MTOR-Mediated Autophagy Is Involved in the Protective Effect of Ketamine on Allergic Airway Inflammation

Abstract

Unresolved inflammation underpins the pathogenesis of allergic airway diseases, such as asthma. Ketamine, accepted as a promising therapy for resistant asthma, has been demonstrated to attenuate allergic airway inflammation. However, the anti-inflammatory mechanism by ketamine in this setting is largely unknown. We aimed to investigate whether autophagy was involved in the protective effect of ketamine on allergic airway inflammation. Female C57BL/6 mice were sensitized to ovalbumin (OVA) and treated with ketamine at 25, 50, or 100 mg/kg prior to OVA challenge. In this model, the pulmonary morphological findings and airway inflammation were significantly inhibited at 50 mg/kg but not at 25 or 100 mg/kg. Moreover, 50 mg/kg ketamine abrogated the increased concentrations of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) of allergic mice, as well as activated the expression of phosphorylated mammalian target of rapamycin (p-MTOR) and inhibited autophagy in allergic mice. To confirm whether the effect of 50 mg/kg ketamine on asthma was mediated by inhibiting autophagy, rapamycin was administered to mice sensitized to OVA and exposed to 50 mg/kg ketamine. All of the effect of 50 mg/kg ketamine was reversed by rapamycin treatment, including increased p-MTOR and decreased autophagy. Taken together, the present study demonstrates that 50 mg/kg ketamine inhibits allergic airway inflammation by suppressed autophagy, and this effect is mediated by the activation of MTOR in the lungs of allergic mice.

Suppression of sirtuin 1 alleviates airway inflammation through mTOR‑mediated autophagy

“…The ratio of lc3-ii to lc3-i is commonly used to analyze autophagic activity, of which Beclin-1 is also considered a hallmark (17). Furthermore, it has been reported that autophagy suppression may inhibit airway inflammation in allergic mice (16). Therefore, the present study assessed whether eX-527 exerted anti-inflammatory effects by suppressing autophagy.…”

“…mTOR activation has been shown to reduce inflammation in an oVa-induced allergic mouse model (16) and autophagy is known to be controlled by the mTor signaling pathway (19). Furthermore, mTor levels were decreased in the lungs of allergic mice, whereas mTor activation inhibited allergic airway inflammation via suppressed autophagy (16). Therefore, mTor could represent a pivotal modulator of asthma development.…”

“…mTOR is an evolutionarily conserved serine/threonine protein kinase, which acts as a central regulator of cell proliferation, cell growth, survival, autophagy and transcription ( 30 , 31 ). mTOR activation has been shown to reduce inflammation in an OVA-induced allergic mouse model ( 16 ) and autophagy is known to be controlled by the mTOR signaling pathway ( 19 ). Furthermore, mTOR levels were decreased in the lungs of allergic mice, whereas mTOR activation inhibited allergic airway inflammation via suppressed autophagy ( 16 ).…”

“…mTOR, an evolutionarily conserved serine/threonine kinase, is a central regulator of cell transcription, growth, proliferation and survival ( 12 ). Previous studies have reported that mTOR signaling is involved in inflammatory diseases, including dermatological ailments ( 13 ), chronic obstructive pulmonary disease ( 14 , 15 ) and asthma ( 16 ). Furthermore, it was revealed that autophagy may be involved in the regulation of asthma ( 17 , 18 ), and enhanced autophagy was reported to be associated with increased asthma severity ( 18 ).…”

“…Autophagy is controlled by the mTOR signaling pathway ( 19 ). In allergic mice, the lung levels of phosphorylated (p)-mTOR were decreased, whereas mTOR signaling activation inhibited allergic airway inflammation by suppressing autophagy ( 16 ). Additionally, the mTOR and SIRT1 signaling pathways are closely integrated and play an important role in the neuroprotective effect of caloric restriction ( 20 ).…”