Two
cannabinoid (CB) receptor subtypes, CB1 and CB2, have been cloned and characterized. Among other activities, receptor activation by
cannabinoid ligands may result in pro- or antifibrogenic effects depending on their interaction with CB1 or CB2, respectively. In the current study, we investigated whether selective activation of hepatic CB2 modifies
collagen abundance in cirrhotic rats with
ascites.
mRNA and
protein expression of CB receptors in the liver of control and cirrhotic rats was assessed by reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry. The effect of chronically activating the
CB2 receptor was investigated in cirrhotic rats with
ascites treated daily (9 days) with the
CB2 receptor-selective agonist 3-(1,1-dimethylbutyl)-1-deoxy-Delta(8)-tetrahydrocannabinol (JWH-133). At the end of treatment, mean arterial pressure and portal pressure were measured, and liver samples were obtained to evaluate infiltrate of mononuclear cells, hepatic apoptosis, alpha-smooth muscle actin (SMA) expression,
collagen content, and
matrix metalloproteinase (MMP)-2 abundance in all animals.
JWH-133 improved arterial pressure, decreased the inflammatory infiltrate, reduced the number of activated stellate cells, increased apoptosis in nonparenchymal cells located in the margin of the septa, and decreased
fibrosis compared with cirrhotic rats treated with vehicle. This was associated with decreased alpha-SMA and
collagen I and increased MMP-2 in the hepatic tissue of cirrhotic rats treated with the CB2 agonist compared with untreated cirrhotic animals. Therefore, selective activation of hepatic CB2 receptors significantly reduces hepatic
collagen content in rats with pre-existing
cirrhosis, thus raising the possibility of using selective CB2 agonists for the treatment of hepatic
fibrosis in human
cirrhosis.