Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing.

Abstract

The liver's response to chronic injury is fibrosis, which is analogous to wound healing in other organs. Hepatic wounding is characterized by the "activation" of resident stellate cells (lipocytes, Ito cells) to myofibroblast-like cells that produce increased amounts of smooth muscle ␣ -actin and extracellular matrix. Stellate cells possess abundant endothelin (ET) receptors (ET A/B ) and, therefore, are subject to the effects of ET-1 and 3. In this study, we investigated whether ETs contribute to the activation of stellate cells and consequently, fibrogenesis. In cultured stellate cells, ET-1 and sarafotoxin S6C (a potent ET B receptor agonist) stimulated stellate cell activation, as assessed by expression of smooth muscle ␣ -actin. Furthermore, the mixed ET A/B receptor antagonist, bosentan, blocked this process. Next, we administered bosentan during the induction of liver injury in two mechanistically distinct forms of hepatic wounding. Bosentan reduced levels of type I collagen and cellular fibronectin mRNAs in whole-liver tissue extracts in both models. In freshly isolated stellate cells from injured livers, bosentan reduced expression of activation markers, including smooth muscle ␣ -actin and extracellular matrix mRNAs. We further demonstrate that endothelin antagonism after establishment of fibrosing injury reduced stellate cell activation and matrix production. These data indicate that ET contributes to stellate cell activation and fibrogenesis. Because ET is upregulated in diverse forms of parenchymal injury, we speculate that ET may play an important role in the wound-healing response.

Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157

“…Occurring proliferation and migration of many cell types, reduced levels of inflammatory markers (MPO, LTB4, TXB2), collagen synthesis, angiogenesis, production of granulation tissue have been coined with pentadecapeptide BPC 157. 1,2,5,7 -9,12,22 Particularly, fibrosis is counteracted, presenting pentadecapeptide BPC 157 to counteract endothelin overexpression, 18 the endothelin role in fibrosis development, 24 fibrosis in a variety of tissues, besides muscle, 14 prevented and reversed chronic hearth failure, 18 chronic liver lesion, and portal hypertension in rat. 19 Like in tendon-transection healing studies and tendon cells presentation, 1 as our posttransection muscle findings accord in pentadecapeptide BPC 157-rats, the final result may be subsequent muscle cells and collagen fibers high organization in an attempt to restore as close as possible the original structure and function of the damaged muscle and severed tendon-muscle unit.…”

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

“…Cells were placed on uncoated plastic and were maintained in standard stellate cell growth medium (modified 199OR containing 10% fetal bovine serum and 10% calf serum) as described previously. 22 Isolated stellate cells were seeded at a density of 3 ϫ 10 2 cells/mm 2. Cultures were incubated at 37°C in a humidified incubator (containing 95% O 2 and 2.5% CO 2 ), and the medium was changed every 24 hours. Cell viability was Ͼ90% in all cultures used.…”

“…The proportion of tissue stained with picrosirus red was assessed by morphometric analysis using MetaView software (Universal Imaging, Downingtown, PA) as described previously. 22 …”

Endothelin-1 Suppresses Plasma Membrane Ca++-ATPase, Concomitant with Contraction of Hepatic Sinusoidal Endothelial Fenestrae

“…23 In liver injury, fibrogenesis occurs after activation of hepatic stellate cells, and the activation cascade includes features of proliferation, fibrogenesis, up-regulation of smooth muscle actin, and enhanced contractility. 24 However, the effects of ETs on SECs has not yet been characterized.…”