OncoWuXi Express: Pancreatitis Animal Models

OncoWuXi Express will continue to keep you informed about updates to our online tumor model database (OncoWuXi Database), as well as our recent progress in cancer and autoimmune research. In this issue, we showcase various induced acute and chronic pancreatitis models and the evaluation of anti-pancreatic drug efficacy.

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Introduction:

Pancreatitis is one of the main diseases leading to gastroenterological hospitalizations, with a high incidence and mortality rate, thus resulting in a significant socioeconomic burden. Pancreatitis is mainly divided into two types:

Acute Pancreatitis (AP): The disease progresses rapidly and is often caused by gallstones and alcohol consumption. Its characteristic is autodigestion of the gland caused by intra-acinar activation of pancreatic enzymes (Figure 1), leading to pancreatic edema, hemorrhage, and necrosis, and possibly inducing multiple organ injuries ^{[1, 2]}.
Chronic Pancreatitis (CP): Chronic pancreatitis is typically caused by repeated episodes of acute pancreatitis leading to pancreatic atrophy or fibrosis, which subsequently results in irreversible structural and functional damage to the pancreas ^[3].

Currently, the treatment goals for pancreatitis mainly include alleviating pain, removing the cause, improving pancreatic secretion function, and preventing complications. Over the past few decades, due to changes in dietary habits and lifestyles, such as alcohol consumption, obesity, and increased risk factors for metabolic syndromes, the incidence of pancreatitis has significantly risen. However, existing treatments may cause side effects such as allergies and gastrointestinal injuries. Therefore, there is an urgent need for more effective treatments.

Figure 1. Pathogenesis of Acute Pancreatitis ^[1]

To aid in the development of new drugs for the prevention and treatment of pancreatitis, WuXi Biology has successfully established various acute and chronic pancreatitis models in mice using methods such as caerulein, arginine, sodium taurocholate (NaT), and pancreatic duct ligation (PDL) (Figure 2).

Figure 2. Pancreatitis Animal Models at WuXi Biology

Case Study: Caerulein induced acute pancreatitis animal model

Caerulein is a cholecystokinin (CCK) receptor agonist, and intraperitoneal injection of caerulein is one of the common methods for establishing an acute pancreatitis animal model ^[4]. Our team successfully developed a mouse model of acute pancreatitis induced by caerulein and treated the mice with the CCK receptor antagonist devazepide. The level of pancreatic injury and repair in mice was evaluated by detecting and analyzing the mouse pancreas/body weight ratio, serum amylase, serum lipase, and histopathological changes.

The experimental results showed that compared with the control group (Sham), the model group (treated with Vehicle) mice showed tissue edema in the pancreas, a significant increase in the pancreas/body weight ratio, and a significant increase in the expression of serum amylase and lipase. Devazepide treatment significantly reversed the upregulation of the pancreas/body weight ratio, serum amylase, and lipase in the model mice caused by caerulein (Figure 3). Consistent with the above changes, H&E staining results showed that the pancreatic tissue of the model group mice was significantly damaged, with interstitial edema, acinar necrosis, scattered distribution of inflammatory cells, pancreatic hemorrhage, and tissue structure disorder observed. Devazepide treatment effectively reversed the pancreatic tissue damage caused by caerulein (Figure 4).

Figure 3. Pancreas/body weight ratio and serum amylase, lipase expression levels in mice

Figure 4. Histopathological examination results of pancreatic tissue in mice

Summary:

These results indicate that the mouse model of acute pancreatitis induced by caerulein can effectively simulate the pathological characteristics of acute pancreatitis. This model not only replicates the key pathological changes of clinical acute pancreatitis, but it is also efficient and repeatable. This model can be applied to preclinical drug screening research, providing a reliable experimental platform for new drug development and helping to evaluate the effectiveness and safety of potential therapeutic drugs.

References

[1] Saluja A, Dudeja V, Dawra R, Sah RP. Early Intra-Acinar Events in Pathogenesis of Pancreatitis. Gastroenterology. 2019 May;156(7):1979-1993. doi: 10.1053/j.gastro.2019.01.268. Epub 2019 Feb 15.

[2] Szatmary P, Grammatikopoulos T, Cai W, Huang W, Mukherjee R, Halloran C, Beyer G, Sutton R. Acute Pancreatitis: Diagnosis and Treatment. Drugs. 2022 Aug;82(12):1251-1276. doi: 10.1007/s40265-022-01766-4.

[3] Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet. 2020 Aug 15;396(10249):499-512. doi: 10.1016/S0140-6736(20)31318-0.

[4] Zheng Y, Sun W, Wang Z, Liu J, Shan C, He C, Li B, Hu X, Zhu W, Liu L, Lan F, Jiang C, Zhao C, Li X, Sun N. Activation of Pancreatic Acinar FXR Protects against Pancreatitis via Osgin1-Mediated Restoration of Efficient Autophagy. Research (Wash D C). 2022 Nov 2;2022:9784081. doi: 10.34133/2022/9784081.

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