Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

Abstract

Kupffer cells (KCs), the liver resident macrophages accounting for 80-90% of the total population of fixed tissue macrophages in the body, not only play a key role in host defense via removing particulate materials from the portal circulation, but may also contribute to the pathogenesis of various liver diseases. We have previously demonstrated that KCs play an important role in controlling portal hypertension and hepatocellular injury via releasing thromboxane A 2 (TXA 2 ) in early fibrosis induced by one-week bile duct ligation (BDL). Production of TXA 2 is controlled by cytosolic phospholipase A 2 (cPLA 2 ) that is activated by the interaction of entothelin-1 (ET-1) with its G-protein coupled ET receptor B (ETBR). However, the signaling pathways that contribute to the ET-1-induced activation of cPLA 2

Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts

“…The constrictor responses of the isolated coronary vessels with ET A R antagonism maintained higher stress levels than those also coupled with ET B R antagonism. Given that ET B R activation has been linked to COX activity and TXA 2 release in other vascular beds (Miller and Zhang 2009; Plante et al 2002), perhaps our findings indicate a similar mechanism in coronary arteries following MWCNT exposure.…”

“…Oxidative stress has been shown to alter vascular responses to ET-1 through activation of the COX pathway, resulting in release of thromboxane (TXA 2 ) from vascular endothelial cells, and thus exaggerating vasoconstriction (Karaa et al 2006; Xu et al 2005). There is evidence that suggests this may be a result of endothelin B receptor (ET B R) activation (Miller and Zhang 2009; Plante et al 2002). …”

Diabetes enhances the intrahepatic vascular response to endothelin‐1 in cirrhotic rats: association with the ETA receptor and pERK up‐regulation

“…In cirrhosis, hepatocytes have been found to have enhanced synthesis of ET‐1 . In Kupffer cells isolated from cirrhotic rats, the response of p38 MAPK to ET‐1 has been found to be significantly enhanced . Among different cells, SECs and HSCs seem to be the cell types that play a major role in ET‐1 induced intrahepatic vasoconstriction.…”

Vasoactive Substances and Inflammatory Factors in Progression of Liver Cirrhosis with Portal Hypertension

“…[55]. In BDL portal hypertensive rats, elevated ET-1 interacted with Kuffer cells, increasing the responsiveness of p38MAPK through ET B receptor, activating cPLA 2 and promoting production of TXA 2 , contributing to progression of portal hypertension [29].…”

“…However, activation of ET B receptor leads to production of other vasoactive molecules, e.g. TXA 2 [29]. Besides, antagonism of ET A receptor alone cannot improve splanchnic circulation indicating ET B receptor plays a role on regulation in PH [30].…”