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Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats.

McIlwrath SL, Westlund KN.

World J Gastroenterol. 2015 ;21(3):836-53.

Sabrina L McIlwrath, Karin N Westlund, Department of Physiology, University of Kentucky, Lexington, KY 40536-0298, United States.

 

Abstract

AIM:

To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices.

METHODS:

Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, μ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States).

RESULTS:

Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher incidence of single and small 2-10 cell insulin-positive cell clusters (P < 0.05). Insulin expressing islet of Langerhans cells appeared hypertrophied while islet number and area measurements were not different from controls. Weekly behavioral tests determined that mechanical and heat sensitivities were significantly increased by 4 wk on AHF diet compared to controls.  Hypersensitivity was attenuated with efficacy similar to morphine with single dose treatment of either metabotropic glutamate receptor 2/3 agonist APDC, or nociceptin, the endogenous ligand for opioid-receptor-like 1 receptor.

CONCLUSION:

The AHF diet induces a chronic alcoholic pancreatitis in rats with measurable features resembling clinical patients with chronicpancreatitis and type 3c diabetes mellitus.

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Significance Statement

Chronic pancreatitis is a multifactorial disease that is progressive and potentially fatal. Caused by persistent unresolved inflammation and pancreatic fibrosis, it is typically accompanied by intractable abdominal pain. Clinically, 10% of patients progress to insufficiency of the exocrine pancreas, type 3c diabetes mellitus (T3cDM). Risk of developing pancreatic cancer is increased 5-20 fold. Factors that increase susceptibility of chronic pancreatitis include lifestyle choices such as smoking, regular alcohol consumption, particularly binge drinking, hyperlipidemia/hypertriglyceridemia caused by a diet high in saturated fat, and heritable factors. Present pharmacological treatments for this disease and its symptoms are inadequate. Better knowledge of the underlying pathophysiology is needed. However, currently used animal models better model acute pancreatitis rather than the clinical etiology of chronic pancreatitis. They are typically chemically induced, invasive, and have short duration and high mortality rates.

Figure Legend.

Micrograph of pancreas histology from (A) a control rat fed regular chow and (B) an animal with AHF diet induced chronic pancreatitis. Sirius red stained collagen fibrosis is clearly visible surrounding pancreatic ducts when counterstained with Fast Green. black arrows: pancreatic ducts; red arrows: blood vessels. Scalebar: 250 μm

 

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