The pancreatic stellate cells : the major mediator of pancreatic fibrosis

Shek, Fanny Wai-Tsing (2006) The pancreatic stellate cells : the major mediator of pancreatic fibrosis. University of Southampton, Doctoral Thesis.

Abstract

We set out to examine the role of PSC in pancreatic fibrosis and their relationship with the mediators of extracellular matrix (ECM) regulation.  This work has confirmed that transforming growth factor-β1 (TGF-β1) is a potent profibrogenic stimulant in pancreatic fibrosis with the net production of collagen protein.  PSC are capable of producing this cytokine autonomously.  This is the first study investigating the antifibrotic role of TGF-β3 in pancreatic fibrosis.  TGF-β3 reduced the production of procollagen type I mRNA which was further confirmed by the reduction of total collagen protein synthesis.  These novel findings suggest that TGF-β3 has fibrolytic properties.

Because PSC apoptosis might be of importance in the resolution of pancreatic fibrosis, I also studied another aspect of the PSC behaviour in relation to nerve growth factor (NGF) induced-apoptosis and the survival factors such as nuclear factor κB (NFκB), to further elucidate the role of PSC in the fibrotic process as well as in the recovery process from what is currently deemed end-stage disease of the pancreas.  We have presented reproducible data demonstrating the expression of low affinity NGF receptors (p75) in the fibrotic bands in CP, this being the same area where PSC reside as demonstrated by the co-expression of α-SMA. NGF expression was demonstrated in the stromal regions in CP tissue away from the areas of fibrosis and furthermore, there was a lack of expression of NGF in cultured PSC.  We have shown that NGF significantly increased the rate of apoptosis and by contrast, decreased the proliferation rate of PSC.

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