Acute pancreatitis: Murine model systems unravel disease‐modifying genes with potential implications for diagnostics and patient stratification

Acute pancreatitis is a devastating inflammatory disease within the pancreas. In most cases, bile stones or excessive alcohol consumption trigger a complex cascade of processes, ultimately resulting in uncontrolled zymogen activation, destruction of pancreatic tissue, infiltration of immune cells, and finally, an affection of the whole body. ¹ , ² While regeneration of the pancreas is observed in mild cases, severe forms lead to hospitalization and up to 43% mortality in the case of organ failure and infected necrotic areas. ² , ³ The complicating disease course arises from necrosis and erosion of neighboring tissue with subsequent bleeding, infection, and affection of the cardiovascular system resulting in potential organ failure, among others. ² , ³ The clinical presentation of mild and severe forms is evidenced at disease onset by sudden, strong abdominal pain and unspecific signs such as nausea and vomiting. To ameliorate the prognosis of patients with severe forms, parameters must be determined to differentiate between the two conditions in an early disease stage.

Several scoring systems, such as the APACHE‐II ⁴ or the BISAP score, ⁵ have been implemented in clinical decision‐making to stratify severe from mild forms. However, the accuracy of several scoring systems at disease onset ranges at a maximum of 80%, ² , ⁶ making it challenging to rely solely on them. Instead, a combination of scoring systems, investigation of enzyme levels in the patient's serum (e.g., lipase), and imaging modalities culminate in a decision to strive the treatment according to the grade of pancreatitis. ²

To date, no reliable biomarkers have been identified to stratify patients during disease onset into severe or mild forms. A better understanding of molecular processes and reliable biomarkers to diagnose severe acute pancreatitis conditions early during disease onset may positively impact individual treatment and survival and, thus, is highly relevant.

Murine model systems of acute pancreatitis can help unveil underlying disease mechanisms and molecular programs and unravel potential biomarkers that predict the disease onset and grade. Among others, caerulein‐induced pancreatitis models in mice are well suited to study all relevant aspects (onset, inflammation, regeneration) of this devastating disease. ⁷ After repetitive intraperitoneal injection of the cholecystokinin analog caerulein, dysregulation of enzyme secretion and their subsequent activation results in the onset of acute pancreatitis in mice. ⁷ Acinar cells undergo acinar‐to‐ductal‐metaplasia, immune cells infiltrate the pancreas, and stellate cells become activated to reshape the pancreatic tissue landscape. ⁸ Using such a model, for example, DKK3 (Dickkopf WNT signaling pathway inhibitor 3) was identified as a roadblock to pancreas regeneration after caerulein‐induced pancreatitis. ⁸ Of note, DKK3 was also elevated in serum samples of patients suffering from acute pancreatitis. ⁸ Hence, in general, caerulein‐induced pancreatitis model systems faithfully reflect the human disease processes, at least to a certain degree. ⁹

In a recent study, Ammer‐Herrmenau, Wolf, and colleagues identified secreted protein acidic and rich in cysteine (SPARC) as a disease‐modifying gene in caerulein‐induced acute and chronic pancreatitis. ¹⁰ SPARC functions as a matricellular protein, which remodels the extracellular matrix. ¹¹ In the pancreas, the role of SPARC is elucidated in the setting of pancreatic cancer, where its ablation results in reduced collagen accumulation and subsequent re‐drafting of the tumor microenvironment. ¹² In addition, SPARC seems to be involved in endocrine cell homeostasis. ¹³ Of note, in both settings, SPARC is mainly expressed by the stromal compartment rather than the epithelium. ¹² , ¹³ However, its role in exocrine homeostasis and regeneration from injury remained poorly understood. In the current study, the authors demonstrate that the presence of SPARC rather than its absence results in a higher degree of inflammation, paralleled by more necrotic and apoptotic cells during a caerulein‐induced acute pancreatitis. ¹⁰ In line with previous studies, ¹² , ¹³ the authors describe the expression of SPARC protein within the pancreatic stellate cells rather than acinar cells. ¹⁰ This compartment‐specific expression correlated with higher amounts of fibrosis in chronic pancreatitis. ¹⁰ Hence, besides unraveling the role of one specific protein, the authors highlight the role of pancreatic stroma for organ homeostasis and regeneration from injury.

The results of this study may prove valuable from two different facets. On the one hand, SPARC may be validated in clinical trials as a biomarker to predict the severity of acute pancreatitis. On the other hand, highlighting the relevance of the stromal compartment for regeneration of the pancreas may urge future investigations to specifically target the stroma for enhancement of the regeneration from acute pancreatitis.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.