Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats

作     者：Karen Louise Thomsen Holger Jon Moller Jonas Heilskov Graversen Nils E Magnusson Soren K Moestrup Hendrik Vilstrup Henning Gronbaek 

作者机构：Department of Hepatology and GastroenterologyAarhus University Hospital Department of Clinical BiochemistryAarhus University Hospital Affinicon ApsIncuba Science Park Institute of Molecular MedicineUniversity of Southern Denmark Department of Clinical MedicineFaculty of HealthMedical Research LaboratoryAarhus University Department of BiomedicineUniversity of Aarhus 

出 版 物：《World Journal of Hepatology》 (世界肝病学杂志（英文版）（电子版）)

年 卷 期：2016年第8卷第17期

页      面：726-730页

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：Supported by The NOVO Nordisk foundation the Aarhus University Research Foundation Clinical Institute,Aarhus University,Denmark 

主　　题：Acute phase response Dexamethasone Endotoxin Hemoglobin scavenger receptor CD163 Cytokines Inflammation Rats 

摘      要：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-a(TNF-a) and interleukin 6(IL-6) 2 h post-LPS and liver m RNAs and serum concentrations of the rat acute phase protein a-2-macroglobulin(a-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 ***: The conjugate halved the a-2-M liver m RNA(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 m RNA or serum levels of a-2-M. Also, the conjugate reduced TNF-a(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 ***: 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.