Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury

Kenzo Soejima, Akitoshi Ishizaka, Tetsuya Urano, Koichi Sayama, Fumio Sakamaki, Hidetoshi Nakamura, Takeshi Terashima, Yasuhiro Waki, Sadatomo Tasaka, Seitaro Fujishima, Tsutomu Kawata, William J. Christ, Minoru Kanazawa

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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-α (TNF-α) 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-α 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-α 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.

Original languageEnglish
Pages (from-to)900-906
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume154
Issue number4 I
Publication statusPublished - 1996
Externally publishedYes

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Lipid A
Acute Lung Injury
Endotoxins
Neutrophils
Lung
Endothelial Cells
Extravascular Lung Water
Neutrophil Activation
B 464
Poisons
Lung Injury
Neutropenia
Intravenous Administration
Lipopolysaccharides
Monocytes
Albumins
Guinea Pigs

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury. / Soejima, Kenzo; Ishizaka, Akitoshi; Urano, Tetsuya; Sayama, Koichi; Sakamaki, Fumio; Nakamura, Hidetoshi; Terashima, Takeshi; Waki, Yasuhiro; Tasaka, Sadatomo; Fujishima, Seitaro; Kawata, Tsutomu; Christ, William J.; Kanazawa, Minoru.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 154, No. 4 I, 1996, p. 900-906.

Research output: Contribution to journalArticle

Soejima, K, Ishizaka, A, Urano, T, Sayama, K, Sakamaki, F, Nakamura, H, Terashima, T, Waki, Y, Tasaka, S, Fujishima, S, Kawata, T, Christ, WJ & Kanazawa, M 1996, 'Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury', American Journal of Respiratory and Critical Care Medicine, vol. 154, no. 4 I, pp. 900-906.
Soejima, Kenzo ; Ishizaka, Akitoshi ; Urano, Tetsuya ; Sayama, Koichi ; Sakamaki, Fumio ; Nakamura, Hidetoshi ; Terashima, Takeshi ; Waki, Yasuhiro ; Tasaka, Sadatomo ; Fujishima, Seitaro ; Kawata, Tsutomu ; Christ, William J. ; Kanazawa, Minoru. / Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury. In: American Journal of Respiratory and Critical Care Medicine. 1996 ; Vol. 154, No. 4 I. pp. 900-906.
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AU - Soejima, Kenzo

AU - Ishizaka, Akitoshi

AU - Urano, Tetsuya

AU - Sayama, Koichi

AU - Sakamaki, Fumio

AU - Nakamura, Hidetoshi

AU - Terashima, Takeshi

AU - Waki, Yasuhiro

AU - Tasaka, Sadatomo

AU - Fujishima, Seitaro

AU - Kawata, Tsutomu

AU - Christ, William J.

AU - Kanazawa, Minoru

PY - 1996

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N2 - 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-α (TNF-α) 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-α 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-α 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.

AB - 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-α (TNF-α) 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-α 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-α 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.

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