Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Abstract

Background and aims: The liver is a major site for the synthesis and actions of platelet activating factor (PAF), a potent hepatic vasoconstrictor and systemic vasodilator. As PAF is implicated in portal hypertension and hyperdynamic circulation associated with liver cirrhosis, we characterised changes in the hepatic PAF system in experimental cirrhosis. Methods: In rats made cirrhotic by carbon tetrachloride (CCl 4 ) administration for eight weeks, we determined hepatic levels of PAF and its cognate receptor, and the effects of PAF and PAF antagonist (BN52021) on portal and arterial pressure. Results: Compared with control rats, cirrhotic rats had higher hepatic PAF levels, higher apparent hepatic efflux of PAF, and higher PAF levels in arterial blood (p,0.01, p,0.01, p,0.05, respectively). Relative to controls, cirrhotic livers had elevated hepatic PAF receptors (by mRNA and protein levels and [ 3 H]PAF binding), higher (p,0.01) baseline hepatic portal pressure, and an augmented (p = 0.03) portal pressure response to PAF infusion (1 mg/kg). Portal infusion of BN52021 (5 mg/kg) showed that elevated endogenous PAF was responsible for 23% of the cirrhotic portal pressure increase but made no contribution to systemic hypotension. Finally, increased PAF receptor density was observed in the contractile perisinusoidal stellate cells isolated from cirrhotic livers relative to those from control livers. Conclusions: In cirrhosis, increased hepatic release of PAF elevates systemic PAF; in combination with upregulated hepatic PAF receptors in stellate cells, this contributes to portal hypertension.

Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis

“…In the present study, cells has been implicated to be an important mediator of hyperdynamic circulation associated with liver cirrhosis. In agreement with the previous reports in cirrhotic patients, increased blood PAF levels were observed in CCl4-induced cirrhotic rats [36] . (Figures 4 and 5), although the number of PAF receptors was increased.…”

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

“…Feeding animals with dietary SM reduced the formation of liver enzyme-altered foci, a hepatic marker of preneoplasia (Silins et al, 2003). Platelet-activating factor, another substrate for alk-SMase, has important implications in carbon tetrachloride-induced liver cirrhosis (Yang et al, 2004), endotoxin-and alcohol-induced hepatic apoptosis and necrosis (Murohisa et al, 2002), and liver metastasis of colon cancer (Denizot et al, 2005). The present study for the first time examines the expression of alk-SMase in human liver cancer cells and diseased liver tissues.…”

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

“…Our finding may also have important implications in liver diseases, because PAF was found to be associated with some types of liver damage, including carbon tetrachloride-induced liver cirrhosis [44], endotoxin-and alcohol-induced hepatic apoptosis and necrosis [45], and liver metastasis of colorectal carcinoma [46]. Alk-SMase is expressed also in human liver [17], and high alkSMase activity was found in human bile [47,48].…”