus the overall contribution of PAR2 to respiratory disease, particularly COPD, is unclear.This study investigated putative PAR2 roles in BSM phenotype, function, and pathogenic mechanisms, including COPD-relevant contexts of oxidative stress and ageing. Since an important COPD comorbidity is rheumatoid arthritis (RA), lung pathology in a murine RA model, collagen-induced arthritis (CIA) was also explored. PAR2 activation induced significant and concentration-dependent calcium mobilisation in human BSM cells (hBSMC), consistent with a direct role in regulation of BSM contractility. In ex vivo murine airway rings, PAR2 activation elicited a substantial dilatory effect on pre-contracted tissue, which was comparable in both sexes and abolished in PAR2-deficient tissue.PAR2-dependent relaxation of both bronchi and trachea was enhanced following induction of oxidative stress, concomitant with increased PAR2 expression, and was inhibited by exogenous superoxide dismutase. Oxidative conditions also increased collagen abundance throughout murine lung tissue. Baseline collagen levels and smooth muscle actin expression were increased in PAR2-deficient tissue.PAR2-dependent bronchodilation was reduced in older mice, as was PAR2 expression. There was a modest decrease in smooth muscle actin (SMA) in tissues from older wild-type mice, whereas SMA expression was reduced in PAR2-deficient airways regardless of age. Collagen abundance was increased with age, whereas in age-matched PAR2-deficient samples SMA expression was reduced.Murine CIA led to strikingly reduced lung tissue density, reflected in decreased alveolar septal width and tissue cell density, whilst a trend toward increased small airway thickness was observed. CIA parenchyma exhibited increased collagen levels, consistent with early fibrosis, whilst arterioles exhibited decreased SMA. Neutrophil elastase was increased in CIA, whilst PAR2 was unchanged or decreased.In conclusion, PAR2 plays a key role in regulating bronchodilation that, importantly, is enhanced inoxidative stress but decreased in age. These findings, along with the influence of PAR2 on lung collagenand SMA levels, may inform possible future PAR2-directed therapeutic strategiesfor COPD and relatedpathologies. Thisstudy also revealsstriking lung changes during murine inflammatory arthritis, offeringthe potential to model RA lung pathology and perhaps illuminate mechanisms underpinning RA-COPDco-morbidity.