Pancreatitis animal models are used to simulate acute acinar cell injury, abnormal pancreatic enzyme activation, inflammatory cascade responses, microcirculatory disturbance, and chronic fibrotic progression. Model selection should be based on the research focus, such as acute pancreatitis (AP), severe necrotizing pancreatitis, chronic pancreatitis (CP), or a specific etiology. Cerulein, sodium taurocholate, L-arginine, pancreatic duct ligation, alcohol combined with a high-fat diet, and genetic background models correspond to different pathological entry points and cannot simply replace one another.

Keywords: pancreatitis model; animal modeling; acute pancreatitis; chronic pancreatitis; cerulein; sodium taurocholate; L-arginine; pancreatic enzyme activation; pancreatic fibrosis

1 Experimental Positioning of Pancreatitis Models

1.1 Core Objectives of Model Establishment

(1) Acute acinar cell injury

Acute pancreatitis models focus on acinar cell edema, vacuolization, premature pancreatic enzyme activation, inflammatory cell infiltration, and increased serum amylase and lipase levels. The cerulein model is suitable for studies of mild to moderate edematous AP. The sodium taurocholate retrograde pancreaticobiliary duct injection model is more suitable for biliary and necrotizing AP research. The L-arginine model is commonly used to evaluate more severe acinar cell injury, oxidative stress, and systemic inflammatory responses.

(2) Chronic inflammation and fibrotic progression

Chronic pancreatitis models focus more on acinar atrophy, ductal reaction, pancreatic stellate cell activation, collagen deposition, and decreased exocrine function. Repeated cerulein stimulation, pancreatic duct ligation, and alcohol combined with a high-fat diet can all be used for CP research, but their emphases differ. The repeated cerulein model emphasizes recurrent inflammatory injury, the pancreatic duct ligation model emphasizes duct obstruction and fibrosis, and the alcohol combined with high-fat diet model is closer to metabolism- and lifestyle-related etiologies.

(3) Etiological and molecular mechanism simulation

Different models correspond to different etiological clues. Biliary AP research can use the sodium taurocholate model; hereditary pancreatitis mechanisms can use PRSS1 mutation- or SPINK1 deficiency-related models; alcoholic CP research is better suited to alcohol exposure combined with a high-fat diet or repeated stimulation models. If the research focus is NF-κB, NLRP3, TGF-β/Smad, autophagy, or oxidative stress, the model should be selected according to the disease stage in which the pathway is involved, rather than only according to modeling convenience.

1.2 Experimental Animals and Model Selection

Mice and rats are the most commonly used animals in pancreatitis research. Mice are suitable for mechanistic studies, genetically modified models, and multi-index molecular detection. Rats are suitable for surgical manipulation, pancreaticobiliary duct injection, tissue sampling, and serum biochemical testing. When selecting a model, disease type, lesion severity, observation window, mortality risk, operational stability, and compatibility with evaluation indicators should all be considered.

Table 1 Selection Logic of Pancreatitis Animal Models

1.3 Common Inducing Factors and Modeling Positioning

Modeling reagents and inducing factors should be placed at the front end of model selection to explain the etiological background and applicable research directions simulated by different models. Evaluation products should be placed in the latter part of the article to explain how injury, inflammation, pancreatic enzyme activation, and histopathological changes are detected after model establishment.

Table 2 Common Inducing Factors and Modeling Positioning in Pancreatitis Animal Models

2 Chemically Induced Models of Acute Pancreatitis

2.1 Cerulein-Induced Model

(1) Model mechanism

Cerulein is a cholecystokinin analog that can overstimulate acinar cell secretory responses, causing abnormal zymogen granule trafficking, disrupted intracellular calcium signaling, and premature trypsinogen activation. This model usually shows pancreatic edema, acinar cell vacuolization, inflammatory cell infiltration, and increased serum amylase and lipase levels. It is suitable for studying early inflammatory amplification, acinar cell injury, and drug protective effects in AP.

