ANTIFIBROTIC EFFECT ON LIVER OF A NOVEL TRUNCATED ISOFORM OF THE HUMAN TGF-Β TYPE II RECEPTOR FC-TAG PROTEIN

LA COLLA A; RODRÍGUEZ TM; DEWEY RA; BERTOLIO MS; CAMARA C; CHISARI AN; CAMPISANO SE; VELASCO ZAMORA J

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC-SAI-SAFIS 2018; 2018

SAIC-SAI-SAFIS

Liver fibrosis is a hallmark feature of chronic liver diseases,which affects millions of patients worldwide,and leads to liver failure. Current protective options forthese patients are limited. We have recently describedthe presence in human cells of a new splicing variantof TGF-β type II receptor (TGFBR2) lacking the transmembraneand intracellular domains, thus rendering atruncated protein of 80 amino acids known as soluble endogenousTGFBR2 (TGFBR2-SE). It is well establishedthat transforming growth factor beta (TGF-β) promotesliver fibrosis. Thus, the development of agents with asignificant potential to achieve a specific and long-lastinginterference of TGF-β action in vivo, is of clinicalrelevance. The aim of this work was to study the effectof lentiviral-mediated overexpression of TGFBR2-SEfused in frame with the human IgG1 (Lv-TGFBR2-SE/Fc), in a carbon tetrachloride (CCl4)-induced liver fibrosisrat model. We compared three experimental groups:vehicle, CCl4 and CCl4 previously administrated withLv-TGFBR2-SE/Fc intrahepatically. In this way, we observedpartial recovery of body weight in rats treated withLv-TGFBR2-SE/Fc + CCl4 compared to the CCl4 group.In addition, gross appearance of liver in the Lv-TGFBR2-SE/Fc + CCl4 group showed reversion of the irregularshape and shrinkage observed in the CCl4 group.Moreover, administration of Lv-TGFBR2-SE/Fc diminishedCCl4-induced liver enzyme increase, indicative ofliver injury recovery. Histological analysis of liver sectionsrevealed that Lv-TGFBR2-SE/Fc significantly decreasedthe deposition of collagen fibers induced by CCl4 as wellas practically restored liver architecture. Moreover, immunohistochemicaland Western-blot studies showedthat the administration of Lv-TGFBR2-SE/Fc significantlydiminished α-smooth muscle actin (α-SMA) expression,indicative of a reduced activation of hepatic stellate cells(HSC). These results suggest that lentiviral delivery ofTGFBR2 exerts a protective effect against liver fibrosisinduced by CCl4 in rats.