Astragaloside IV Ameliorates Airway Inflammation in an Established Murine Model of Asthma by Inhibiting the mTORC1 Signaling Pathway

Abstract

Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF-γ), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined. AS-IV markedly suppressed airway hyperresponsiveness and reduced IL-4, IL-5, and IL-17 levels and increased INF-γ levels in the BALF. Histological studies showed that AS-IV markedly decreased inflammatory infiltration in the lung tissues. Notably, AS-IV inhibited mTORC1 activity, whereas it had limited effects on mTORC2, as assessed by phosphorylation of mTORC1 and mTORC2 substrates S6 ribosomal protein, p70 S6 Kinase, and Akt, respectively. CD4+CD25+Foxp3+Treg cells in BALF were not significantly changed by AS-IV. Together, these results suggest that the antiasthmatic effects of AS-IV were at least partially from inhibiting the mTORC1 signaling pathway.

The effect of astragaloside IV on JAK2‐STAT6 signalling pathway in mouse model of ovalbumin‐induced asthma

“…Besides, infiltration and levels of inflammatory cells and AHR were also significantly upregulated in OVA‐induced mice (Figure ). These phenomena are corresponding to mouse model of asthma in previous studies (Jin et al, ; Qiu et al, ).…”

“…Besides, some studies showed AS‐IV attenuates the eosinophilic infiltration in ovalbumin‐induced asthma (Du et al, ; Gu, Jiang, Wang, Du, & Cai, ; Huang, Tang, Wang, & Song, ). Previous study used 20–40 mg/kg doses of astragaloside IV (AS‐IV) daily to treat OVA‐induced mouse model of asthma and had different degree levels to inhibit asthma syndrome (Jin et al, ). Cytokine levels, IL‐4 and ‐5, in BALF of mouse model and airway inflammation in the lung tissue were more dominantly affected by 40 mg/kg dose daily of AS‐IV.…”

“…Cytokine levels, IL‐4 and ‐5, in BALF of mouse model and airway inflammation in the lung tissue were more dominantly affected by 40 mg/kg dose daily of AS‐IV. In contrast, IL‐13 was not regulated by AS‐IV treatment (Jin et al, ). On the other hand, 20 mg/kg dose daily of AS‐IV only had effects on IL‐4 and ‐5 levels in BALF (Jin et al, ).…”

“…Airway hyperresponsiveness (AHR) was measured 24 hr after ovalbumin challenge. The technique for measuring non‐invasive respiratory function was previously described (Jin et al, ). We used the whole‐body plethysmography (Buxco's unrestrained WBP systems) to measure the pulmonary function and record the net (or sum) of nasal and thoracic flows.…”

“…Accumulated evidences indicated that AS‐IV possess a broad range of pharmacological properties, including immunomodulatory effects, as well as anti‐inflammatory, antiviral and antitumor activities (Mcculloch et al, ). Previous studies showed that AS‐IV treatment markedly inhibited airway inflammation and airway hyperresponsiveness which could remodel asthma (Jin et al, ; Li, Hou, Xu, Liu, & Tu, ; Qiu et al, ). Although some studies explored the possible signalling mechanisms of AS‐IV treatment in asthma therapy, the related information is still few (Jin et al, ; Qiu et al, ).…”