Chronic pancreatitis fibrogenesis : the role of TGFB pathway inhibitor Smad7 in the fibrosis development

Abstract

Chronic pancreatitis is characterized by progressive inflammation, acinar atrophy and fibrosis. Transforming growth factor-B signaling (TGFB) is the most potent fibrogenic cytokine known, and its increased expression is a common denominator for fibrosis in chronic pancreatitis. Smad7 is induced by the TGFB superfamily members as an intracellular inhibitory feedback antagonizing TGFB signaling.

To investigate the functional role of Smad7 in vivo, we induced chronic pancreatitis by repeated administration of cerulein in mice that are either ubiquitous or conditional deficient of Smad7. Mice with general deficient of Smad7 showed more severe response to chronic pancreatitis induction as indicated by a stronger accumulation of extracellular matrix (ECM), increased levels of inflammatory cells and mesenchymal cells/myofibroblasts. Mice with fibroblasts-specific deficient of Smad7 showed slightly higher fibrotic index but the production of different ECM proteins and the number of fibroblasts and inflammatory cells were not affected, although in vitro studies confirmed increased activation of mutant pancreatic stellate cells. Mice with myeloid cells-specific deficient of Smad7 exhibited fewer number of macrophages and pancreatic stellate cells and less fibronectin deposition, which might be related to the reduced capacity of Smad7 deficient macrophages to support pancreatic stellate cells’ survival. Thus, targeting TGFB signaling by Smad7 demonstrates diverse effects in different contexts, and Smad7 can exert both exacerbated and protective properties in experimental chronic pancreatitis.

Tamoxifen is widely used for the induction of CreERT-mediated genomic recombination in conditional mouse models, but it also affects the fibrotic response in several disease models. In order to investigate a possible effect of tamoxifen on pancreatic fibrogenesis and to evaluate an optimal treatment scheme in an experimental pancreatitis mouse model, we gave administered tamoxifen by oral gavage to both male and female C57BL/6J mice, and then waited for different periods of time before inducing chronic pancreatitis by cerulein. We observed a sex-specific and time-dependent effect of tamoxifen on the fibrotic response both in vivo and in vitro, and a 2-week waiting period before cerulein administration is suggested to reduce tamoxifen side effects to a minimum for the described fibrosis model in female mice.