COMBINED IMMUNOSUPPRESSIVE AND ANTIBIOTIC THERAPY IMPROVES BACTERIAL CLEARANCE AND SURVIVAL OF POLYMICROBIAL SEPTIC PERITONITIS
COMBINED IMMUNOSUPPRESSIVE AND ANTIBIOTIC THERAPY IMPROVES BACTERIAL CLEARANCE AND SURVIVAL OF POLYMICROBIAL SEPTIC PERITONITIS
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DOI：
10.1097/shk.0b013e3181ab9014
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发表时间：
2010-02-01
期刊：
影响因子：
3.1
通讯作者：
Emmanuel, Klaus L.
中科院分区：
文献类型：
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作者：
Assfalg, Volker;Hueser, Norbert;Emmanuel, Klaus L.
有效的免疫抑制治疗是预防移植排斥反应的关键，但会使患者容易受到机会性感染。本研究探讨了常见免疫抑制药物对实验性小鼠感染性腹膜炎病程的影响。我们发现联合应用他克莫司、霉酚酸酯和甲基强的松龙可显著提高感染性腹膜炎的死亡率。然而，当免疫抑制药物与抗生素治疗相结合时，小鼠几乎完全得到了保护。霉酚酸酯和甲基强的松龙的联合应用被证明是必要的，并且足以在抗生素治疗的情况下改善败血症腹膜炎的预后。联合免疫抑制和抗生素治疗，但不是单独使用抗生素治疗，可以提高细菌清除能力。这些有益的影响与腹膜中性粒细胞激活标志物的表达增加和活性氧代谢物的产生增加有关，并与抑制细胞因子IL-22的信使RNA表达减少有关。而全身或腹膜IL-10、IL-12、肿瘤坏死因子-α、角质形成细胞趋化因子和单核细胞趋化蛋白-1水平以及脾组织中干扰素-γ的信使RNA水平不受免疫抑制治疗的影响。因此，这些结果表明，免疫抑制和抗生素联合治疗可能通过增强中性粒细胞的激活和抗菌活性以及减少IL-22的产生来改善感染性腹膜炎的细菌清除和存活率。
Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and m ethyl prednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.