Modulation of the phosphoinositide innate resistance to polymicrobial 3-kinase pathway alters sepsis

被引:150
作者
Williams, DL
Li, CF
Ha, TZ
Ozment-Skelton, T
Kalbfleisch, JH
Preiszner, J
Brooks, L
Breuel, K
Schweitzer, JB
机构
[1] E Tennessee State Univ, James H Quillen Coll Med, Dept Surg, Johnson City, TN 37614 USA
[2] E Tennessee State Univ, James H Quillen Coll Med, Dept Biometry & Med Comp, Johnson City, TN 37614 USA
[3] E Tennessee State Univ, James H Quillen Coll Med, Dept Pathol, Johnson City, TN 37614 USA
[4] E Tennessee State Univ, James H Quillen Coll Med, Dept Obstet & Gynecol, Johnson City, TN 37614 USA
关键词
D O I
10.4049/jimmunol.172.1.449
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
We examined the effect of modulating phosphoinositide 3-kinase (PI3K) activity in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Inhibition of PI3K activity with wortmannin increased serum cytokine levels and decreased survival time in septic mice. We have reported that an immunomodulator, glucan phosphate, induces protection in murine polymicrobial sepsis. We observed that glucan stimulated tissue PI3K activity, which positively correlated with increased survival in septic mice. We investigated the effect of PI3K inhibition on survival in septic mice treated with glucan. Treatment of mice with the PI3K inhibitors, wortmannin and LY294002, completely eliminated the protective effect of glucan, indicating that protection against septic mortality was mediated through PI3K. Inhibition of PI3K resulted in increased serum levels of IL1-beta, IL-2, IL-6, IL-10, IL-12, and TNF-alpha in septic mice. Apoptosis is thought to play a central role in the response to septic injury. We observed that inhibition of PI3K activity in septic mice resulted in increased splenocyte apoptosis and a change in the anatomic distribution of splenocyte apoptosis. We conclude that PI3K is a compensatory mechanism that suppresses proinflammatory and apoptotic processes in response to sepsis and/or inflammatory injury. Thus, PI3K may play a pivotal role in the maintenance of homeostasis and the integrity of the immune response during sepsis. We also observed that glucan phosphate decreased septic morbidity and mortality through a PI3K-dependent mechanism. This suggests that stimulation of the PI3K pathway may be an effective approach for preventing or treating sepsis and/or septic shock.
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页码:449 / 456
页数:8
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