The development of fibrosis in a novel model of chronic pancreatitis is mediated by complement factor C5

Aim: Chronic pancreatitis is accompanied with the loss of exocrine function and the development of fibrosis. We investigate the effect of complement factor 5 (C5) in a newly established murine model of chronic pancreatitis and compared it to repetitive caerulein injections.

Methods: Chronic pancreatitis was induced in C5+/+ and C5–/– mice by ligation of the pancreatic duct in the body of the organ (leaving the pancreatic head unaffected) and a single supramaximal injection of caerulein. Animals were sacrificed 21 days after ligation. As a second model we used supramaximal caerulein stimulation twice a week over 10 weeks. We used serum amylase and lipase as markers for pancreatic damage, collagen as a marker for fibrosis and histology for morphological evaluation. Isolated pancreatic stellate cells were stimulated with C5a in vitro.

Results: Pancreatic damage in the initial phase of the disease was comparable in both animal strains. In contrast to the early phase, C5–/– mice displayed a reduced rate of pancreatic fibrosis in both models. Histology showed decreased collagen I and α smooth muscle actin (αSMA) staining. Also the amount of Ki67 positive cells was decreased in C5-deleted animals. In pancreatic tissue of wild type animals with chronic pancreatitis C5a receptor and αSMA positive stellate cells were observed by fluorescence staining. Isolated pancreatic stellate cells could be activated with C5a showing increased αSMA expression and decreased proliferation.

Conclusion: C5 is an important regulator for the development of pancreatic fibrosis during chronic pancreatitis, but does not contribute to the severity of the disease during the acute phase. C5a has direct effects on fibrosis by activating stellate cells.