炎症動物モデルを用いた敗血症治療への展望(最終講義)

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  • サイシュウ コウギ エンショウ ドウブツ モデル オ モチイタ ハイケツショウ チリョウ エ ノ テンボウ
  • A Perspective of Prophylactic Therapies for Sepsis : Study Using Vascular Permeability in the Skin of Mice(Lecture)

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Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria. Our previous study showed that subcutaneous injection of LPS dose-dependently increased plasma leakage in a mouse's skin. Tolerance to plasma leakage can be achieved by pretreating with low-dose LPS. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Lipoteichoic acid (LTA) is the cell wall component of Gram-positive bacteria. Its potency to induce microvascular inflammatory response has not been clarified. In this study, we compared the effect of LPS, lipid A, and LTA on local plasma leakage in the skin of mice. Lipid A andLTA dose-dependently increased plasma leakage. Among the inflammatory mediators, eicosanoids, plateletactivating factor and histamine mediated the effect of both LPS and LTA, whereas nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-1α did not play a major role in the LTA-induced plasma leakage. Plasma leakage did not affect with LTA in the LTA-primed mice. Serum corticosterone levels, which were suggested to induce tolerance, did not increase with LTA pretreatment but increased with LPS. These results suggest that endogenous glucocorticoids may play a role in the development of LPS-induced tolerance in microcirculation. The tolerance against the change of LPS-induced vascular permeability may be mediated by the NO produced by inducible NO synthase (iNOS). Although lipid A mimics LPS in their increasing vascular permeability, the mechanisms of permeability change elicited by lipid A were not identical to those of LPS. The tolerance by LPS could provide a base for future treatment of sepsis. NO, cytokine and lipid A analog may be used as a prophylactic therapy of septic shock.

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