Chronic Alcohol Consumption Accelerates Fibrosis in Response to Cerulein-Induced Pancreatitis in Rats

Abstract

Alcohol consumption is a risk factor for chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5% ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without pancreatitis (P0), with cerulein pancreatitis induced once (P1), or with cerulein-induced pancreatitis weekly for 3 weeks (P3). AP markers, inflammation, and fibrosis were measured histologically, by gene expression profiling and protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe necrosis, and early calcification were only induced in the EP3 rats. Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology, hydroxyproline content, and mRNA expression for collagen alpha1(1) and procollagen alpha2(1). Proinflammatory cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory cytokines (interleukin-10 and transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of fibrosis-associated genes was associated with expression of anti-inflammatory cytokines in alcohol-fed rats.

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

“…Because of this, the inflammatory response in chronic alcoholic pancreatitis has also been investigated [80] . Using rats pair-fed the Lieber-Decarli diet, Deng et al [80] demonstrated that chronic ethanol administration reduced the number of resident mononuclear cells in the pancreas.…”

“…Because of this, the inflammatory response in chronic alcoholic pancreatitis has also been investigated [80] . Using rats pair-fed the Lieber-Decarli diet, Deng et al [80] demonstrated that chronic ethanol administration reduced the number of resident mononuclear cells in the pancreas. They, like others, suggested that this reduction likely reflects a general immunologic suppression in the pancreas of animals chronically fed ethanol [17,78] .…”

“…They, like others, suggested that this reduction likely reflects a general immunologic suppression in the pancreas of animals chronically fed ethanol [17,78] . Furthermore, the authors suggested this suppression might explain why animals chronically provided ethanol do not develop chronic pancreatitis in the absence of acute pancreatic damage [80] . Similar to previous findings, induction of acute pancreatitis enhanced the inflammatory response in these animals [80] .…”

Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol

“…Alcohol abuse may not be the sole risk for the development of CP [32] ; rather alcoholic CP is likely the result of an interaction of several co-factors [2] . It has been demonstrated that chronic alcohol consumption accelerates fibrosis in response to cerulein-induced CP in rats [33] . Alcohol metabolites in pancreatic acinar cells induce persistent cytosolic Ca 2+ signals in a concentration-dependent manner and depolarize mitochondria.…”

Immune modulation in acute and chronic pancreatitis

“…Notably, the macrophages are found in proximity to areas of fibrosis (16,98). Lipopolysaccharide (LPS)-activated macrophages stimulate pancreatic stellate cell (PSC) activation and promote collagen and fibronectin synthesis in cultured PSCs (77).…”