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 endo toxin (LPS; lipopolysaccharide). We investigated the effects of B464 o n both LPS-induced cellular responses in vitro and acute lung injury i n vivo. In the in vitro study, B464 inhibited tumor necrosis factor-al pha (TNF-alpha) production from human monocytes, priming and stiffenin g 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 vi vo. Guinea pigs were divided into saline control, B464 alone, LPS alon e, and LPS + B464 groups. Animals were observed for 4 h after LPS admi nistration, and lung injury was evaluated by extravascular lung water, I-125-albumin leakage in lung tissue, and lung neutrophil accumulatio n. 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 l ung injury parameters (p < 0.05) were observed. In the LPS + B464 grou p, no changes were observed in either plasma TNF-alpha or lung injury parameters. Transient peripheral neutropenia and subsequent rapid reco very (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 res ponses, suggest that B464 (1) inhibits neutrophil accumulation in lung tissue, and (2) attenuates the development of acute lung injury by bl ocking the activation of neutrophils and mononuclear cells as well as the interaction between neutrophils and endothelial cells.