(2) Experimental interpretation

The advantages of the cerulein model are good reproducibility, relatively stable operation, and low mortality. Its limitation is that the lesions are mostly edematous and mild to moderate, while necrosis and multi-organ injury are less prominent than in sodium taurocholate or L-arginine models. If used for drug screening, serum enzymology, pancreatic wet/dry weight ratio, HE score, MPO activity, and inflammatory factors should be evaluated together, rather than judging model severity only by increased amylase.

2.2 Sodium Taurocholate Retrograde Pancreaticobiliary Duct Injection Model

(1) Model mechanism

The sodium taurocholate model simulates bile reflux, pancreaticobiliary duct hypertension, and bile acid toxic injury through retrograde pancreaticobiliary duct injection. Bile acids can directly damage acinar cells and ductal epithelium, causing calcium overload, mitochondrial dysfunction, abnormal pancreatic enzyme activation, and tissue necrosis. This model is commonly used in biliary AP, severe AP, and necrotizing pancreatitis research.

(2) Experimental interpretation

This model produces severe lesions and can form marked edema, hemorrhage, necrosis, and systemic inflammatory responses, but it is highly sensitive to surgical technique, injection location, injection speed, and animal condition. Studies should focus on tissue necrosis extent, inflammatory infiltration, NLRP3 inflammasome, IL-1β, MPO activity, and remote organ injury. If the experimental goal is mild to moderate AP or early drug screening, this model may be too strong and should be used cautiously.

2.3 L-Arginine-Induced Model

(1) Model mechanism

High-load L-arginine can induce acinar cell metabolic stress, mitochondrial injury, and increased oxidative stress, thereby causing pancreatic parenchymal injury and inflammatory responses. This model is commonly used in studies of severe AP, pancreatic necrosis, systemic inflammatory response, and remote organ injury, and is especially suitable for observing the relationship between pancreatic injury and responses in the liver, lung, kidney, and other organs.

(2) Experimental interpretation

The lesion severity and animal tolerance of the L-arginine model are strongly affected by administration conditions, animal strain, body weight, and nutritional status. Evaluation should simultaneously detect pancreatic histology, serum enzymology, LDH, oxidative stress indicators, and multi-organ injury indicators. If the research focus is biliary etiology or ductal hypertension mechanisms, this model has insufficient etiological correspondence.

2.4 Choline-Deficient Ethionine-Supplemented Diet Model

The choline-deficient ethionine-supplemented diet model can induce severe acute pancreatic injury and systemic inflammatory responses and is commonly used in nutrition/metabolism disorder-related AP research. This model may show pancreatic necrosis, elevated inflammatory factors, and high mortality risk, but it is sensitive to animal sex, age, and feeding status. Because the model is relatively severe, ethical endpoints and observation windows should be clearly defined in the experimental design.

Table 3 Comparison of Acute Pancreatitis Models

3 Chronic Pancreatitis Models

3.1 Repeated Cerulein Stimulation Model

(1) Model mechanism

Repeated cerulein stimulation causes acinar cells to repeatedly undergo injury, inflammatory infiltration, and repair. Long-term stimulation leads to acinar atrophy, ductal reaction, stellate cell activation, and collagen deposition. This model is commonly used to study early inflammation-to-fibrosis transition in CP and is also suitable for evaluating anti-inflammatory and anti-fibrotic candidate drugs.

(2) Experimental interpretation

The key to the repeated cerulein model is not the severity of a single acute injury, but the accumulation of fibrosis after repeated injury. Masson staining, Sirius Red staining, α-SMA, Collagen I/III, TGF-β, and Smad3 should serve as core evaluation indicators. If only amylase and lipase are detected, it is difficult to demonstrate whether CP modeling is sufficient.

3.2 Pancreatic Duct Ligation Model

(1) Model mechanism

Pancreatic duct ligation blocks pancreatic juice drainage, causing increased ductal pressure, acinar atrophy, inflammatory cell infiltration, and fibrosis formation. This model is suitable for simulating duct obstruction-related CP and pancreatic parenchymal structural remodeling, and is commonly used to study acinar-to-ductal metaplasia, stellate cell activation, and extracellular matrix deposition.

(2) Experimental interpretation

The evaluation focus of the pancreatic duct ligation model includes duct dilation, acinar atrophy, fibrosis extent, and changes in pancreatic tissue structure. This model requires high surgical consistency, and ligation site and postoperative observation time can significantly affect results. If used for drug intervention, the effects of drugs on inflammation, fibrosis, and tissue atrophy should be distinguished, rather than using pancreatic weight change as the only endpoint.

