Abstract
Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.
Highlights
Pancreatitis is an excruciating and debilitating disease with no available treatments
Hepatocyte Growth Factor Receptor (MET) expression was significantly increased in the acinar (Fig 1A and 1C) and ductal cells (Fig 1B and 1C) of chronic pancreatitis (CP) patients with expression higher in pancreatic intraepithelial neoplasia (PanIN) 1A and 1B lesions (Fig 1), established precursors to invasive pancreatic adenocarcinoma
We show that MET levels are low in the normal adult pancreas, but are elevated in ductal and acinar cells in human CP specimens
Summary
Pancreatitis is an excruciating and debilitating disease with no available treatments. The disease initially presents as an acute attack characterized by abdominal pain, nausea and/or vomiting. Repeated bouts of acute pancreatitis (AP) produce a persistent inflammatory response that can rapidly progress to chronic disease characterized by fibrosis, with long-term consequences including increased risk of diabetes or pancreatic cancer [2]. Failure to resolve these responses can lead to the destructive complications of chronic inflammation. Acute pancreatic injury induced by the cholecystokinin analogue cerulein, causes increased acinar nuclear factor-ĸB (NF-ĸB) signaling with subsequent leukocyte recruitment [5]. Increased intrapancreatic inflammation amplifies the severity of injury, resulting in acinar cell death with induction of a regenerative response [6,7]. A detailed understanding of the upstream receptor signaling pathways guiding injury-associated acinar repair is far from complete
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