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

基本信息

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

项目摘要

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.

皮下注射脂多糖（LPS）会增加小鼠皮肤中的血浆泄漏。通过LPS条件预处理小鼠对LPS诱导的血浆泄漏的耐受性。一氧化氮（NO）被认为参与了这些LPS效应。使用iNOS缺乏小鼠研究了在LPS诱导的血浆泄漏中，研究了诱导的NO合酶（INOS）的特定作用。据推测，LPS的大多数生物学活性都检查了脂质A类似物（Ono-4007）对增加血浆泄漏的影响。皮下注射LPS在预注射静脉注射的小鼠中随着浮蓝色染料的剂量增加，INOS防御和野生型小鼠的染料泄漏的剂量增加，INOS防御性小鼠的染料泄漏量降低了约40％。 LPS诱导的染料泄漏没有受到iNOS缺乏小鼠的NOS和LPS预处理的抑制剂的抑制。这些研究表明，LPS诱导的染料泄漏是由INOS，Prostaglandin（PG），组胺和TNF-α产生的NO介导的。对LPS诱导的血管通透性变化的耐受性可以通过iNOS诱导介导。皮下注射ONO-4007诱导染料泄漏的剂量依赖性增加。在iNOS缺乏小鼠中，Ono-4007增加了染料泄漏。组成型NOS衍生的NO，TNF-α和IL-1α，但PG或组胺不起作用，在ONO-4007引起的血浆泄漏的增加中起作用。尽管ONO-4007模仿LPS在增加血管通透性中，但Ono-4007引起的渗透性变化的机制与LPS的渗透性变化不同。 ONO-4007诱导了LPS，ONO-4007和炎症介质引起的对等离子体泄漏的短暂耐受性。内源性皮质酮至少在耐受性的发展中起作用。 LPS诱导的耐受性可能为治疗败血症提供潜在的基础，脂质A模拟可能可作为败血性休克的预防性治疗。