Am. J. Respir. Crit. Care Med., Vol 154, No. 4, Oct 1996, 900-906.
Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury
K Soejima, A Ishizaka, T Urano, K Sayama, F Sakamaki, H Nakamura, T Terashima, Y Waki, S Tasaka, S Fujishima, T Kawata, WJ Christ and M Kanazawa
Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
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.
