Rapamycin Attenuates Acute Pancreatitis-Induced Acinar Injury in Mice With Pancreatic Loss of Gα13.

Background and Aims: While Gα13 transduces signals from G protein-coupled receptors to regulate inflammation, its role in pancreatitis remains poorly understood. This study aims to understand how Gα13 regulates pancreatitis-induced inflammation and acinar injury. Methods: Expression of Gα13 in mouse and human pancreas tissue was examined by immunostaining. Experimental pancreatitis was induced by administering cerulein to mice with wild-type and conditional knockout of Gα13 in the pancreas. The impact of Gα13 loss on pancreatitis was assessed by histology, immunostains, and cytokine proteome array. The Gα13-deficient mice were cotreated with the mammalian target of rapamycin (mTOR) inhibitor rapamycin during cerulein treatment to determine the effects of mTOR inhibition on pancreatitis. Results: We found reduced Gα13 expression in acute and chronic human pancreatitis samples. We show that induction of acute and chronic pancreatitis in mice with cerulein treatment reduces Gα13 expression. Moreover, we found worsening of acute and chronic pancreatitis-induced acinar injury in mice with pancreas-specific deletion of Gα13. While pancreatic deletion of Gα13 did not exacerbate acute pancreatitis-induced inflammation, we found that Gα13 loss mildly exacerbated chronic pancreatitis. Gα13 loss increased cerulein-induced mTOR signaling in the acute and chronic pancreatitis mouse models; however, the mTOR inhibitor rapamycin attenuated the effects of cerulein only in the acute pancreatitis model, whereas it exacerbated the effects of cerulein in the chronic pancreatitis model. Conclusion: This work demonstrates that Gα13 loss promotes tissue damage in acute and chronic pancreatitis, which can be attenuated by the mTOR inhibitor rapamycin in acute pancreatitis.