UNLABELLED: Dexamethasone (Dexa) was coupled to human serum albumin (Dexa10-HSA) for the targeting of this anti-inflammatory drug to Kupffer cells (KC) and sinusoidal endothelial cells (SEC) in the liver: key players in the pathogenesis of acute and chronic inflammatory liver diseases like fibrosis. Cell-specific delivery of Dexa may increase its efficacy and prevent side effects. We, therefore, studied the pharmacokinetic profile, efficacy, and toxicity of Dexa10-HSA in bile duct ligation (BDL)-induced fibrosis in rats. RESULTS: Dexa10-HSA was taken up by scavenger receptors on KC and SEC and was rapidly cleared from the blood stream, with no differences in kinetic parameters between normal and fibrotic rats. KC isolated from livers of rats treated wi th Dexa10-HSA were unresponsive to lipopolysaccharide in contrast to controls. A dose of 0.1 mg kg(-1) three times a week reduced intrahepatic reactive oxygen species production strongly as compared to untreated BDL rats. This dose, however, also stimulated the depositions of collagens I and III. Overdosing of Dexa10-HSA (10 mgkg(-1)) led to a lethal reduction of body and spleen weight. CONCLUSIONS: Dexa10-HSA has potent anti-inflammatory effects during BDL at extremely low doses, demonstrating the cell-specific targeting. However, the fibrotic process was not favourably affected. These results indicate a dual role for Dexa; besides blocking the release of pro-inflammatory cytokines it also reduces the release of antifibrotic mediators by SEC and KC.
UNLABELLED: Dexamethasone (Dexa) was coupled to human serum albumin (Dexa10-HSA) for the targeting of this anti-inflammatory drug to Kupffer cells (KC) and sinusoidal endothelial cells (SEC) in the liver: key players in the pathogenesis of acute and chronic inflammatory liver diseases like fibrosis. Cell-specific delivery of Dexa may increase its efficacy and prevent side effects. We, therefore, studied the pharmacokinetic profile, efficacy, and toxicity of Dexa10-HSA in bile duct ligation (BDL)-induced fibrosis in rats. RESULTS:Dexa10-HSA was taken up by scavenger receptors on KC and SEC and was rapidly cleared from the blood stream, with no differences in kinetic parameters between normal and fibrotic rats. KC isolated from livers of rats treated wi th Dexa10-HSA were unresponsive to lipopolysaccharide in contrast to controls. A dose of 0.1 mg kg(-1) three times a week reduced intrahepatic reactive oxygen species production strongly as compared to untreated BDL rats. This dose, however, also stimulated the depositions of collagens I and III. Overdosing of Dexa10-HSA (10 mgkg(-1)) led to a lethal reduction of body and spleen weight. CONCLUSIONS:Dexa10-HSA has potent anti-inflammatory effects during BDL at extremely low doses, demonstrating the cell-specific targeting. However, the fibrotic process was not favourably affected. These results indicate a dual role for Dexa; besides blocking the release of pro-inflammatory cytokines it also reduces the release of antifibrotic mediators by SEC and KC.
Authors: Chi Wei Lee; Jiin Haur Chuang; Pei Wen Wang; Nyuk Kong Chang; Hsiu Chuan Wang; Chao Cheng Huang; Mao Meng Tiao; Sing Kai Lo Journal: World J Surg Date: 2006-12 Impact factor: 3.352