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.