Mice treated with a leumedin or antibody to Mac-1 to inhibit leukocyte sequestration survive endotoxin challenge.
Endotoxin challenge causes metabolic dysfunction mediated by TNF, and sequestration of leukocytes. NPC 15669, N-carboxy-L-leucine, N-[2,7-dimethylfluoren-9-yl)methyl] ester, inhibits leukocyte recruitment into inflammatory lesions in animals, and inhibits endotoxin-induced neutropenia and lymphopenia in mice. This study was carried out to determine whether the ability of NPC 15669 to inhibit leukocyte sequestration is sufficient to promote survival after endotoxin challenge. To inhibit leukocyte sequestration directly, mice were treated with anti-CD11a (LFA-1) or anti-CD11b (Mac-1) before endotoxin challenge. Anti-CD11b partly inhibited neutropenia and lymphopenia in response to challenge with LPS, but anti--CD11a had little effect on leukopenia. At doses of 100 and 1000 micrograms/kg, anti-CD11b increased survival to endotoxin challenge from 0 to 20 and 40%, respectively, whereas anti-CD11a was without effect. These observations, coupled with the finding that NPC 15669 does not inhibit endotoxin-induced TNF release suggest that inhibition of leukocyte sequestration can increase survival after endotoxin challenge, and that NPC 15669 or antibodies to Mac-1 may represent effective therapies for gram-negative sepsis and shock.
Burch
R M
RM
Scios-Nova, Freeport Centre, Baltimore, MD 21224.
Noronha-Blob
L
L
Bator
J M
JM
Lowe
V C
VC
Sullivan
J P
JP
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008297:Male; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D015121:6-Ketoprostaglandin F1 alpha; D007930:Leucine