Effect of LY2109761 on TGF-β1/TGFβRI/Smad Pathway and Hepatic Fibrosis Cysts Formation in Rats Infected with Echinococcus granulosus: an In Vitro and In Vivo Study.

PURPOSE: Echinococcus granulosus infection is a zoonotic parasite disease that threatens animal husbandry development and farmer and herder health. Hepatic fibrosis cysts induced by protoscoleces (PSCs) are a common pathological alteration. The formation of these cysts is related to the stimulation of TGF-β1/TGFβRI/Smad signaling in hepatic stellate cells (HSCs). TGF-β1 activates the TGFβRI/Smad pathway in HSCs, which is needed in the formation of fibrosis cysts.

METHODS

LY2109761, a TGF-β receptor inhibitor, is hypothesized to reduce the formation of hepatic fibrosis cysts by limiting TGF-β1 binding to TGFβRI receptors on HSCs and decreasing the activation of the TGFβRI/Smad pathway. Herein, a liver infection model in rats with PSCs was constructed, and the infected rats were treated with LY2109761 in vivo. The pathological morphology, serum IL-1β, IL-2, IL-4, IL5, IL-6, IL-10, IL-13, IL-17 concentrations, TGF-β1 cytokine, and fibrosis TGF-β1/Smad pathway protein expression were detected to verify the mechanism how PSCs infection activates the HSC TGF-β1/ Smad pathway to promote liver fibrosis.

RESULTS

The study examined how LY2109761 affected TGF-β1 secretion in hepatocytes co-cultured with PSCs and BRL cells in vitro, and the activation of the TGF-β1/Smad in HSC-T6 cells induced by the co-culture supernatant, which ultimately led to liver fibrosis. Prolonged infection duration raised blood concentrations of IL-1β, IL-2, IL-4, IL5,IL-6, IL-10, and IL-17 as well as hepatocyte TGF-β1 production and secretion.

CONCLUSION

TGF-β1 acts on HSC surface, where it binds to TGF-βRI to stimulate the production of hepatic fibrosis cysts via TGF-β1/TGFβRI/Smad. Blocking TGF-β1 linking to the TGFβRI receptor can lessen PSCs damage to liver cells, prevent fibrotic cyst formation, and activate the immune system in the body to kill invaders.