Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Abstract

Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis. Core tip: There is currently no specific pharmacotherapy for pancreatitis. Although ethanol abuse is commonly associated with both acute and chronic pancreatitis, ethanol does not itself cause pancreatitis. Instead it appears that ethanol and its metabolic by-products sensitize the pancreas to damage from other factors. Detailed understanding of the mechanisms by which ethanol sensitizes the pancreas to damage has identified a number of promising targets for therapy. It is hoped that further preclinical and clinical studies will lead to the development of successful treatment of both acute and chronic pancreatitis. REVIEWClemens DL, Schneider KJ, Arkfeld CK, Grode JR, Wells MA, Singh S. Alcoholic pancreatitis: New insights into the pathogenesis and treatment.

Lipopolysaccharide enhances TGF‐β1 signalling pathway and rat pancreatic fibrosis

“…This notion is further supported by the fact that administration of ethanol alone to experimental animals does not cause pancreatitis . Currently, it is widely believed that ethanol sensitizes the pancreas to injury and that additional factors are required for the manifestation of overt pancreatitis . Bacterial endotoxin LPS has been recognized as a trigger factor, as shown by our clinical data that enhanced chemotactic factors and TGF‐β1 are found in the sera of ACP patients with endotoxemia as well as by other experimental evidence that an LPS challenge in ALC‐fed rats leads to pancreatitis .…”

“…Pancreatic fibrosis is a key pathological feature of alcoholic chronic pancreatitis (ACP) in which pancreatic stellate cells (PSCs) play a critical role . Quiescent PSCs are activated by ethanol, its metabolites and reactive oxidation species resulting in their conversion into myofibroblast‐like cells which express the cytoskeletal protein alpha‐smooth muscle actin (α‐SMA) and which have the capacity to proliferate, synthesize extracellular matrix proteins including type I collagen (Col1) .…”

Hypertriglyceridemic pancreatitis: Epidemiology, pathophysiology and clinical management

“…27,28 Alcohol competes for oxidation with FFAs, which results in increased FFA availability for triglyceride synthesis and increased hepatic VLDL secretion that may lead to HTG and chylomicronemia. 5 However, given that alcohol abuse is commonly associated with AP, 29 the diagnosis of HTGP may be overlooked in some alcoholic patients.…”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…The risk factors such as cigarette smoking, hereditary predispositions (hereditary chronic pancreatitis), obesity, alcohol intake and type-II diabetes are connected to inflammation processes [5]. Anti-inflammatory bioactive lipids including lipoxins and resolvins and their mediators are important for the inflammatory process [57,58].…”