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Decreased type IV collagenase activity in experimental pancreatic fibrosis
E K Ng1, B L Barent, G S Smith
1Department of Surgery, Lakeside DVA Medical Center, Chicago, Illinois, USA.
Background:
Severe hyperstimulation and duct obstruction pancreatitis (SHOP) is characterized by pancreatic fibrosis and loss of acinar cell mass. MMP-2 and MMP-9 are type IV collagenases and gelatinases. We hypothesized that fibrosis results from disruption of the normal collagen homeostasis and that altered activity of the type IV collagenases may contribute to pancreatic fibrosis in SHOP.
Methods:
SHOP rats (n = 15) were prepared with pancreatic duct obstruction and cerulein (50 microg/kg/d, ip) hyperstimulation. Pancreas from unoperated control (n = 8), 48 h SHOP (n = 8), and 96 h SHOP (n = 7) rats was harvested, homogenized, and assayed for protein concentration (BCA method). Type IV collagenase (MMP-2 and MMP-9) expression was measured by zymography using gelatin as substrate. Type IV collagenase activity was quantified with a fluorescence assay.
Results:
Expression of the active form of MMP-9 decreased while latent MMP-9 and active and latent MMP-2 increased on gelatin zymography. Activity of type IV collagenases (MMP-2 and MMP-9) progressively decreases with SHOP injury. The differences between expression and activity are likely due to posttranslational regulators such as MT-MMPs and TIMPs.
Conclusions:
Collagenase expression and activity are decreased in the SHOP model of pancreatitis, suggesting a decrease in the homeostatic mechanisms for type IV collagen in the extracellular matrix. Therefore, early fibrosis in the SHOP model is, at least in part, due to alterations in collagen homeostasis and not simply increased collagen production.