Astragaloside IV Protects from PM2.5-Induced Lung Injury by Regulating Autophagy via Inhibition of PI3K/Akt/mTOR Signaling in vivo and in vitro

Abstract

Introduction Prolonged exposure to air polluted with airborne fine particulate matter (PM2.5) can increase respiratory disease risk. Astragaloside IV (AS-IV) is one of the main bioactive substances in the traditional Chinese medicinal herb, Astragalus membranaceus Bunge. AS-IV has numerous pharmacological properties; whereas there are few reports on the prevention of PM2.5-induced lung injury by AS-IV through modulation of the autophagic pathway. This study aimed to investigate the protective effects and the underlying mechanisms of AS-IV in PM2.5-induced lung injury rats and rat alveolar macrophages (NR8383 cells). Methods The pneumotoxicity model was established by intratracheal injection of PM2.5 in rats, and PM2.5 challenge in NR8383 cells. The severity of lung injury was evaluated by wet weight to dry weight ratio and McGuigan pathology scoring. Inflammatory factors and oxidative stress were detected through ELISA. The expressions of p-PI3K, p-Akt, and p-mTOR proteins were analyzed by immunohistochemistry. Immunofluorescence and transmission electron microscopy were used to detect autophagosomes. The expressions of autophagy marker protein (LC3B and p62), PI3K/Akt/mTOR signaling and NF-κB translocation were detected by Western blot in lung tissue and NR8383 cells. Results After PM2.5 stimulation, rats showed severe inflammation and oxidative stress, along with inhibition of autophagy in lung tissue. AS-IV not only decreased pulmonary inflammation and oxidative stress by inhibiting nuclear factor kappa B translocation, but also regulated autophagy by inhibiting PI3K/Akt/mTOR signaling. After treatment with 3-methyladenine (a classic PI3K inhibitor, blocking the formation of autophagosomes), the protective effect of AS-IV on PM2.5-induced lung injury was further strengthened. In parallel, using Western blot, immunohistochemistry, and transmission electron microscopy, we demonstrated that AS-IV restore autophagic flux mainly through regulating the degradation of autophagosomes rather than suppressing the formation in vivo and in vitro. Conclusion Our data indicated that AS-IV protects from PM2.5-induced lung injury in vivo and in vitro by inhibiting the PI3K/Akt/mTOR pathway to regulate autophagy and inflammation.

Pretreatment with rosavin attenuates PM2.5‐induced lung injury in rats through antiferroptosis via PI3K/Akt/Nrf2 signaling pathway

“…Meanwhile, sham and PM2.5 rats were treated with saline intraperitoneally. The dosage of rosavin and PM2.5 was chosen based on previously reported studies (Pei et al, 2021; Xin et al, 2019).…”

“…PM2.5‐induced lung injury is often accompanied by different types of cell death. Our previous studies reported the presence of cell apoptosis and autophagy in lung injury stimulated by PM2.5 exposure (Pei et al, 2021; Wu et al, 2021). It is confirmed that exposure to PM2.5 could cause lung inflammation and oxidative stress by generating reactive oxygen species (ROS) (Long et al, 2020).…”

Adenophora Stricta Root Extract Protects Lung Injury from Exposure to Particulate Matter 2.5 in Mice

“…Therefore, consumption of nutraceuticals to prevent PM 2.5 -mediated pulmonary damage would be an alternative and attractive option. In regards, several medicinal herbs or those-derived phytochemicals have been suggested to possess pulmonary protective effects against PM 2.5 without serious side effects [ 5 , 6 , 9 , 10 , 11 ].…”

Progress in preclinical studies of macrophage autophagy in the regulation of ALI/ARDS

“…The mTOR signaling pathway regulates the cell cycle, cell growth, and cell metabolism in physiological and pathological settings; it also plays a crucial role in lung injury (143)(144)(145). In an ALI model, LPS treatment significantly increased the expressions of p-mTOR, p62, and Beclin1, decreased LCII/LCI ratio expression, and enhanced the levels of inflammatory factors in macrophages (123).…”