Abstract
Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.
Highlights
Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas
Wildtype mice as well as Cathepsin G (CTSG) deficient animals show a clear positive signal for Neutrophil cytosolic factor 1 (NCF-1) (p47-phox) or NCF-2 (p67-phox) in infiltrating neutrophils (Fig. 4d). These results indicate that the course and severity of pancreatitis do not depend on CTSG expression in mice, despite the transient decrease of neutrophil invasion into the pancreas seen at 8 hours (Fig. 3)
Trypsinogen activation occurs in macrophages that harbor cathepsin B (CTSB) and ingest acinar cell components including trypsinogen once they have infiltrated the pancreas[17]
Summary
Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Intracellular digestive protease activation is considered to initiate acute pancreatitis followed by an infiltration of inflammatory cells into the pancreas which exacerbates the disease. It could be shown that cathepsin C can modulate the severity of pancreatitis, not by participating in intra-acinar cell zymogen activation but by interfering with the infiltration of neutrophil granulocytes into the pancreas. CTSG reduces invasion of neutophil granulocytes this effect was not sufficient to decrease the severity of acute pancreatitis, giving it an inferior role to neutrophil granulocyte enzymes such as PNM elastase. These results suggest only a subordinate role of CTSG in progression of acute pancreatitis
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