Inhibiting autophagy promotes collagen degradation by regulating matrix metalloproteinases in pancreatic stellate cells

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Aims:Autophagy is an intracellular metabolic process that degrades and recycles own constituents to maintain homeostasis and supply substrates. Disruption of collagen degradation is one of the pathogenesis of pancreatic fibrosis. In this study, we investigated the effects of inhibiting autophagy on the collagen degradation of PSCs.Main methods:Rats were injected dibutyltin dichloride (DBTC) to induce chronic pancreatitis (CP) model. The expression of LC3B was measured by western blotting. Rat PSCs were isolated from pancreas tissues, and the experiments used the primary PSCs. Autophagosome was confirmed by transmission electron microscope. Immunofluorescence for LC3B and α-SMA were applied to assess autophagy and activated PSCs. The effects of autophagy inhibition of 3-MA on the expressions of LC3B, Atg5, and Beclin-1 were investigated by real-time PCR and Western blotting, as well as the α-SMA, TGF-β1, ColI, Col III, FN, MMP-2, MMP-13, TIMP-1 and TIMP-2. Meanwhile, the secretion of ColI, Col III and FN were investigated by ELISA.Key findings:The LC3-II/I ratio was increased in rat CP model. Autophagosomes and an increased autophagic level were observed during PSCs activation. Inhibiting autophagy could down-regulate the expressions of α-SMA, TGF-β1, FN, ColI, Col III, TIMP-1 and TIMP-2, while the expressions of MMP-2 and MMP-13 were increased.Significance:This study confirmed that autophagic level is increased during PSCs activation in vivo and in vitro. Inhibiting autophagy prevents the activation of PSCs, and suppresses fibrosis through promoting extracellular matrix (ECM) degradation by decreasing the expression of TGF-β1 and increasing MMPs/TIMPs ratio.

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