Role of leukocyte beta 2-integrin in PAF-induced shock and intestinal injury.
Leukocyte adhesion and diapedesis, critical steps in the inflammatory process, depend on the expression of integrin CD11b/CD18. In this study, we examined the preventive effect of monoclonal antibodies (MAb) against CD11b (1B6), CD11a, or CD18 (CL26) on platelet-activating factor (PAF)-induced bowel injury. Young male Sprague-Dawley rats were anesthetized and injected with either of two doses of PAF (2.5 or 3 micrograms/kg iv) to induce transient hypotension and irreversible shock. Some rats wee also injected intravenously with 1B6 (anti-CD11b), anti-CD11a, CL26 (anti-CD18), or combined anti-CD11a and 1B6, 30 min before PAF. Animals receiving a low dose of PAF developed mild hypotension, hemoconcentration, increased intestinal myeloperoxidase, and bowel injury after 1 h. These effects were completely prevented by pretreatment with 1B6. A high dose of PAF induced irreversible shock and gross intestinal necrosis. Both CL26 and 1B6 were partially effective in attenuating PAF-induced bowel injury. Addition of anti-CD11a to 1B6 in the treatment further ameliorated the systemic adverse effects of PAF and intestinal injury. However, focal minor injury still developed. Anti-CD11a alone, fucoidin, or anti-P-selectin was ineffective. Rats depleted of neutrophils were also largely protected from the adverse effects of PAF at high doses, although minor intestinal injury often persisted. We conclude that leukocyte beta 2-integrins play an important role in PAF-induced hypotension, leukopenia, hemoconcentration, and intestinal necrosis, and that CD11b/CD18 is the main adhesion molecule involved in the pathogenesis of injury. However, CD11/CD18- and neutrophil-independent pathways exist for mediating PAF-induced bowel injury, although their role is probably a minor one.
Sun
X M
XM
Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.
Qu
X W
XW
Huang
W
W
Granger
D N
DN
Bree
M
M
Hsueh
W
W
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000276:immunology; D008297:Male; D009336:Necrosis; D009195:Peroxidase / Q000037:antagonists & inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012769:Shock / Q000139:chemically induced*
D000906:Antibodies; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D010972:Platelet Activating Factor; D009195:Peroxidase