A Redundant System of Thioredoxin and Glutathione Is Essential for Pancreatic Acinar Integrity

Oxidative stress and antioxidant defense mechanisms have long been implicated in the pathogenesis of acute pancreatitis (AP). However, there is a notable lack of in vivo experimental evidence clarifying their precise role.

We generated and analyzed mice with a pancreas-specific deletion of Txnrd1 (Txnrd1^Δpanc). AP was induced in these mice using cerulein injections. Pancreatic tissue was subsequently analyzed using immunoblotting, histology, immunohistochemistry, RNA sequencing, and biochemical assays.

Txnrd1^Δpanc mice exhibited normal growth, pancreatic weight, histology, and pancreatic function comparable to controls, although they experienced a slightly more severe course of AP. An increase in glutathione levels and upregulation of components within the glutathione system were observed in these mice. However, depletion of the glutathione pool led to pancreatic necrosis, followed by regeneration. When glutathione depletion was combined with AP, Txnrd1^Δpanc mice suffered a profound and permanent loss of acinar tissue.

These findings indicate that the response to AP is closely linked to alterations in antioxidant systems. The thioredoxin and the glutathione systems appear to perform overlapping protective roles in safeguarding acinar cells during AP. A simultaneous disruption of both systems proves detrimental to pancreatic integrity during acute pancreatitis.