Introduction
Asthma produces heavy social and financial burdens, making it one of the major non-communicable diseases worldwide (1). Asthma manifests as chronic airflow obstruction, with characteristic chronic airway inflammation and hypersensitivity/hyperresponsiveness. Increased airway vagal activity is well known to play important roles in the asthmatic constriction, mucous secretion, inflammation and remodeling of the airway (2-5). Accordingly, inhaled muscarinic antagonists, alone or in combination with glucocorticoids and/or β2-adrenergic agonists, have become the common therapy for asthma clinically, especially in its severe attacks (6). In patients with obstinate severe asthma symptoms, high selective vagotomy of hilus pulmonis has become a choice of treatment (7). Regretfully, none of these inhaled anti-asthma drugs is able to eradicate the asthmatic increase of airway vagal activity; and surgical treatment is less acceptable clinically due to the invasiveness. Therefore, it is still urgent to find therapies that are more specifically against the genesis of the asthmatic increase of airway vagal activity.
In a rat model of allergic asthma, we recently proved that the decreases in the expression and activity of central ecto-5’-nucleotidase (CD73 or 5’-NT) play an important role in the genesis of asthmatic increase of airway vagal activity (8). Medullary airway vagal preganglionic neurons (AVPNs) are normally excited by extracellular ATP via P2X receptor-mediated facilitation of the excitatory inputs and a direct postsynaptic excitation, and inhibited by extracellular adenosine (ADO) via ADO A1 receptor (ADOA1R)-mediated opposite actions. Allergic decreases in the expression and activity of central CD73 reduce the degradation of extracellular ATP to ADO. As a result, the excitation of AVPNs by extracellular ATP is enhanced; and the inhibition of AVPNs by extracellular ADO is weakened, leading to asthmatic increase of airway vagal activity (8). Therefore, to withstand the asthmatic increase of airway vagal activity, it might be a reasonable strategy to interfere with the downregulation of central CD73.
Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. These drugs are widely used in the treatment of hyperlipidemia and cardiovascular disease clinically. Both preclinical studies in animal models and some randomized clinical trials have implicated that statins also act as modulators of immune cells and are able to alleviate asthma and chronic obstructive pulmonary diseases (COPD) [for review, see (9-13)]. In particular, inhaled statins are thought to be more prospective in asthma treatment due to the assumed heavier drug deposition in the lungs (10). A latest retrospective clinical study even shows that in-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19 (14).
The therapeutic effects of statins on cardiovascular diseases have been proved to be closely related to the upregulation of CD73 in the heart and vascular endothelium (15-21). It then becomes interesting whether statins are able to interfere with the asthmatic deceases in the expression and activity of central CD73, and, subsequently, alleviate asthma through attenuation of the asthmatic increase of airway vagal activity. Elucidation of this issue is essential to understand the therapeutic effects of statins not only on asthma/COPD but also on some other diseases with disordered autonomic function, such as cardiovascular diseases and inflammatory intestinal diseases.
This study aims to test the hypothesis that in rat model of allergic asthma, inhaled rosuvastatin is able to reverse the decreases in the central expression and activity of CD73, which attenuates the increase of airway vagal activity and, subsequently, improves pulmonary function.
Materials and methods