CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection.
CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection.
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DOI：
10.4049/jimmunol.1001002
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Gunn MD
中科院分区：
文献类型：
--
作者：
Lin KL;Sweeney S;Kang BD;Ramsburg E;Gunn MD
流感病毒感染诱导严重的肺部免疫病理，导致大量人类死亡。虽然抗病毒治疗在预防感染方面是有效的，但目前没有任何治疗可以预防或治疗流感引起的肺损伤。以前，我们报道了流感诱导的肺部免疫病理是由炎症单核细胞通过CCR 2运输到病毒感染的肺部介导的，并且CCR 2缺陷小鼠中流感诱导的发病率和死亡率降低。在此，我们评估了使用小分子抑制剂（PF-04178903）阻断CCR 2对单核细胞进入肺部以及随后流感感染小鼠发病率和死亡率的影响。在感染流感病毒株PR 8前一天开始皮下注射PF-04178903。与溶剂对照组相比，PF-04178903给药小鼠的死亡率显著降低（75% vs. 0%），并且在随后的流感感染期间体重减轻和体温过低显著降低。药物处理的小鼠还显示支气管肺泡灌洗液（BALF）总蛋白、白蛋白和乳糖脱氢酶（LDH）活性显著降低。PF-04178903给药不会改变病毒滴度、继发性细菌感染的严重程度（S。肺炎）的水平，或抗流感中和Ab的水平。药物治疗的小鼠显示流感核蛋白特异性细胞毒性T细胞活性增加。我们的研究结果表明，CCR 2拮抗剂可能是一种有效的预防流感诱导的肺部免疫病理。
Infection with influenza virus induces severe pulmonary immune pathology that leads to substantial human mortality. While antiviral therapy is effective in preventing infection, no current therapy can prevent or treat influenza-induced lung injury. Previously, we reported that influenza-induced pulmonary immune pathology is mediated by inflammatory monocytes trafficking to virus-infected lungs via CCR2, and that influenza-induced morbidity and mortality are reduced in CCR2-deficient mice. Here, we evaluated the effect of pharmacologically blocking CCR2 with a small molecule inhibitor (PF-04178903) on the entry of monocytes into lungs and subsequent morbidity and mortality in influenza-infected mice. Subcutaneous injection of mice with PF-04178903 was initiated one day prior to infection with influenza strain PR8. Compared to vehicle controls, PF-04178903-treated mice demonstrated a marked reduction in mortality (75% vs. 0%), and had significant reductions in weight loss and hypothermia during subsequent influenza infection. Drug-treated mice also displayed significant reductions in bronchial alveolar lavage fluid (BALF) total protein, albumin, and lactose dehydrogenase (LDH) activity. Administration of PF-04178903 did not alter viral titers, severity of secondary bacteria infections (S. pneumonae), or levels of anti-influenza neutralizing Abs. Drug-treated mice displayed an increase in influenza nucleoprotein-specific cytotoxic T cell activity. Our results suggest that CCR2 antagonists may represent an effective prophylaxis against influenza-induced pulmonary immune pathology.
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DOI：
10.1016/s0140-6736(04)15595-5
发表时间：
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期刊：
Lancet (London, England)
影响因子：
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