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

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.