Prophylactic therapies to treat septic shock - Tolerance to LPS-induced microvascular change in mouse skin

治疗感染性休克的预防性疗法 - 对 LPS 诱导的小鼠皮肤微血管变化的耐受性

• 批准号: 13672401
• 负责人: FUJII Emiko
• 金额: $ 1.47万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672401/
• 关键词: endotoxin; lipid A analog; vascular permeability; cytokine; nitric oxide (NO); septic shock; endotoxin tolerance; glucocorticoid; 敗血症性ショック; 誘導型NO合成酵素(iNOS); iNOS欠損マウス; プロスタグランジン

Subcutaneous injection of lipopolysaccharide (LPS) increases plasma leakage in mouse skin. Pretreatment with LPS conditions mice tolerant to the LPS-induced plasma leakage. Nitric oxide (NO) has been suggested to be involved in these LPS effects. A specific role of inducible NO synthase (iNOS) was investigated in the LPS-induced plasma leakage using iNOS deficient mice. It has been postulated that most biological activities of LPS are derived from lipid A moiety. We examined the effect of lipid A analog (ONO-4007) in increasing plasma leakage. Subcutaneous injection of LPS in mice that were preinjected I.v. with Pontamine sky blue dye produced a dose-related increase in dye leakage in both iNOS deficient and wild-type mice with about 40% less dye leakage in iNOS deficient mice. The LPS-induced dye leakage was not inhibited by inhibitors of NOS and LPS pretreatment in iNOS deficient mice. These studies indicate that LPS-induced dye leakage is mediated by NO produced by iNOS, prostaglandin (PG), histamine and TNF-α. The tolerance against LPS-induced vascular permeability change may be mediated by iNOS induction. Subcutaneous injection of ONO-4007 induced a dose-dependent increase in dye leakage. In iNOS deficient mice, ONO-4007 increased the dye leakage. A constitutive NOS-derived NO, TNF-α and IL-1α but not PG or histamine play a role in ONO-4007-induced increase in plasma leakage. Although ONO-4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO-4007 were not identical to those of LPS. ONO-4007 induced transient tolerance to plasma leakage elicited by LPS, ONO-4007 and inflammatory mediators. Endogenous corticosterone, at least in part, plays a role in development of tolerance. The tolerance induced by LPS may provide a potential basis for the treatment of sepsis, lipid A analog may be useful as a prophylactic therapy of septic shock.

脂多糖的皮下注入（LPS）诱导的氧化物（NO）。在iNOS中，脂质的年龄和野生型小鼠的疾病泄漏中的年龄较小由iNOS介导的前列腺素（PG），组合和TNF-α的耐受性IL-1α而不是PG或组胺在Ono-4007-Althooth Ono-4007中发挥作用，模仿LPS，增加了血管含量，渗透率变化的机制与Ono-4007引起的机制与LPS的瞬时耐受性并不相同。 LPS ST的引起，有效地在耐受性的发展中起作用。

项目成果

Kaoru IRIE, Emiko FUJII, Hiroyasu ISHIDA, Keiji WADA, Taiyo SUGANUMA, Tomohiro NISHIKORI, Toshimasa YOSHIOKA & Takamura MURAKI: "Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability change in mou

入江薰、藤井惠美子、石田博康、和田敬二、菅沼大洋、锦织知宏、吉冈丰正

入江かをる: "「エンドトキシン研究5 研究と治療の進歩」Rho kinase阻害薬の抗炎症作用"日本エンドトキシン研究会編 医学図書出版、東京. 187 (2002)

Kaoru Irie：“‘内毒素研究的 5 个研究和治疗进展’Rho 激酶抑制剂的抗炎作用”，日本内毒素研究组编辑，医学东照出版社，东京 187（2002）。

Kaoru IRIE: "Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability change in mouse skin"Br. J. Pharmacol.. 133(2). 237-242 (2001)

Kaoru IRIE：“环 AMP 升高剂对脂多糖 (LPS) 诱导的小鼠皮肤微血管通透性变化的抑制作用”Br。

Hiroyasu ISHIDA: "A lipid A analog ONO-4007 induces tolerance to plasma leakage in mice"Inflamm. Res.. 51(1). 38-43 (2002)

Hiroyasu ISHIDA：“脂质 A 类似物 ONO-4007 诱导小鼠对血浆渗漏的耐受性”炎症。

Kaoru IRIE: "Anti-inflammatory effect of a Rho kinase inhibitor, Y27632, on the lipopolysaccharide (LPS)-induced increase in vascular permeability in mice"Jpn. J. Pharmacol.. 88 Suppl I. 122 (2002)

Kaoru IRIE：“Rho 激酶抑制剂 Y27632 对脂多糖 (LPS) 诱导的小鼠血管通透性增加的抗炎作用”Jpn。