Endotoxin-induced desensitization for mouse dermal vascular permeability.

皮下注射内毒素（LPS）和一些炎症介质增加了注射部位的染料泄漏，表明皮肤微血管通透性增加。我们研究了在雄性小鼠全身给予单一低剂量LPS后，脱敏是否发展为LPS或炎症介质引起的通透性增加。血浆外渗通过LPS及介质注射部位的Pontamine sky blue渗漏来测定。LPS诱导小鼠的5-羟色胺（5-HT）、血小板活化因子、P物质或组胺引起的染料渗漏*明显减少60-80%，提示同源和异源耐受的形成。预处理肿瘤坏死因子(TNF)- α和白细胞介素(IL)- α可诱导LPS耐受，而IL-6不能诱导，抗TNF- α抗体和抗IL-1 α抗体逆转LPS诱导的耐受。肾上腺切除小鼠的同种耐受性消失。同时给予LPS和一氧化氮合酶抑制剂N^ g -硝基- l -精氨酸甲酯预处理后，小鼠对LPS和5-HT的低反应性消失。这些结果提示内源性细胞因子、糖皮质激素和NO可能在lps诱导的微循环耐受的发展中起作用。LPS诱导的耐受性可能为脓毒性休克的治疗提供潜在的基础。

Subcutaneous injection of endotoxin (LPS) and some inflammatory mediators to mice increases the dye leakage at the site of injection indicating the increased dermal microvascular permeability. We investigated whether desensitization develops to the increase in permeability elicited by LPS or inflammatory mediators after systemic administration of a single low-dose LPS in male mice. Plasma extravasation was determined by Pontamine sky blue leakage at the site of the skin where LPS and mediators were injected s.c. The dye leakage *duced by LPS, 5-hydroxytryptamine (5-HT), platelet-activating factor, substance P or histamine was significantly decreased by 60-80% in LPS-primed mice, which indicates the development of homologous and heterologous tolerance. Pretreatment with tumor necrosis factor (TNF)-alpha and interleukin (IL)-lalpha but not IL-6 induced the tolerance to LPS, and anti-TNF-alpha antibody and anti-IL-1alpha antibody reversed the LPS-induced tolerance. Homologous tolerance disappeared in the adrenalectomized mice. When mice were pretreated with both LPS and N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, the hyporesponsiveness to LPS and 5-HT disappeared. These results suggest that endogenous cytokines, glucocorticoids and NO 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 septic shock.