Pancreatic Disorders & Therapy

Pancreatic Disorders & Therapy
Open Access

ISSN: 2165-7092

+1-504-608-2390

Abstract

Role of JNK Signalling and AHR in Fibrosis, Implications for New Therapeutics

Theresa C Hemsworth-Peterson

In this study a role for signalling molecules in experimental fibrosis is established using a novel model of fibrosis. The yellow phosphorous treatment of AHR-/- knockout mice caused fibrosis within 7 days and provided a narrow window in which to characterize the regulation of signalling molecules. The mice used were AHR-/- mice (5 weeks) with and without Yellow Phosphorous (YP) treatment compared to C57BL/6 (5 weeks). YP (0.6 mg/kg) was administered to AHR-/- mice for 1 week. A subgroup of mice were also administered c-jun antisense. A group of AHR-/- mice (aged 10 to 24 week old) were also studied to verify the spontaneous development of liver fibrosis over time in these animals. As an index of fibrosis, the liver collagen content was determined by Sirius red/fast green staining in these animals, the levels of hepatic c-Jun and collagen were also assessed by Western analysis. Results indicate that without YP treatment, there was a significant spontaneous increase in the liver collagen content in the AHR-/- mice from weeks 5 to 24. Further, the results indicate that YP treatment increased the rate of fibrosis in AHR-/- mice and this increase in collagen content with only one week of YP treatment produced fibrosis ( i.e., elevated collagen levels) equivalent to that seen in spontaneously in untreated 24 week old AHR-/- mice. Using Western analysis both c-Jun and collagen were found to be elevated in livers of 5 weeks old AHR-/- mice treated with YP. We thus identified an up regulation of c-jun and collagen indicating an increased rate of fibrosis in this new model. The use of c-jun antisense technology effectively reduced target molecules. In conclusion, molecular targets were identified in an accelerated model of hepatic fibrosis and using antisense technology the targets were inhibited and fibrosis was blocked.

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