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不清楚。我们已经证明，S.C.注射内毒素会增加小鼠皮肤局部的血浆渗漏(Fujii等人，1996)。在本研究中，我们比较了LTA和LPS对小鼠皮肤局部血浆渗漏的影响。由于我们先前的研究表明，小剂量的内毒素可诱导耐受(Fujii et al.，1996)，因此我们也研究了小剂量的LTA预处理是否能像LPS一样诱导耐受。随着蓬塔明天蓝色染料在皮肤中局部渗漏增加。吲哚美辛、苯海拉明和PAF拮抗剂可抑制LTA诱导的染料渗漏，但不能被一氧化氮合酶、环氧合酶-2、鸟苷环化酶抑制剂或抗肿瘤坏死因子-α或白介素1-α抗体所抑制。在炎性介质中，二十烷基类化合物、PAF和组胺同时介导LTA和LTA的作用，而NO、肿瘤坏死因子-α和IL-1α在LTA诱导的染料渗漏中可能不起主要作用。LTA诱导的小鼠的染料渗漏不受影响。提示内源性糖皮质激素在微循环中可能参与内源性糖皮质激素耐受的形成。内毒素诱导的耐受性可能为脓毒症的治疗提供潜在的基础，尽管LTA可能不能作为感染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.