Selective depletion of neutrophils by a monoclonal antibody, RP-3, suppresses dextran sulphate sodium-induced colitis in rats.
Administration of dextran sulphate sodium to animals induces acute colitis characterized by infiltration of large numbers of neutrophils into the colonic mucosa, which histologically resembles human active ulcerative colitis. It has been reported that neutrophils and the reactive oxygen metabolites produced by them are involved in the progress of ulcerative colitis. This study was intended to clarify their roles by using this animal model. First, possible sources and species of reactive oxygen metabolites were determined using luminol-dependent chemiluminescence with addition of enzyme inhibitors and reactive oxygen metabolite scavengers. Next, to examine whether neutrophils and hypochlorous acid derived from them contribute to tissue injury, we administered RP-3, a monoclonal antibody capable of selectively depleting neutrophils, and taurine, a hypochlorous acid scavenger, to rats treated with dextran sulphate sodium. Addition of azide, taurine, catalase, superoxide dismutase and dimethyl sulphoxide into colonic mucosal scrapings significantly inhibited chemiluminescence production, but allopurinol and indomethacin had no effects. These results suggest that excessive hypochlorous acid, hydrogen peroxide, superoxide anion and hydroxyl radical are generated by the inflamed colonic mucosa. Intraperitoneal injections of RP-3 significantly suppressed bleeding, tissue myeloperoxidase activity, chemiluminescence production and erosion formation. On the other hand, administration of taurine tended to inhibit bleeding and erosion formation to some extent, although it could not significantly suppress them. These data suggest that neutrophils play an important role in the development of this colitis and that hypochlorous acid might be one of the causes of tissue injury induced by neutrophils.
Natsui
M
M
Third Department of Internal Medicine, Niigata University School of Medicine, Japan.
Kawasaki
K
K
Takizawa
H
H
Hayashi
S I
SI
Matsuda
Y
Y
Sugimura
K
K
Seki
K
K
Narisawa
R
R
Sendo
F
F
Asakura
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001772:Blood Cell Count / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology; D016264:Dextran Sulfate; D004804:Eosinophils / Q000473:pathology; D007202:Indicators and Reagents; D007958:Leukocyte Count / Q000187:drug effects; D008163:Luminescent Measurements; D008165:Luminol; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007202:Indicators and Reagents; D013654:Taurine; D008165:Luminol; D016264:Dextran Sulfate; D009195:Peroxidase