Anti-asthmatic effect of pitavastatin through aerosol inhalation is associated with CD4+ CD25+ Foxp3+ T cells in an asthma mouse model

Abstract

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-A) reductase, and studies have shown that statins also have anti-inflammatory and immunomodulatory properties. The purpose of this study was to investigate the anti-asthmatic effects of pitavastatin, a type of statin, in an asthma mouse model. Mice were sensitized and challenged with ovalbumin (OVA) to establish the asthma model. These mice were then treated with inhaled pitavastatin (5 mg/kg) or dexamethasone (2 mg/kg), the latter of which served as a positive control. The results of the study showed that pitavastatin reduced allergen-induced increases in airway resistance and alleviated bronchial tube thickness and goblet cell hyperplasia in lung tissues. In addition, the results showed that pitavastatin inhibited OVA-induced increases in eosinophil counts and total inflammatory cell counts in bronchoalveolar lavage fluid (BALF) and increased the percentage of CD4+ CD25+ Foxp3+ Treg in the BALF of asthmatic mice. IL-4 and IL-17 levels were decreased, whereas IFN-γ levels were significantly increased in the BALF of pitavastatin-treated mice compared with the BALF of OVA-challenged mice. These results suggest that pitavastatin has potential as a therapy for allergic airway disease and that its effects are associated with its ability to regulate CD4+ CD25+ Foxp3+ T cell counts.

Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma

“…This is inconsistent with some reports that simvastatin can upregulate IL-10 in human subjects with chronic obstructive lung disease (Maneechotesuwan et al, 2015). A limitation of our experiments is that though we observed a suppression of lymphocyte influx with simvastatin therapy, our cytokine array did not include IL-17, which is downregulated by statin treatment in ovalbumin-primed mice (Imamura et al, 2009;Wu et al, 2017). Changes in IL-17 levels could have shed light on the effects of therapy on Th17 / Treg cell balance as a mechanism for Treg-associated suppression of Th2 cell-mediated inflammation.…”

“…Another mechanism for limiting accumulation of simvastatin is the presence of the simvastatin metabolizing enzyme, CYP3A11 in mouse lung (CYP3A4 in humans) (Haag et al, ; Biggs et al, ; Li et al, ; Shah et al, ). Recent evidence indicates that direct delivery of statins to the lung may be needed to reverse airway hyperreactivity and hypersensitivity (Zeki et al, ; Wu et al, ). Thus our evidence indicated that systemic administration of simvastatin was not able to mitigate airway dysfunction, despite its capacity to prevent immune cell influx and release of pro‐inflammatory cytokines.…”

“…Lovastatin appears to reduce contractility of bronchi isolated from ovalbumin challenged rodents (Chiba et al, ,b). Systemic simvastatin treatment reportedly prevents increased lung resistance in ovalbumin exposed mice (Zeki et al, ; Ahmad et al, ) Recent pre‐clinical studies in mice suggest that inhaled statins may affect lung function (Wu et al, ), but delivery of statins to the lungs is not approved for humans. Real world interpretation and translation of results from pre‐clinical studies of systemically delivered statins is limited as none have investigated the effects of long‐term, prophylactic treatment or monitored the concentration of statins that accumulate in the lung; and, all used ovalbumin as an aeroallergen (Johnson et al, ; Johnson et al, ; Gregory and Lloyd, ).…”

Innovations in asthma therapy: is there a role for inhaled statins?

“…Given the present uncertainty regarding the use of statins in asthma, we and others began investigating the safety and efficacy of delivering statins via inhalation in animal models, as an alternative approach to orally administered statins [100–102,104,105,128–130]. We are currently designing studies using mass spectrometry to measure concentrations of statins and their active metabolites in the plasma, airways, and lungs of patients ingesting oral statins.…”

Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

“…The mice were subsequently challenged with aerosolized PBS (baseline) acetylcholine treatment doses of 0, 1, 2, 4, 8, and 16 mg/mL. Average compliance values were recorded during a 3 min period following each challenge [19].…”