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LIVER |
1 Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
2 Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA
3 Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
4 Mirus Corporation, 505 S Rosa Rd, Madison, WI, USA
5 Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA, and Department of Pathology and VA Medical Center, University of Pittsburgh, Pittsburgh, PA, USA
Correspondence to:
Correspondence to:
Dr C R Gandhi
Thomas E Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop St, Pittsburgh, PA 15213, USA; Gandhics{at}msx.upmc.edu
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 (CCl4) 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 [3H]PAF binding), higher (p<0.01) baseline hepatic portal pressure, and an augmented (p = 0.03) portal pressure response to PAF infusion (1 µg/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.
Keywords: cirrhosis; platelet activating factor; hepatic stellate cells; endothelin; portal hypertension; liver
Abbreviations: PAF, platelet activating factor; CCl4, carbon tetrachloride; MAP, mean arterial pressure; RT-PCR, reverse transcriptase-polymerase chain reaction; SNK, Student-Newman-Keuls test; ET-1, endothelin 1; BSA, bovine serum albumin; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; DMSO, dimethylsulphoxide; PGE2, prostaglandin E2
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  S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]
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C Thirunavukkarasu, Y Yang, V M Subbotin, S A K Harvey, J Fung, and C R Gandhi Endothelin receptor antagonist TAK-044 arrests and reverses the development of carbon tetrachloride induced cirrhosis in rats Gut, July 1, 2004; 53(7): 1010 - 1019. [Abstract] [Full Text] [PDF]
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