Abstract
Pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma, is a serious, widespread medical condition usually caused by alcohol abuse or gallstone-mediated ductal obstruction. However, many cases of pancreatitis are of an unknown etiology. Pancreatitis has been linked to bacterial infection, but causality has yet to be established. Here, we found that persistent infection of mice with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) was sufficient to induce pancreatitis reminiscent of the human disease. Specifically, we found that pancreatitis induced by persistent S. Typhimurium infection was characterized by a loss of pancreatic acinar cells, acinar-to-ductal metaplasia, fibrosis and accumulation of inflammatory cells, including CD11b+ F4/80+, CD11b+ Ly6Cint Ly6G+ and CD11b+ Ly6Chi Ly6G− cells. Furthermore, we found that S. Typhimurium colonized and persisted in the pancreas, associated with pancreatic acinar cells in vivo, and could invade cultured pancreatic acinar cells in vitro. Thus, persistent infection of mice with S. Typhimurium may serve as a useful model for the study of pancreatitis as it relates to bacterial infection. Increased knowledge of how pathogenic bacteria can cause pancreatitis will provide a more integrated picture of the etiology of the disease and could lead to the development of new therapeutic approaches for treatment and prevention of pancreatitis and pancreatic ductal adenocarcinoma.
Highlights
Pancreatitis affects over 80,000 Americans every year, and, in its chronic form, is a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA) [1,2]
Acute pancreatitis ranges in severity from mild interstitial pancreatitis to a much more severe condition associated with necrosis and concomitant multi-organ failure [3]
Typhimurium LPS induces pancreatic inflammation, but fails to induce the reactive epithelial and fibrotic responses that are characteristic of pancreatitis
Summary
Pancreatitis affects over 80,000 Americans every year, and, in its chronic form, is a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA) [1,2]. Acute pancreatitis ranges in severity from mild interstitial pancreatitis to a much more severe condition associated with necrosis and concomitant multi-organ failure [3]. Most patients with acute pancreatitis suffer from mild interstitial pancreatitis, but up to 20% of patients suffer from severe pancreatitis, which is often fatal [4]. Other established risk factors for the development of pancreatitis include excessive alcohol consumption, cigarette smoking, and genetic predisposition [6]. Even though 70% of chronic pancreatitis cases are attributed to alcohol abuse, 95% of alcoholics never develop pancreatitis. The remaining chronic pancreatitis cases are considered idiopathic in nature [1]
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