title: Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Karen Louise
authors.initials: KL
authors.lastname: Thomsen
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Holger Jon
authors.initials: HJ
authors.lastname: Møller
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Jonas Heilskov
authors.initials: JH
authors.lastname: Graversen
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Nils E
authors.initials: NE
authors.lastname: Magnusson
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
keywords: Acute phase response; Cytokines; Dexamethasone; Endotoxin; Hemoglobin scavenger receptor CD163; Inflammation; Rats