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Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis.

Methods: In the present study for the first time, we have investigated the role of DDR1 and DDR2 in cerulein-induced CP. Pancreatic DDR1 and DDR2 expression was examined by immunoblotting and immunostaining analysis. Subsequently, the protective effects of selective DDR1 and DDR2 inhibitor, imatinib (IMT) was investigated in CP mice as a therapeutic intervention.

Results: Activated pancreatic stellate cells (PSCs) and CP mice showed significant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, inflammation, extracellular matrix (ECM) deposition and PSCs activation were significantly inhibited by IMT. Further, we found a significant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated fibrosis.

Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.