Einfluss von SPARC auf den Schweregrad der akuten Pankreatitis in einem genetischen Mausmodell

by Laurin Christian Michael Wolf
Doctoral thesis
Date of Examination:2024-06-21
Date of issue:2024-06-21
Advisor:Dr. Albrecht Prof Neeße
Referee:Dr. Albrecht Prof Neeße
Referee:Prof. Dr. Annalen Bleckmann
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-10559

 

 

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Abstract

English

Acute pancreatitis (AP) is a common but severe inflammatory disease that develops upon unspecific acinar cell damage which, via intraparenchymal activation of digestive enzymes, can result in multi organ failure and death. Even though countless well-designed studies have shed light into the pathogenesis of AP, it is still challenging to predict disease severity early during the disease course or find a pharmaceutical target that can improve the clinical outcome. SPARC is a matricellular protein that modulates matrix composition and thereby influences a variety of cell-matrix interactions, including collagen deposition, distribution of cytokines, angiogenesis and inflammatory processes. Recently, serum SPARC-levels were suggested as an independent predictor of AP and disease severity. Therefore, the present experimental study aimed to characterize intrapancreatic SPARC expression via immunohistochemistry and immunoblotting during Caerulein-induced pancreatitis using a genetically engineered mouse model carrying a germline SPARC knockout. Disease severity was compared using serum analysis as well as a histological scoring system that included well known hallmark features of AP. Primary cell isolation was used to assess secretory properties of acinar cells in the presence and absence of a functional SPARC gene. Although SPARC is not expressed in physiological conditions in the pancreas, expression is rapidly induced during early AP. While acinar cells showed no SPARC expression, activated PSCs as well as infiltrating immune cells are the main source of SPARC during early pancreatitis. SPARCWT mice showed significantly elevated levels of serum amylase levels during early phase of AP. However, primary isolated acinar cells showed comparable secretory capabilities when treated with caerulein in in vitro experiments. During early AP, knockout of SPARC alleviated vacuolization of acinar cells, infiltration of immune cells as well as acinar cell apoptosis and necrosis. However, these differences were equalized in later stages. Taken the findings together, SPARC expression was linked to a more severe course of pancreatitis in early stages. The present study indicates that the expression of matricellular protein SPARC, by activated PSC and immune cells play a regulatory role during early stages of AP that affects disease severity. Consequently, SPARC should be considered as a potential therapeutic target in AP.
Keywords: acute pancreatitis; SPARC; caerulein-induced pancreatitis; ECM; matricellular proteins
Schlagwörter: SPARC; akute Pankreatitis; extrazelluläre Matrix; Caerulein-induzierte Pankreatitis; matrizelluläre Proteine
 
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