Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA
Division of Infectious Diseases, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York, USA.
Antimicrob Agents Chemother. 2018 Nov 26;62(12). doi: 10.1128/AAC.01462-18. Print 2018 Dec.
Neonatal sepsis and its accompanying inflammatory response contribute to substantial morbidity and mortality. Pentoxifylline (PTX), a phosphodiesterase inhibitor which suppresses transcription and production of proinflammatory cytokines, is a candidate adjunctive therapy for newborn sepsis. We hypothesized that PTX decreases live microbe-induced inflammatory cytokine production in newborn blood. Cord blood was stimulated with live microorganisms commonly encountered in newborn sepsis (, , , or ) and simultaneously treated with antimicrobial agents (gentamicin, vancomycin, or amphotericin B) and/or clinically relevant concentrations of PTX. Microbial colony counts were enumerated by plating, supernatant cytokines were measured by multiplex assay, intracellular cytokines and signaling molecules were measured by flow cytometry, and mRNA levels were measured by quantitative reverse transcription-PCR. PTX inhibited concentration-dependent -, -, -, and -induced tumor necrosis factor (TNF) and -induced interleukin-1β (IL-1β) production in whole blood, with greater suppression of proinflammatory cytokines in combination with antimicrobial agents. Likewise, PTX suppressed -induced monocytic TNF and IL-1β, whereby combined PTX and gentamicin led to significantly greater reduction of TNF and IL-1β. The anti-inflammatory effect of PTX on microbe-induced proinflammatory cytokine production was accompanied by inhibition of mRNA expression and was achieved without suppressing the production of the anti-inflammatory IL-10. Of note, microbial colony counts in newborn blood were not increased by PTX. Our findings demonstrated that PTX inhibited microbe-induced proinflammatory cytokine production, especially when combined with antimicrobial agents, without enhancing microbial proliferation in human cord blood , thus supporting its utility as candidate adjunctive agent for newborn sepsis.
新生儿败血症及其伴随的炎症反应导致了大量的发病率和死亡率。己酮可可碱（PTX）是一种磷酸二酯酶抑制剂，可抑制促炎细胞因子的转录和产生，是新生儿败血症的候选辅助治疗药物。我们假设 PTX 可降低新生血液中活微生物诱导的炎症细胞因子的产生。用新生败血症中常见的活微生物（、、、或）刺激脐血，并同时用抗生素（庆大霉素、万古霉素或两性霉素 B）和/或临床相关浓度的 PTX 进行处理。通过平板计数法对微生物菌落进行计数，通过多重分析测量上清液细胞因子，通过流式细胞术测量细胞内细胞因子和信号分子，通过定量逆转录-PCR 测量 mRNA 水平。PTX 抑制全血中浓度依赖性的、、、和 -诱导的肿瘤坏死因子（TNF）和 -诱导的白细胞介素-1β（IL-1β）产生，与抗生素联合使用时对促炎细胞因子的抑制作用更强。同样，PTX 抑制 -诱导的单核细胞 TNF 和 IL-1β，其中 PTX 和庆大霉素联合使用导致 TNF 和 IL-1β的显著减少。PTX 对微生物诱导的促炎细胞因子产生的抗炎作用伴随着对 mRNA 表达的抑制，且不会抑制抗炎性白细胞介素-10（IL-10）的产生。值得注意的是，PTX 未增加新生儿血液中的微生物菌落计数。我们的研究结果表明，PTX 抑制了微生物诱导的促炎细胞因子的产生，尤其是与抗生素联合使用时，而不会增强人脐血中的微生物增殖 ，因此支持其作为新生儿败血症的候选辅助药物的应用。
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