Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTRtm1HGU) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTRtm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild‐type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK‐induced trypsin activation and necrosis in acini from CFTRtm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTRtm1HGU resulted in increased INF‐γ and IL‐6, but decreased IL‐10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis—mostly via impairing duct cell function and a shift towards a pro‐inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli.
Highlights
Pancreatitis is a common disease, often leading to hospital admission 1 and its underlying genetic susceptibilities are increasingly recognized,[2] in patients with chronic or relapsing forms of pancreatitis
CFTR mutations were originally identified in patients with cystic fibrosis (CF), but later they were found to be associated with male vas deference infertility and chronic or recurrent pancreatitis
The variable extent of pancreatitis that develops in patients with CFTR mutations16-18 is quite distinct from the exocrine pancreatic insufficiency that develops in CF patients and typically arises in subjects without overt impairment of pulmonary function and with preserved exocrine pancreatic function
Summary
Pancreatitis is a common disease, often leading to hospital admission 1 and its underlying genetic susceptibilities are increasingly recognized,[2] in patients with chronic or relapsing forms of pancreatitis. Loss-of-function mutations in the CFTR gene were originally discovered to be associated with cystic fibrosis (CF) in affected patients[15] and later found to play a role in male vas deference infertility and chronic pancreatitis The latter association was initially detected using the original CF-mutation panels,[16,17] subsequently characterized by full exome sequencing, and found to increase the susceptibility for pancreatitis around 2.5-fold to threefold.[18,19] It later became obvious that, unlike in CF, mainly patients with exocrine pancreatic sufficiency and carriers of CFTR mutations with maintained residual CFTR function develop pancreatitis.[20] The question whether and why only some carriers of the more than 1700 known CFTR mutations (around 15% of the population in Western countries carry CFTR mutations) develop pancreatitis, and which cell types known to contribute to the disease pathogenesis are predominantly affected by CFTR impairment, is still under debate.[21] It is further complicated by the fact that the type of mutation,[22] and a number of pleotropic and modifier effects[23] appear to determine the manner and severity by which the pancreas is involved. This occurs independently of acinar cell events, but is due to an impairment of CFTR function in pancreatic duct cells and the immune system
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