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Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.

ABSTRACT: Previously, we have shown that hydrogen sulphide (H₂ S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H₂ S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H₂ S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL-propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre-mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H₂ S exerted on the impaired autophagy during AP was further attributed to over-activation of autophagy rather than hampered autophagosome-lysosome fusion. To elucidate the molecular mechanism that underlies H₂ S-mediated over-activation of autophagy during AP, we evaluated phosphorylations of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC-51-Like kinase 1 (ULK1). Our findings suggested that H₂ S exacerbated taurocholate-induced AP by over-activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H₂ S to restore over-activated autophagy might be a promising therapeutic approach against AP-related injuries.

SUBMITTER: Ji L

PROVIDER: S-EPMC5134374 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.

Ji Liang L Li Le L Qu Fengzhi F Zhang Guangquan G Wang Yongwei Y Bai Xuewei X Pan Shangha S Xue Dongbo D Wang Gang G Sun Bei B

Journal of cellular and molecular medicine 20160715 12

Previously, we have shown that hydrogen sulphide (H2 S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2 S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2 S were artificially intervened by an administration of sodium hydrosulphide ...[more]

PMID: 27419805

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Project description:Astragalus membranaceus (AM), used in traditional Chinese medicine, has been shown to enhance immune functions, and recently, its anti-inflammatory effects were identified. However, the mechanisms of action remain unclear. Most studies have shown that autophagy might be involved in the immune response of the body, including inflammation. Here, we developed an inflammatory model by stimulating macrophages with lipopolysaccharides (LPS) to explore the anti-inflammatory effect and mechanisms of AM injection from the perspective of the regulation of autophagy. Immunoblot, immunofluorescence, and ELISA were used to determine the effects of AM injection on the production of interleukin-6 (IL-6) and alterations of autophagy markers. It was found that AM injection reduced the expression of IL-6 in LPS-stimulated macrophages and reversed the LPS-induced inhibition of cellular autophagy. After treatment with inhibitors of signaling pathways, it was shown that LPS downregulated autophagy and upregulated the production of IL-6 in macrophages via the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. AM injection reversed the effects of LPS by activating the AMP-activated protein kinase (AMPK) instead of inhibiting Akt. These results were further confirmed by testing activators and siRNA silencing of AMPK. Hence, these 2 distinct signaling molecules appear to exert opposite effects on mTOR, which integrates information from multiple upstream signaling pathways, negatively regulating autophagy. In addition, we demonstrated that autophagy might play a key role in regulating the production of IL-6 by testing activators and inhibitors of autophagy and siRNA silencing of ATG5. These findings showed that AM injection might enhance autophagy by activating AMPK and might further play a repressive effect on the LPS-stimulated expression of IL-6. This study explored the relationship between autophagy, signaling pathways, and the production of inflammatory factors in a model of endotoxin infection and treatment with AM injection.

Dataset Information

Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.

Publications

Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.

Similar Datasets

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