3.3 Alcohol Combined with High-Fat Diet Model

(1) Model mechanism

Alcohol exposure can increase ROS through acetaldehyde generation, CYP2E1 activation, and mitochondrial injury. A high-fat diet can enhance lipotoxicity, inflammatory responses, and endoplasmic reticulum stress. Their combination can promote acinar cell injury, stellate cell activation, and chronic fibrosis, making it more suitable for studying alcoholic or metabolism-related CP.

(2) Experimental interpretation

This model usually progresses slowly, and alcohol exposure alone may not reliably produce typical CP lesions. Experiments should focus on ALDH, ALDH2, CYP2E1, CHOP, GRP78, MDA, GSH, and fibrosis indicators. If the research goal is a clear fibrosis endpoint, it is often necessary to combine this model with repeated inflammatory stimulation or other injurious factors.

3.4 Genetic Background Models

PRSS1 mutation models can be used to simulate hereditary pancreatitis related to abnormal trypsinogen activation, while SPINK1 deficiency models can be used to study pancreatic enzyme imbalance caused by decreased trypsin inhibition capacity. Some models can also be combined with CFTR, CPA1, autophagy-related genes, or inflammatory pathway genes to study genetic susceptibility. The advantage of genetic background models is clear mechanism, while their limitation is a relatively single etiology and difficulty in fully covering human CP caused by the combined effects of alcohol, biliary factors, metabolism, genetics, and environmental factors.

Table 4 Comparison of Chronic Pancreatitis Models

4 Mechanistic Evaluation of Pancreatitis Models

4.1 Pancreatic Enzyme Activation and Acinar Cell Injury

Premature trypsinogen activation is an important step in early AP injury. Cathepsin B can promote abnormal intracellular activation of trypsinogen, leading to acinar cell autodigestion, cell membrane injury, and initiation of inflammatory responses. Trypsin activity, TAP, trypsinogen, Cathepsin B, intracellular calcium signaling, and acinar cell vacuolization can serve as evaluation indicators for this step.

4.2 Inflammatory Cascade Response

After NF-κB pathway activation, the release of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6 is promoted, further recruiting neutrophils and macrophages. In severe AP, the NLRP3 inflammasome, Caspase-1, and IL-1β maturation are closely associated with necrotizing inflammation and systemic inflammatory responses. MPO activity can be used to reflect the degree of neutrophil infiltration.

4.3 Oxidative Stress and Microcirculatory Disturbance

ROS accumulation, mitochondrial dysfunction, and reduced antioxidant capacity can aggravate acinar cell injury. Increased MDA and decreased SOD and GSH are commonly used to assess oxidative injury. In necrotizing AP, vascular endothelial injury, platelet activation, local ischemia, and microcirculatory disturbance should also be considered. When necessary, tissue perfusion, endothelial injury, and coagulation-related indicators should be detected together.

4.4 Chronic Fibrosis and Stellate Cell Activation

The core pathological changes of CP are acinar atrophy, ductal reaction, and fibrosis. After activation, pancreatic stellate cells express α-SMA and secrete Collagen I, Collagen III, and Fibronectin. The TGF-β/Smad3 pathway is an important regulatory axis in fibrosis formation. When evaluating CP models, histological staining and fibrosis-related molecular indicators should be used together to avoid judging chronic lesions only by inflammatory factors.

Table 5 Common Evaluation Indicators for Pancreatitis Models

5 Supplementary Applications of In Vitro and Ex Vivo Models

5.1 Acinar Cell Injury Models

AR42J cells and primary pancreatic acinar cells can be used to simulate acinar cell stress, pancreatic enzyme activation, abnormal calcium signaling, oxidative stress, and inflammatory factor release. Cell models are suitable for preliminary mechanistic screening, such as NF-κB, NLRP3, autophagy, mitochondrial injury, and candidate drug protective effects.

Cell models cannot fully simulate pancreatic tissue structure, ductal pressure, immune cell infiltration, and microcirculatory disturbance. Therefore, in vitro results should be used as mechanistic clues, while key conclusions still need validation by animal models and histological results.

