The ciliary protein Spef2 stimulates acinar Ampkα/Sirt1 signaling and ameliorates acute pancreatitis and associated lung injury.

Background: Pancreatic acinar cells are susceptible to nuclear factor kappa B (NF-κB)-mediated inflammation and resulting cell necrosis during early acute pancreatitis. As adenosine monophosphate-activated protein kinase alpha (Ampkα)/sirtuin 1 (Sirt1) pathway activity attenuates NF-κB activity, we examined whether the Ampkα/Sirt1 axis affects the progression of acute pancreatitis and associated lung injury Methods: Pancreatic injury, oxidative stress, acinar cell necrosis and apoptosis, acinar levels of Ampkα/Sirt1/NF-κB signaling activity, NF-kB-mediated inflammatory markers, and markers of associated lung injury were measured in rat models of acute pancreatitis following pharmacological Ampkα activation with A769662 or self-complementary recombinant adeno-associated virus serotype 6 (scAAV6)-mediated Spef2 overexpression. Additional Results: Pharmacological Ampkα activation or Spef2 overexpression reduced acute pancreatitis severity, oxidative stress, necrosis, apoptosis, NF-kB-mediated inflammatory markers, and the degree of associated lung injury. Spef2 overexpression in AR42J cells Conclusions: This study established the existence of a Spef2/Ampkα/Sirt1 axis in pancreatic acinar cells that is involved in the regulation of NF-κB-mediated acinar cell inflammation and resulting cell necrosis during acute pancreatitis.