The matrix metalloproteinase inhibitor BB-1101 prevents experimental autoimmune uveoretinitis (EAU).
EAU is characterized by breakdown of the blood-retinal barrier and extravasation of leucocytes into retinal tissue leading to destruction of photoreceptor cells. Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7, to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of clinical disease. When administered from day 7 until day 21, EAU was completely abrogated. A quantitative polymerase chain reaction (PCR) assay showed an increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with naive controls. These enzymes are produced by activated leucocytes and act on components of the basement membrane. These results therefore implicate these MMP as integral to the development of pathology in EAU.
Wallace
G R
GR
Department of Academic Ophthalmology, GKT, St Thomas' Campus, London. g.wallace@rayne.umds.ac.uk
Whiston
R A
RA
Stanford
M R
MR
Wells
G M
GM
Gearing
A J
AJ
Clements
J M
JM
D000818:Animals; D019393:Arrestin; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D001593:Benzyl Compounds; D003907:Dexamethasone / Q000008:administration & dosage*; D004338:Drug Combinations; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics; D010431:Pentoxifylline / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D012173:Retinitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D013386:Succinates; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*
D019393:Arrestin; C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D020782:Matrix Metalloproteinases; D010431:Pentoxifylline