Ethanol Administration Impairs Pancreatic Repair After Injury

Abstract

Objectives Alcohol abuse is one of the most common factors associated with acute and chronic pancreatitis. Although it is evident that alcohol abuse can have an important role in the development of pancreatitis, it does not appear that alcohol abuse alone is responsible for this disease. We investigated the involvement of ethanol in impairment of pancreatic repair after induction of pancreatitis. Methods A biologically relevant mouse model of alcoholic pancreatitis, combining chronic ethanol consumption and coxsackievirus infection, was used to investigate the effects of ethanol on pancreatic regeneration. Tissues were harvested and analyzed by RT-PCR and immunoblot. Results These studies demonstrate that chronic ethanol consumption impairs the structural repair of the exocrine pancreas. This is accompanied by a delay in the restitution of lipase expression. Additionally, impaired expression of the critical pancreatic transcription factors, PDX1 and PTF1, and the mediator of Notch signaling, HES1, were observed. Conclusions Chronic ethanol consumption impairs the structural repair and functional restitution of the pancreas after severe injury. These impairments may, in part, be explained by impaired expression of factors important in the development and maintenance of the exocrine pancreas. Impaired pancreatic regeneration may have a role in the pathogenesis of alcoholic pancreatitis.

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

“…Based on clinical observations in human beings, it is believed that in cases of acute pancreatitis, which resolve, the pancreas regenerates to its full structural and functional capacity after an acute episode. This concept is supported by many studies in experimental animals, which have demonstrated structural and functional repair of the pancreas after experimentally induced pancreatitis [1][2][3][4][5] . In cases of severe acute pancreatitis systemic inflammation develops and can lead to multiorgan failure and death.…”

“…These findings have lead to the suggestion that these cytokines and growth factors act on pancreatic stellate cells in an autocrine manner, thereby perpetuating their activation [16] . This autocrine loop may help to explain both the apparent inability of the pancreas to fully recover from injury in the continued presence of ethanol, and the extremely common association between alcohol abuse and chronic pancreatitis [3,14] . Although it is well established that pancreatic stellate cells are primarily responsible for the deposition and degradation of components of the extracellular matrix, acinar cells can also contribute to the deposition of extracellular matrix components.…”

“…We have shown that chronic administration of ethanol delays the structural and functional regeneration of the pancreas in mice [1] . This delayed regeneration is associated with the decreased expression of a number of important pancreatic developmental factors including PDX-1 and Ptf-1α, as well as activation of the notch signaling pathway, a developmental pathway, which is required for pancreatic regeneration [3,4] . Ethanolmediated alterations in the expression of these important developmental factors affect the dedifferentiation/ redifferentiation of acinar cells and therefore, the repair of the damaged organ.…”

Use of Coxsackievirus B3 as a Model of Acute Pancreatitis

“…In experimentally infected mice, the viral titers in the spleen peak 2-4 days post infection (PI) (30). Because of the highly vascular nature of the spleen, the titer in the spleen presumably represents the titer in the blood (level of viremia) of infected animals.…”

“…Although typically associated with heart disease, these viruses have been isolated from the pancreata of patients with pancreatitis (11,26,46). Furthermore, coxsackieviruses have been shown to replicate to high titers in the pancreas and cause extensive pancreatic tissue damage in experimental animal models (30,34). In fact, in mice, if these viruses do not replicate to high titer in the pancreas, they do not cause heart disease (13,34).…”