Prophylactic therapies to treat septic shock - Study using vascular permeability in the skin of mice

治疗感染性休克的预防性疗法 - 利用小鼠皮肤血管通透性的研究

• 批准号: 11672279
• 负责人: FUJII Emiko
• 金额: $ 0.77万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672279/
• 关键词: endotoxin; lipoteichoic acid; vascular permeability; prostaglandin; nitric oxide; septic shock; endotoxin tolerance; glucocorticoid; サイトカイン

The potency of lipoteichoic acid (LTA) to induce microvascular inflammatory response has not been clarified. We have shown that s.c. injection of endotoxin (LPS) increases local plasma leakage in the skin of mice (Fujii et al., 1996). In this study, we compared the effect of LTA and LPS on local plasma leakage in the mouse skin. Because our previous study had shown that pretreatment with low-dose LPS induces tolerance (Fujii et al., 1996), we also examined whether pretreatment with low-dose LTA induces tolerance as does LPS.Subcutaneous injection of LTA in mice that were preinjected i.v. with Pontamine sky blue dye increased local dye leakage in the skin. The LTA-induced dye leakage was inhibites by indomethacin, diphenhydramine, and PAF antagonist but not by inhibitors of nitric-oxide (NO) synthase, cycloxygenase-2, or guanylate cyclase or by antibodies against tumor necrosis factor-α (TNF-α) or interleukin-1α (IL-1α). Among the inflammatory mediators, eicosanoids, PAF, and histamine mediate the effect of both LTA and LPS, whereas NO, TNF-α, and IL-1α may not play a major role in LTA-induced dye leakage. The dye leakage induced by LTA was not affected in LTA-primed mice. Serum corticosterone levels, which were suggested to induce tolerance, were not increased by LTA pretreatment but were increased by LPS.These results suggest that endogenous glucocorticoids may play a role for development of LPS-induced tolerance in microcirculation. The tolerance induced by LPS may provide a potential basis for the treatment of sepsis, although LTA may not be useful as a prophylactic therapy of septic shock.

已经表明，二毒素（LPS）的注射会增加小鼠皮肤中的局部血浆泄漏（Fujii等，1996），我们指出了LTA和LPS对小鼠皮肤的局部血浆泄漏的影响。 PS诱导耐受性（Fujii等，1996），我们还检查了低剂量LTA的预处理是否会诱导耐受性，因为LPS。通过吲哚美辛，二苯胺和PAF拮抗剂，但是一氧化物（NO）合酶，环氧酶-2或鸟苷酸环化酶Leuukin-1α（IL-1α）的抑制剂。在LTA和LPS中，NO，TNF-α和IL-1α可能在LTA诱导的染料泄漏中起主要作用。建议诱导耐受性，而不是通过LTA预处理增加，而是通过LP提高了。作为败血性休克的预防性疗法没有用。

项目成果

Toshimasa YOSHIOKA: "Antiinflammatory potency of dehydrocurdione, a zedoary-derived sesquiterpene"Inflamm.Res. 47(12). 476-481 (1998)

Toshimasa YOSHIOKA：“脱氢库二酮（一种莪术衍生的倍半萜烯）的抗炎功效”Inflamm.Res。

Hiroyasu ISHIDA: "Role of inflammatory mediators in lipid A analog (ONO-4007)-induced vascular permeability change in mouse skin"Br J Pharmacol. 130(6). 1235-1240 (2000)

Hiroyasu ISHIDA：“炎症介质在脂质 A 类似物 (ONO-4007) 诱导的小鼠皮肤血管通透性变化中的作用”Br J Pharmacol。

Takamura MURAKI: "Impaired response of dermal microvessels to platelet activating factor (PAF) in streptozotocin-diabetic mice"Naunyn-Schmied Arch Pharmacol. 358(1)(Suppl2). R552 (1998)

Takamura MURAKI：“链脲佐菌素糖尿病小鼠真皮微血管对血小板活化因子 (PAF) 的反应受损”Naunyn-Schmied Arch Pharmacol。

Emiko FUJII: "Evaluation of iNOS-dependent and independent mechanisms of the microvascular permeability change induced by lipopolysaccharide"Br J Pharmacol. 130(1). 90-94 (2000)

Emiko FUJII：“脂多糖诱导的微血管通透性变化的 iNOS 依赖性和独立机制的评估”Br J Pharmacol。

Kaoru IRIE: "The Biology of Nitric Oxide Pt 6(Moncada S et al.eds)"Portland Press, London. 350 (1998)

Kaoru IRIE：“一氧化氮生物学第 6 部分（Moncada S 等编辑）”波特兰出版社，伦敦。