Hepatic fibrogenesis and TGF/Smad signaling activation in rats exposed to low doses of lead

PEREZ AGUILAR R.C.; HONORE S.M.; GENTA S.B.; SÁNCHEZ S.S.

JOURNAL OF APPLIED TOXICOLOGY

JOHN WILEY & SONS LTD

Lugar: Londres; Año: 2014 vol. 34 p. 1320 - 1331

0260-437X

Lead is an important heavy metal pollutant in the environment, primarily as the result of anthropogenic activities. The nervous system, kidney and liver are the most susceptible organs to lead deposition, showing that this pollutant has no single target system. Although morphological and functional alterations in these organs have been highlighted, cellular and molecular mechanisms involved in their pathobiology are not fully understood. In this work we report that low levels of lead induced a significant increase in extracellular proteins such as laminin, collagen IV and fibronectin, located at the perisinusoidal space, in a rat model of long-term lead acetate exposure (0.06% lead acetate in the drinking water). Moreover, phenotypic transformation of hepatic stellate cells into myofibroblast-like cells was evidenced at the ultrastructural level. A significant expression of α-smooth muscle actin (α-SMA) in the liver parenchyma, particularly in Disse?s space, was also observed. These changes indicate an activation of quiescent hepatic stellate cells. Furthermore, we determined that the TGFb1 signaling pathway is involved in the toxic action of lead. In conclusion, low levels of lead exposure induced a phenotypic change in stellate cells, increased the synthesis of extracellular matrix in the liver and up-regulated TGFb1/Smad signaling. These lead triggered alterations are associated with the onset of a fibrogenic process.