Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation

Abstract

Alcohol abuse increases the risk for pancreatitis. The pattern of alcohol drinking may impact its effect. We tested a hypothesis that chronic ethanol consumption in combination with binge exposure imposes more severe damage to the pancreas. C57BL/6 mice were divided into four groups: control, chronic ethanol exposure, binge ethanol exposure and chronic plus binge ethanol exposure. For the control group, mice were fed with a liquid diet for two weeks. For the chronic ethanol exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks. In the binge ethanol exposure group, mice were treated with ethanol by gavage (5 g/kg, 25% ethanol w/v) daily for 3 days. For the chronic plus binge exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks and exposed to ethanol by gavage during the last 3 days. Chronic and binge exposure alone caused minimal pancreatic injury. However, chronic plus binge ethanol exposure induced significant apoptotic cell death. Chronic plus binge ethanol exposure altered the levels of alpha-amylase, glucose and insulin. Chronic plus binge ethanol exposure caused pancreatic inflammation which was shown by the macrophages infiltration and the increase of cytokines and chemokines. Chronic plus binge ethanol exposure increased the expression of ADH1 and CYP2E1. It also induced endoplasmic reticulum stress which was demonstrated by the unfolded protein response. In addition, chronic plus binge ethanol exposure increased protein oxidation and lipid peroxidation, indicating oxidative stress. Therefore, chronic plus binge ethanol exposure is more detrimental to the pancreas.

Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration

“…In the NIAAA mouse model, ad libitum EtOH feeding for 10 days (5% v / v , 10 d) resulted in a BAC of ~180 mg/dL, but 10 days combined with a single binge (10 d + 1 B) induced BAC levels as high as ~400 mg/dL 1 h and 2 h following the binge bolus [ 20 ]. In mice fed an EtOH-containing liquid diet (5% EtOH) for two weeks and administered EtOH binges (5 g/kg) during the last three days, BAC was significantly increased 1 h post-binge in chronic-binge EtOH group compared to chronic EtOH alone (406 ± 76 mg/dL vs. 93 ± 69 mg/dL after one binge and 428 ± 84 mg/dL vs. 82 ± 43 mg/dL after three binges) [ 60 ]. Similarly, in a rat model [ 61 ], chronic EtOH feeding for four weeks (5% v / v ) followed by either single (5 g/kg) or repeated binge EtOH administration (5 g/kg, three doses, 12 h intervals) significantly increased BAC levels (~40 mM (175.7 mg/dL) and ~120 mM (540.3 mg/dL) respectively) compared to chronic alcohol feeding alone (~20 mM (101.5 mg/dL)), and these increases were associated with augmented liver injury.…”

“…For example, Matyas et al employed variations of the NIAAA model (such as 10 d + 1 B, 20 d + 2 B, and 40 d + 4 B), and demonstrated that chronic-binge EtOH feeding in mice leads to alcoholic cardiomyopathies characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, cardiomyocyte hypertrophy, and enhanced cardiac steatosis [ 58 ]. Paradigms of binge EtOH exposure in rodents were utilized to study the impact of drinking patterns on alcoholic pancreatitis [ 59 , 60 ]. In these studies, male C57BL/6 mice were maintained on a standard rodent chow diet and administered EtOH binges (5 g/kg) daily for 10 days (10 B) [ 59 ], or were fed an EtOH liquid diet (5% EtOH) for two weeks with EtOH binges daily during the last three days (2 w + 3 B) [ 60 ].…”

“…Paradigms of binge EtOH exposure in rodents were utilized to study the impact of drinking patterns on alcoholic pancreatitis [ 59 , 60 ]. In these studies, male C57BL/6 mice were maintained on a standard rodent chow diet and administered EtOH binges (5 g/kg) daily for 10 days (10 B) [ 59 ], or were fed an EtOH liquid diet (5% EtOH) for two weeks with EtOH binges daily during the last three days (2 w + 3 B) [ 60 ]. The addition of EtOH binges caused a more severe (compared to standard chow or chronic EtOH feeding) spectrum of pancreatic injury as shown by significant apoptotic cell death, macrophage infiltration and increased inflammation, and altered pancreatic function via mechanisms involving increased oxidative and ER stress [ 60 ].…”

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

“…Since it was published in 2010 11, 12 , the chronic-plus-binge model has been widely used by many investigators, and many novel mechanisms underlying liver inflammation and injury in this model have been revealed. Recently, the chronic-plus-binge ethanol mouse model has also been used to examine other organ damage such as the heart 13 , pancreas 14 , and adipose tissues 15 . In addition, this model was also established in rats 16, 17 .…”

Alcohol Intake Interacts with CDKAL1, HHEX, and OAS3 Genetic Variants, Associated with the Risk of Type 2 Diabetes by Lowering Insulin Secretion in Korean Adults

“…Chronic alcohol intake suppresses glucokinase transcriptional activity, which induces β‐cell dysfunction in C57BL/6J male mice (Kim et al., ). Alcohol is also known to decrease β‐cell mass by increasing oxidative stress and inflammation in rats, leading to increased β‐cell apoptosis (Ren et al., ; Zhao et al., ). The decrease in β‐cell mass is also associated with a decrease in β‐cell proliferation (Koko et al., ).…”