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

脂磷壁酸 (LTA) 诱导微血管炎症反应的效力尚未明确。我们已经证明了 s.c.注射内毒素（LPS）会增加小鼠皮肤的局部血浆渗漏（Fujii et al., 1996）。在这项研究中，我们比较了 LTA 和 LPS 对小鼠皮肤局部血浆渗漏的影响。因为我们之前的研究表明，低剂量 LPS 预处理会诱导耐受性 (Fujii et al., 1996)，因此我们还检查了低剂量 LTA 预处理是否会像 LPS 一样诱导耐受性。 Pontamine天蓝色染料增加了皮肤局部染料的渗漏。 LTA 诱导的染料渗漏可被吲哚美辛、苯海拉明和 PAF 拮抗剂抑制，但不能被一氧化氮 (NO) 合酶、环加氧酶 2 或鸟苷酸环化酶抑制剂或肿瘤坏死因子 α (TNF-α) 或白细胞介素 1α (IL-1α) 抗体抑制。在炎症介质中，类二十烷酸、PAF 和组胺介导 LTA 和 LPS 的作用，而 NO、TNF-α 和 IL-1α 可能在 LTA 诱导的染料渗漏中不起主要作用。 LTA 诱导的染料渗漏在 LTA 引发的小鼠中不受影响。 LTA 预处理不会增加血清皮质酮水平，而 LTA 预处理不会增加血清皮质酮水平，而 LTA 会增加血清皮质酮水平。这些结果表明，内源性糖皮质激素可能在微循环中 LPS 诱导的耐受性的发展中发挥作用。 LPS 诱导的耐受性可能为败血症的治疗提供潜在的基础，尽管 LTA 可能无法用作败血性休克的预防性治疗。

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.