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