Abstract

Animals that spontaneously show phenotypic characteristics similar to those seen in human disorders, or animals subjected to various procedures that empirically induce symptoms resembling human clinical symptoms, can be used as models for human disorders. Such animal models are mainly used to clarify the mechanisms of diseases or to evaluate possible treatments. An understanding of the mechanisms involved in animal models should help researchers to uncover the mechanisms underlying the corresponding human disorders. Moreover, successful treatment of the symptoms in animal models suggests that similar treatment might be effective in humans. In any event, it is important to consider fully the anatomical and physiological differences between humans and animals. Also of importance is the choice of a suitable model(s) - it is often the case that more than one model is needed for clarification of a human disorder. As regards pancreatitis, the mechanisms involved are very complex in humans, and animal models can reflect only a part of them. Nevertheless, animal models may provide useful information, especially when they are carefully selected in accordance with the experimental purpose or design. Therefore, researchers need to have a sufficient knowledge of the characteristics of the various models. Pancreatic fibrosis was spontaneously observed in WBN/Kob rats, ALY mice and OLETF rats. Experimentally induced pancreatic fibrosis models include caerulein- or dibutyltin dichloride-treated rats and a pancreatic duct-ligation model. We describe the pancreatic histology observed in our experiments with various animal models.

Copyright © 2007 S. Karger AG, Basel

Numerous animal models of pancreatitis in humans have been established, but the complexity of the human disease, especially chronic pancreatitis, means that it is difficult to extrapolate the findings in such models to the human situation [1]. The differences between these animal models and humans with pancreatitis are probably largely due to anatomical and physiological species differences. On the other hand, there seems little doubt that animal models are useful, since studies using them often help to clarify the mechanisms at work in human disorders, or to define medical guidelines for treatments [2-10]. For the proper utilization of animal models in studies on human pancreatitis, it is first necessary to know the characteristics of acute and chronic pancreatitis.

In general, acute pancreatitis is classified into alcoholic, biliary, idiopathic, and other types, in accordance with the major causes [11-14]. The alcoholic and biliary types are closely associated with alcohol abuse and biliary abnormalities, respectively [15-17]. On the other hand, idiopathic pancreatitis, which occurs at high incidence, may be caused by anatomical abnormalities, circulatory disorders, metabolic disturbances etc. [18, 19]. Ductular, lymphogenous, hematogenous, nervous, metabolic and other factors are considered to be associated with the acute disease, and to interact with each other [20-23]. Several theories to explain the formation or progression of acute pancreatitis have been proposed, including the common channel theory [24-27] and the obstruction-hypersecretion theory [28-30]. In the common channel theory, the underlying condition is thought to be the existence of an anatomical channel between the common bile duct and the main pancreatic duct. This channel permits the reflux of bile into the pancreatic duct, resulting in activation of pancreatic enzymes [29, 31-34], and self-digestion of pancreatic tissues ensues. Disturbance of the outflow through aberrant pancreatic secretion also induces acute pancreatitis [35, 36]. On the other hand, the obstruction-hypersecretion theory is better suited to explain the mechanism of alcoholic pancreatitis [28, 30]. This theory has been further subdivided into the big duct theory [29, 31] and the small duct theory [34, 37]. According to the former, edema or spasmus of the duodenal papilla occurs after alcohol ingestion, constricting the orifice of the pancreatic duct, while according to the latter, alcohol-induced protein plugs occlude the small pancreatic ducts. As suggested above, more than one mechanism may exist, with interaction between them. In general, acute pancreatitis is reversible, except for severe cases, which may have a fatal progression [38-40].

Unlike most acute pancreatitis, chronic pancreatitis is irreversible and the pathological condition gradually progresses [41-45]. The causal factors for chronic pancreatitis are thought to be the same as those for acute pancreatitis, i.e. alcoholic, biliary, idiopathic, and so on [28, 34, 40, 46-48]. Moreover, some cases evolve from acute pancreatitis [38, 39]. It is noteworthy that irreversible fibrosis is a major characteristic of chronic pancreatitis [43, 44, 49, 50]. Fibrous elements expand into the periductular, interlobular and intralobular areas to various extents. The characteristics of fibrous spreading, the kinds of inflammatory cells, and the existence of cysts, protein plaques or calculus are used for classification [28, 51-53]. Autoimmune pancreatitis, a concept proposed in recent years, is also a type of chronic pancreatitis with the involvement of immune mechanisms [54]. In such cases, nodular lesions consisting of accumulated lymphocytes are often observed around the pancreatic ducts [51, 55-58]. If the mechanisms of the various forms of pancreatitis, including the autoimmune type, are to be established in greater detail, animal models must be further categorized with respect to their detailed characteristics, so that they can be utilized more effectively. It should also be noted that chronic pancreatitis is often reactivated [40, 59, 60]. The necrosis-fibrosis sequence theory has been proposed to explain the mechanism of reactivation. This theory claims that pancreatitis-induced fatty necrosis triggers stenosis or occlusion of the pancreatic ducts, resulting in elevation of the intraductal pressure and leakage of pancreatic fluid into the peripheral tissue, leading to further necrosis of the adipose tissues [28, 59, 61].

In summary, numerous animal models have been used in studies of pancreatitis, and each of them has particular pathological features, which cannot necessarily be extrapolated to pancreatitis in humans. Therefore, it is critically important to utilize appropriate models depending on the particular research aim in each case.

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