title: Transgenic sickle mice have vascular inflammation.
abstract: Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human alpha- and sickle beta-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-S(Antilles), NY-S/S(Antilles) (NY-S x Berk-S(Antilles)), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P </=.01) in the Berk-S(Antilles), NY-S/S(Antilles), and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P </=.001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P </=.05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P </=.05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P </=.01). Nuclear factor kappaB (NF-kappaB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P </=.006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vaso-occlusion in sickle cell disease.
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis 55455, USA. belcher@umn.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bryant
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Bowlin
authors.forename: Miroslaw C
authors.initials: MC
authors.lastname: Kielbik
authors.forename: John C
authors.initials: JC
authors.lastname: Bischof
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D003433:Crosses, Genetic; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D000683:Serum Amyloid P-Component / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000683:Serum Amyloid P-Component; D002097:C-Reactive Protein