Table I. Summary of the advantages, disadvantages and clinical relevance of non-invasive experimental models of acute pancreatitis.

Model	Advantages	Disadvantages	Clinical relevance	References
Hormone-induced	Causes acute pancreatitis in a variety of animals, i.e. rats, mice, dogs and Syrian hamsters Can induce acute pancreatitis by a number of injection routes, i.e. intravenous, subcutaneous or intraperitoneal; the preferred method is intravenous route Allows accurate control of the infusion rate, thereby enabling control of the timing and severity of acute pancreatitis Useful for studying cell biology, gut endocrine interactions such as secretin and CCK levels, pathogenesis of acute pancreatitis-related pulmonary pathology, systemic disease manifestation, and healing and regeneration of damaged tissue after the toxic substance has been discontinued Relatively simple Inexpensive to perform	Only mild acute pancreatitis develops Negligible mortality High variability in the course and severity of underlying acute pancreatitis and thus unsuitable for controlled studies	Pulmonary injury in rats resembles the early stages of the adult respiratory distress syndrome in human Structural changes of acinar cells are similar to human acute pancreatitis Specific changes to intracellular membrane systems of acinar cells resemble human acute pancreatitis Simulates acute pancreatitis induced by Trinidadian scorpion toxin or anti-cholinesterase insecticide poisoning in humans	30,31,32,33,34
Alcohol-induced	Useful for studying changes to pancreatic blood flow and the microcirculation, the effect on pancreatic acinar damage by alcohol-related free oxygen radical generation, metabolites and the effect on pancreatic regeneration Has been used in several animal models, i.e. rats, cats and dogs Various route of ethanol administration, i.e. intravenous, oral and direct intragastric instillation Relatively simple Cheap to perform Selectively lessens pancreatic blood flow and microcirculation Gene knockout animals may be used to determine the effect of genetic factors on the development of acute alcohol-related pancreatic injury	Animal models of pancreatitis, induced by acute ethanol application alone, have been difficult to produce significant pancreatic damage, and thus require prior sensitization with other agents Lack of reproducibility	Lack of correlation with the clinical situation	50,53,56,57,60,61,62,63,64,65,66
Immune-mediated	Possible application in the field of drug- or toxin-induced acute pancreatitis	Challenging to set up in laboratory Time-consuming Limited reproducibility Costly High early mortality rate, difficult for studying pathogenesis or treatment options Development of secondary diabetes due to the involvement of the islets of Langerhans	Clinical relevance uncertain	72,73,76,77,78,79
Diet-induced	Simplest method to study acute haemorrhagic pancreatitis Well-established Cheap High reproducibility No surgical procedure involved Mortality rate can be controlled at any desired level between 0% and 100% by modifying feeding protocol Useful for studying the pathophysiology for acute pancreas and potential experimental treatment by measuring survival, biochemistry, histology, changes in haematocrit, pH and blood gases Produces haemorrhage and necrosis with a lethal course Inflammatory lesions are homogeneously distributed	Species-specific; may only be used in mice, whose small size causes technical difficulties Sex-specific; female mice Variable onset of acute pancreatitis Requires careful monitoring to ensure that intake of the CDE diet is the same in different experimental groups	Produces severe necrotizing that approximates human pancreatitis Gross and histological appearance of the pancreatic and peripancreatic inflammation, and clinical and biochemical course of diet-induced pancreatitis, resemble the human disease Ascites, acidosis, hypoxia and hypovolaemia similar to human acute pancreatitis	82,84
Gene knockout	Useful for studying the function or effect of a specific gene of interest Avoids the use of pharmacological manipulations that often cause side effects	Time-consuming Expensive Complex Altering the specific gene from the time of its conception could mean that other protein expressions may result to compensate for the mutation Mutation may stimulate unforeseen phenotypic changes if a gene is expressed in different tissues Expression of two genes may overlap and the alteration in a single gene might mask an abnormal phenotype	Extrapolation of experimental data to humans is difficult	90,91,92,93,94,95,96,97,98,99,101,102,103,104,105,106,107
L-arginine (Arg)	High reproducibility Ability to achieve selective dose-dependent pancreatic acinar cell necrosis Suitable for investigating the early and late phases of acute pancreatitis Useful for investigating the insulo-acinar axis, extrapancreatic organ damage and its mechanisms	Long-term administration of Arg produces chronic pancreatitis induction	In a clinical situation, the circulatory, pulmonary, renal and hepatic failure (multi-organ failure) significantly affects the morbidity and mortality of acute pancreatitis	189,199,200,201,202,203