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Prevention of endotoxin shock by an antibody against leukocyte integrin {beta}2 through inhibiting production and action of TNF |
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| Authors: | Watanabe, Shun-ichi Mukaida, Naofumi Ikeda, Naoki Akiyama, Mariko Harada, Akihisa Nakanishi, Isao Nariuchi, Hideo Watanabe, Yoh Matsushima, Kouji |
| Affiliation: | 1 Department of Pharmacology, Cancer Research Institute, School of Medicine, Kanazawa University 13-1 Takara-machi, Kanazawa 920, Japan 2 First Department of Surgery, School of Medicine, Kanazawa University 13-1 Takara-machi, Kanazawa 920, Japan 3 First Department of Internal Medicine, School of Medicine, Kanazawa University 13-1 Takara-machi, Kanazawa 920, Japan 4 First Department of Pathology, School of Medicine, Kanazawa University 13-1 Takara-machi, Kanazawa 920, Japan 5 Department of Allergology, Institute of Medical Science, University of Tokyo 4-6-1 Shirokanedai, Minatoku, Tokyo 108, Japan |
| Abstract: | Septic shock remains a serious disorder associated with highmortality. Accumulating evidence indicates that TNF is a majorand essential mediator of endotoxin shock. We report here thatadministration of an antibody against CD18 dramatically reducedendotoxin-induced shock inrabbits as revealed by preventionof severe hypotension, metabolic acidosis and a pathologicalchange suggestive of disseminated intravascular coagulationwith concomitant inhibition of elevation of plasma TNF activity.The anti-CD18 antibody also inhibited the hypotension inducedby administering recombinant TNF. Furthermore, an antibody againsta ligand for CD18 complexes, intercellular adhesion molecule-1,also prevented TNF-induced shock as well as endotoxin shockinrabbits. These observations suggest that adhesion of leukocytesto endothelium may be of primary importance in the action ofTNF as well as in the production of TNF in vivo and that theantibody against adhesion molecules could be of therapeuticbenefit in life-threatening septic shock in humans. |
| Keywords: | endotoxin shock, ICAM-1, leukocyte integrin ß 2 (CD18), TNF |
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