5.2 Pancreatic Stellate Cell Models

Pancreatic stellate cells are suitable for studying CP fibrosis mechanisms. TGF-β stimulation, alcohol metabolites, or inflammatory factors can induce stellate cell activation, characterized by increased α-SMA, increased collagen secretion, and enhanced extracellular matrix deposition. This model is suitable for preliminary screening of anti-fibrotic drugs, but cannot independently represent the complete CP disease course.

5.3 Pancreatic Tissue Slices and Organoid Models

Ex vivo pancreatic tissue slices can preserve partial tissue structure and cell-cell interactions, making them suitable for observing short-term effects of drugs on acinar cells, ductal reactions, and inflammatory signaling. Pancreatic organoids are more suitable for studying ductal epithelium, regeneration and repair, and genetic background-related mechanisms, but have limited ability to simulate inflammatory infiltration and blood flow factors.

Table 6 Application Positioning of In Vivo and In Vitro Models in Pancreatitis Research

6 Related Product and Material Selection

Table 7 Products Related to Pancreatic Injury and Serum Enzymology Evaluation

Table 8 Products Related to Trypsin Activation and Cathepsin B Mechanism Evaluation

Table 9 Supplementary Evaluation Products for Alcohol-Related Chronic Pancreatic Injury

Table 10 Products Related to Pancreatic Histopathological Evaluation

7 Common Questions

7.1 How Should the Cerulein Model and Sodium Taurocholate Model Be Selected in Acute Pancreatitis Research?

The cerulein model is suitable for mild to moderate AP, acinar cell injury, and early inflammatory mechanism research. It has relatively good model stability and is suitable for preliminary drug screening. The sodium taurocholate model is more suitable for biliary AP, necrotizing AP, and severe inflammatory response research, but has higher operational difficulty and mortality risk. If the research goal is inflammatory pathways or preliminary screening of protective effects, the cerulein model is more appropriate. If the research focuses on necrosis, microcirculatory disturbance, or severe AP, the sodium taurocholate model should be selected.

7.2 Can Chronic Pancreatitis Models Be Evaluated Only by Serum Amylase and Lipase?

This is not recommended. Serum amylase and lipase mainly reflect acute acinar injury and have limited explanatory power for CP fibrosis, acinar atrophy, and decreased exocrine function. CP models should focus on histological staining, α-SMA, Collagen I/III, TGF-β/Smad, hydroxyproline, and ductal reaction indicators.

7.3 Why Does the Alcohol Combined with High-Fat Diet Model Often Need Additional Stimulation?

Alcohol exposure or a high-fat diet alone may sometimes induce only metabolic stress and mild inflammation, and may not reliably form typical CP fibrosis. Combining repeated inflammatory stimulation or other injurious factors can enhance acinar cell injury, stellate cell activation, and collagen deposition, making it more suitable for studying chronic progression of alcoholic or metabolism-related CP.

7.4 How Should Inflammatory Indicators and Histological Results Be Interpreted Together in Pancreatitis Models?

Elevated inflammatory factors indicate that inflammatory responses are activated, but they cannot independently prove the extent of pancreatic tissue injury. In AP models, TNF-α, IL-1β, IL-6, and MPO should be interpreted together with HE score, necrosis extent, and serum enzymology. In CP models, fibrosis staining and ECM indicators should be further combined to determine the degree of chronic remodeling.

7.5 What Is the Significance of TAP Detection in AP Models?

TAP, or trypsinogen activation peptide, reflects the degree of abnormal trypsinogen activation. Compared with serum amylase detection alone, TAP is closer to pancreatic enzyme activation and acinar autodigestion mechanisms, and is suitable for early mechanistic evaluation in AP models such as cerulein, sodium taurocholate, and L-arginine models.

Pancreatitis animal models should be selected according to AP, severe AP, CP fibrosis, or specific etiologies. Chemical models are suitable for acute injury and inflammatory mechanism research. Surgical and dietary models are suitable for chronic progression and fibrosis research. Genetic background models are used to analyze genetic susceptibility and key molecular pathways.

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