Published online Jun 18, 2016. doi: 10.4254/wjh.v8.i17.726
Peer-review started: February 22, 2016
First decision: March 24, 2016
Revised: May 4, 2016
Accepted: May 31, 2016
Article in press: June 2, 2016
Published online: June 18, 2016
AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats.
METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects.
RESULTS: The conjugate halved the α-2-M liver mRNA (3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein (201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver mRNA or serum levels of α-2-M. Also, the conjugate reduced TNF-α (7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6 (15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight (421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group.
CONCLUSION: Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.
Core tip: We aimed to study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. The central finding of the study was a reduction in liver mRNA and plasma levels of the acute phase protein α-2-macroglobulin, and plasma tumour necrosis factor-α and interleukin 6 by administration of the conjugate prior to a lipopolysaccharide-induced inflammatory response. This anti-acute phase effect exceeded that of the therapeutic dexamethasone dose and did not cause systemic adverse effects. Thus, the antibody conjugate may be a potential candidate in future anti-inflammatory macrophage-directed therapy, e.g., in liver diseases with Kupffer cells activation.