Walker Adam K, Hsieh Jennifer, Luu Katherine V, Radwan Aiat A, Valverde Gabriella R, Dickey Burton F, Tuvim Michael J, Dantzer Robert
Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Brain Behav Immun. 2014 May;38:211-9. doi: 10.1016/j.bbi.2014.02.004. Epub 2014 Feb 15.
Pneumonia represents a leading cause of death. Recently, a novel treatment strategy for pneumonia has involved enhancing the host pulmonary innate immune response by pre-exposure to aerosolized toll-like receptor (TLR)9 and TLR2/6 agonists, known as O/P. O/P inhalation in mice has been demonstrated to stimulate innate lung immunity, and thus increase survival against subsequent pneumonia infection while producing barely detectable increases in systemic cytokines. Here, we examined the safety of O/P treatment when used in mice that are inflamed systemically. Swiss-Webster mice were treated with two doses of aerosolized O/P (1× or 8×) vs phosphate buffered saline (PBS) either immediately before intraperitoneal injection of 0.1mg/kg lipopolysaccharide (LPS) or PBS (equivolume) or 2h after. Sickness responses (reduced body weight, food intake, activity and social interaction) were examined at 2 and 5.5h post-treatment. Immediately following behavioral testing, mice were euthanized, perfused with PBS, and brains, spleens, livers and lungs snap frozen for assessment of pro-inflammatory cytokine mRNAs. While O/P treatment alone increased lung IL-1β, IFNγ and TNF-α, no such effects were observed in the brain, spleen or liver. Furthermore, there was no evidence that O/P treatment administered before or after LPS had any synergizing effect to potentiate the cytokine response to LPS in any compartment measured. Supportive of these findings were the measures of sickness behaviors that did not show any increased sickness response in O/P-treated mice exposed to LPS, suggestive that the cytokine signal produced in the lungs from O/P inhalation did not propagate to the brain and synergize with LPS-induced neuroinflammation. These findings support the safety of the use of O/P inhalation as a preventative measure against pneumonia and demonstrate a unique ability of the lungs to compartmentalize pulmonary inflammation and limit propagation of the cytokine signal to the brain.
肺炎是主要的死亡原因之一。最近，一种针对肺炎的新型治疗策略涉及通过预先暴露于雾化的Toll样受体（TLR）9和TLR2/6激动剂（称为O/P）来增强宿主肺部的固有免疫反应。已证明在小鼠中吸入O/P可刺激肺部固有免疫，从而提高其在后续肺炎感染中的存活率，同时全身细胞因子的增加几乎检测不到。在此，我们研究了在全身炎症的小鼠中使用O/P治疗的安全性。将瑞士韦伯斯特小鼠在腹腔注射0.1mg/kg脂多糖（LPS）或PBS（等体积）之前或之后2小时，用两剂雾化的O/P（1倍或8倍）与磷酸盐缓冲盐水（PBS）进行处理。在处理后2小时和5.5小时检查疾病反应（体重减轻、食物摄入量、活动和社交互动减少）。行为测试后立即对小鼠实施安乐死，用PBS灌注，然后将脑、脾、肝和肺速冻以评估促炎细胞因子mRNA。虽然单独的O/P治疗可增加肺部的IL-1β、IFNγ和TNF-α，但在脑、脾或肝中未观察到此类作用。此外，没有证据表明在LPS之前或之后给予O/P治疗有任何协同作用来增强在任何测量隔室中对LPS的细胞因子反应。支持这些发现的是疾病行为测量结果，其显示在暴露于LPS的O/P处理小鼠中没有任何疾病反应增加，这表明吸入O/P在肺部产生的细胞因子信号没有传播到大脑并与LPS诱导的神经炎症协同作用。这些发现支持将吸入O/P用作预防肺炎措施的安全性，并证明了肺部将肺部炎症分隔开并限制细胞因子信号向大脑传播的独特能力。
