VLA-4 blockade suppresses endotoxin-induced uveitis: in vivo evidence for functional integrin up-regulation.
Leukocyte adhesion to the vascular wall is a critical early step in the pathogenesis of inflammatory diseases and is mediated in part by the leukocyte integrin, VLA-4, which binds to endothelial vascular cell adhesion molecule (VCAM) -1. Here, we investigate VLA-4's role in endotoxin-induced uveitis (EIU). At various time points (6-48 h) after EIU induction, the severity of the inflammation was evaluated by quantifying cell and protein content in the aqueous fluid, firm leukocyte adhesion in the retinal vessels, and the number of extravasated leukocytes into the vitreous. Functional activation of VLA-4 in vivo was investigated in our previously introduced autoperfused micro flow chamber assay. Firm adhesion of EIU leukocytes to immobilized VCAM-1 under physiological blood flow conditions was significantly increased compared with normal controls (P<0.05), suggesting an important role for VLA-4 in EIU. VLA-4 blockade in vivo significantly suppressed all uveitis-related inflammatory parameters studied, decreasing the clinical score by 45% (P<0.01), protein content in the aqueous fluid by 21% (P<0.01), retinal leukostasis by 68% (P<0.01), and leukocyte accumulation in the vitreous by 75% (P<0.01). Our data provide novel evidence for functional up-regulation of VLA-4 during EIU and suggest VLA-4 blockade as a promising therapeutic strategy for treatment of acute inflammatory eye diseases.
Hafezi-Moghadam
A
A
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, USA. ahm@meei.harvard.edu
Noda
K
K
Almulki
L
L
Iliaki
E F
EF
Poulaki
V
V
Thomas
K L
KL
Nakazawa
T
T
Hisatomi
T
T
Miller
J W
JW
Gragoudas
E S
ES
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D005136:Eye Proteins / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D016023:Integrins / Q000378:metabolism* / Q000502:physiology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004731:Endotoxins; D005136:Eye Proteins; D039041:Integrin alpha4beta1; D016023:Integrins; D019010:Vascular Cell Adhesion Molecule-1