Discussion
There are three major new finding in this study. First, inhaled
rosuvastatin reversed the decreases in the expression and activity of
medullary CD73, and, consistently, reversed the increase of ATP
concentration in CSF, in OVA-sensitized rats. Second, inhaled
rosuvastatin blocked the vagal-mediated decrease of pulmonary function
in OVA-sensitized rats. Third, rosuvastatin reversed the increase in the
expression of ECP1 in the lungs of OVA-sensitized rats.
In this study, OVA-sensitized rats showed significant increases in
Ri and Re, and a significant decrease in
Cdyn, indicating decreased pulmonary function.
Meanwhile, Western-blot essay showed increased expression of ECP1 in the
lungs, indicating infiltration of eosinophils and pulmonary
inflammation. These functional and inflammatory changes suggest a
successful model of allergic asthma, as we have previously reported
(22).
In this study, acute atropine treatment abolished the changes in the
Ri, Re and Cdyn of rats
in sensitization group, but not in those of rats in control group and
treatment group. And, after atropine treatment, the Ri,
Re and Cdyn of rats in sensitization
group are not significantly different with those of rats in control
group and treatment group, whether compared with the values before or
those after atropine treatment. These results suggest that
physiologically, airway vagal nerves might exert little tonic effect on
pulmonary function; and, in an acutely or subacutely prepared animal
model of allergic asthma, the decrease of pulmonary function is
primarily caused by increased airway vagal activity.
In consistence with the findings of many previous studies, this study
also provided evidence that inhaled rosuvastatin is able to alleviate
pulmonary inflammation, as is manifested by the reversed increase in the
expression of ECP1 in the lungs. However, since acute atropine treatment
alone abolished the decrease of pulmonary function in OVA-sensitized
rats, inflammatory changes might be poorly related to pulmonary
function; and, in rosuvastatin-treated rats, alleviated pulmonary
inflammation might contribute little, if any, to the improvement of
pulmonary function. Our conclusions are consistent with those of
previous studies that increased airway vagal activity is the major
factor that induces asthma symptoms and decrease of pulmonary function
(5, 7).
Since the pulmonary function decrease in OVA-sensitized rat is
vagal-mediated, and was accompanied by decreases in the expression and
activity of central CD73, the changes of central CD73 might play a key
role in the asthmatic increase of airway vagal activity. Likewise, since
the rosuvastatin-induced improvement of pulmonary function was
accompanied by reversed expression and activity of central CD73, this
reversal might play a key role in the rosuvastatin-induced attenuation
of airway vagal activity. Therefore, this study for the first time
provides evidence that the asthma-alleviating effect of rosuvastatin
involves a central effect that attenuates the asthmatic increase of
airway vagal activity, which either is mediated through a direct central
action or is secondary to the modulatory action on peripheral immune
cells, or involves both of these actions.
Statins have been in clinical use for decades for the treatment of
hyperlipidemia and cardiovascular disease, with the tolerable side
effects and relatively better affordability. In the last decade,
preclinical studies in animal asthma models have obtained rather solid
evidence that statins are effective both in improvement of pulmonary
function and in alleviation of pulmonary inflammation. However, some
small randomized clinical trials using oral statins have yielded
contradictory results. While a consistent anti-inflammatory effect of
statins is validated, improved clinical outcomes in terms of symptoms or
pulmonary function are not demonstrated [for review, see (10)]. The
results from this study suggest that in OVA-sensitized rats, the
rosuvastatin-induced improvement of pulmonary function is closely
related to the reversed increase of airway vagal activity. Therefore,
whether statins are effective in alleviating the symptoms and decrease
of pulmonary function of asthma might be determined by whether these
asthmatic changes are caused by increased airway vagal activity. In
human patients, asthma is known to have multiple phenotypes, such as
allergic asthma, non-allergic asthma, asthma with fixed obstruction,
eosinophilic asthma and neutrophilic asthma (23); and, it is unclear
whether increased airway vagal activity exists in all of these
phenotypes and is the major factor that induces asthma symptoms and
decrease of pulmonary function. Therefore, without considering the
diversity of human asthma phenotypes and the level of airway vagal
activity in different phenotypes, it might be hard for randomized
clinical trials to demonstrate the effectiveness of statins in
alleviating asthma symptoms or decrease of pulmonary function. Airway
vagal activity and/or ATP concentration in CSF might should be
clinically evaluated/tested and used as indices of asthma, either in
predicting the effectiveness of statins or in the design of new clinical
trials using statin therapy. Further clinical trials in selected asthma
patients with clearly increased airway vagal activity is expected.
In terms of the alleviating effects of statins on asthma symptoms and
asthmatic decrease of pulmonary function, our results do not support the
assumption that inhaled statins might have more advantage over those
ingested or injected (10), since these effects might involve a direct
central drug action that is independent of the deposition of inhaled
drugs in the lungs.
Purinergic signaling plays important roles in the function of brain
cells; and aberrant purinergic signaling is involved in the pathogenesis
of brain injuries in many brain disorders, such as trauma, stroke,
epilepsy and multiple types of chronic neurodegeneration. Meanwhile,
statins have been proved to be beneficial to many brain disorders.
However, it has never been reported that the beneficial effects of
statins on disordered brain involve an effect on the expression and
activity of CD73. This study for the first time shows that in
OVA-sensitized rats, rosuvastatin is able to restore the expression and
activity of CD73 in the brain, and by which attenuate allergic airway
vagal dysfunction. Our results implicate that in many peripheral
diseases with concurrent neural disorders, the therapeutic effects of
statins might also involve unrevealed central actions. For instance,
increased extracellular ATP in the medullary sympathoexcitatory centers
has been implicated to participate in the genesis of hypertension (24);
however, it is unknown whether the anti-hypertensive effect of statins
involves a central sympatholytic action through upregulation of CD73.
Therefore, this study has opened a new scope for disease-based
neuropharmacology of statins.
In conclusion, this study demonstrates that in rat model of allergic
asthma, inhaled rosuvastatin reverses the decreases in the expression
and activity of central CD73, which prevents pulmonary function decrease
through abolished increase of airway vagal activity.