Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury.
B464 is a novel synthetic analog of lipid A, a toxic component of endotoxin (LPS; lipopolysaccharide). We investigated the effects of B464 on both LPS-induced cellular responses in vitro and acute lung injury in vivo. In the in vitro study, B464 inhibited tumor necrosis factor-alpha (TNF-alpha) production from human monocytes, priming and stiffening of neutrophils, and expression of adhesion molecules on endothelial cells induced by LPS. We then studied the effects of B464 pretreatment on acute lung injury elicited by intravenous LPS administration in vivo. Guinea pigs were divided into saline control, B464 alone, LPS alone, and LPS + B464 groups. Animals were observed for 4 h after LPS administration, and lung injury was evaluated by extravascular lung water, 125I-albumin leakage in lung tissue, and lung neutrophil accumulation. In the LPS alone group, rapid and sustained peripheral neutropenia (p < 0.001 versus saline at 15 min and at 1, 2, and 4 h), an increased plasma TNF-alpha concentration (p < 0.005 at 1 h), and increases in lung injury parameters (p < 0.05) were observed. In the LPS + B464 group, no changes were observed in either plasma TNF-alpha or lung injury parameters. Transient peripheral neutropenia and subsequent rapid recovery (p > 0.05, p < 0.001, p < 0.01, and p > 0.05 at 15 min and 1, 2, and 4 h, respectively) were observed in the LPS + B464 group. These in vivo data, together with in vitro evidence of suppressed cellular responses, suggest that B464 (1) inhibits neutrophil accumulation in lung tissue, and (2) attenuates the development of acute lung injury by blocking the activation of neutrophils and mononuclear cells as well as the interaction between neutrophils and endothelial cells.
Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
K
K
Soejima
A
A
Ishizaka
T
T
Urano
K
K
Sayama
F
F
Sakamaki
H
H
Nakamura
T
T
Terashima
Y
Y
Waki
S
S
Tasaka
S
S
Fujishima
T
T
Kawata
W J
WJ
Christ
M
M
Kanazawa
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D009503:Neutropenia / Q000517:prevention & control; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C088580:B 464; D015815:Cell Adhesion Molecules; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli