Prevention of endotoxin shock by an antibody against leukocyte integrin beta 2 through inhibiting production and action of TNF.
Septic shock remains a serious disorder associated with high mortality. Accumulating evidence indicates that TNF is a major and essential mediator of endotoxin shock. We report here that administration of an antibody against CD18 dramatically reduced endotoxin-induced shock in rabbits as revealed by prevention of severe hypotension, metabolic acidosis and a pathological change suggestive of disseminated intravascular coagulation with concomitant inhibition of elevation of plasma TNF activity. The anti-CD18 antibody also inhibited the hypotension induced by administering recombinant TNF. Furthermore, an antibody against a ligand for CD18 complexes, intercellular adhesion molecule-1, also prevented TNF-induced shock as well as endotoxin shock in rabbits. These observations suggest that adhesion of leukocytes to endothelium may be of primary importance in the action of TNF as well as in the production of TNF in vivo and that the antibody against adhesion molecules could be of therapeutic benefit in life-threatening septic shock in humans.
Department of Pharmacology, Kanazawa University, Japan.
S
S
Watanabe
N
N
Mukaida
N
N
Ikeda
M
M
Akiyama
A
A
Harada
I
I
Nakanishi
H
H
Nariuchi
Y
Y
Watanabe
K
K
Matsushima
D000210:Acute-Phase Reaction / Q000276:immunology / Q000401:mortality; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018821:CD18 Antigens / Q000276:immunology*; D005260:Female; D006439:Hemodynamics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D008107:Liver Diseases / Q000276:immunology / Q000517:prevention & control; D011817:Rabbits; D012772:Shock, Septic / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1