期刊
CRITICAL CARE MEDICINE
卷 31, 期 6, 页码 1808-1818出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.CCM.0000069343.27691.F3
关键词
Toll-like receptor; sepsis; cecal ligation and puncture
资金
- NIAID NIH HHS [AI 45829] Funding Source: Medline
- NIGMS NIH HHS [GM 53522] Funding Source: Medline
Objective: To determine whether there was a correlation between induction of polymicrobial sepsis, modulation of tissue Toll-like receptor (TLR) gene, and protein expression and survival outcome. Design: Prospective, randomized animal study. Setting: University medical school research laboratory. Subjects: Age- and weight-matched ICR/HSD mice. Interventions: Sepsis was induced by cecal ligation and puncture (CLP). No-surgery and sham (laparotomy)-operated mice were controls. We also examined tissue TLR2 and TLR4 messenger RNA and TLR4 protein levels in mice treated with an immunomodulator that increases survival in polymicrobial sepsis. In the immunomodulator study, mice were treated with glucan phosphate (50 mg/kg, intra peritoneally) 1 hr before CLP. No-surgery, sham surgery, glucan + no-surgery, sham surgery + glucan, and CLP groups were employed as controls. Measurements and Main Results. Total RNA was isolated from liver, lung, and spleen at 0, 1, 3, 6, 8, and 24 hrs after CLP. TLR gene expression was assessed by reverse transcription-polymerase chain reaction. Tissue TLR4 protein levels were evaluated at 24 hrs by Western blot and immunohistochemistry. CLP sepsis increased (p < .05) liver and lung TLR2 and TLR4 gene expression compared with controls. TLR4 protein concentrations also were increased. Increased TLR2/4 gene and TLR4 protein expression correlated with mortality. Immunoprophylaxis with glucan phosphate increased (P < .001) long-term survival (20% vs. 70%) but inhibited (p < .05) CLP-induced increases in tissue TLR2 and TLR4 messenger RNA expression as well as TLR4 protein expression. Conclusions: Early increases in TLR2/4 gene and TLR4 protein expression correlated with mortality, whereas blunting TLR gene and protein expression correlated with improved long-term survival. This suggests that early up-regulation of tissue TLR2/4 may play a role in the proinflammatory response and pathophysiology of polymicrobial sepsis.
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