Suppression of Hyperactive Immune Responses Protects against Nitrogen Mustard Injury.
Suppression of Hyperactive Immune Responses Protects against Nitrogen Mustard Injury.
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DOI：
10.1038/jid.2015.322
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Lu KQ
中科院分区：
文献类型：
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作者：
Au L;Meisch JP;Das LM;Binko AM;Boxer RS;Wen AM;Steinmetz NF;Lu KQ
DNA烷化剂如氮芥（NM）容易通过皮肤吸收，并且暴露于此类试剂不仅表现为直接细胞死亡，而且还表现为引发炎症。我们表明，局部芥子气暴露引起的毒性部分介导的启动夸大宿主先天免疫反应。使用皮肤暴露于NM的实验模型，我们观察到炎症性真皮巨噬细胞的活化，其以诱导型一氧化氮合酶（iNOS）依赖的方式加剧局部组织损伤。随后，这些活化的真皮巨噬细胞重新出现在骨髓中，以帮助破坏造血，并最终导致局部NM暴露实验小鼠模型的死亡率。单剂量25-羟基维生素D3（25（OH）D）干预能够抑制巨噬细胞介导的iNOS产生，从而减轻局部皮肤破坏，增强组织修复，防止骨髓耗竭，并从严重的急骤消瘦中拯救出来。这些保护作用通过使用iNOS的药理学抑制剂或通过局部消耗皮肤巨噬细胞的化合物进行实验来重现。总之，这些数据突出了宿主先天免疫系统在暴露于NM后加重损伤中的关键未被认识到的作用，并支持25（OH）D在针对这些化学试剂的治疗用途中的翻译。
DNA alkylating agents like nitrogen mustard (NM) are easily absorbed through the skin and exposure to such agents manifest not only in direct cellular death but also in triggering inflammation. We show that toxicity resulting from topical mustard exposure is mediated in part by initiating exaggerated host innate immune responses. Using an experimental model of skin exposure to NM we observe activation of inflammatory dermal macrophages that exacerbate local tissue damage in an inducible nitric oxide synthase (iNOS)-dependent manner. Subsequently these activated dermal macrophages reappear in the bone marrow to aid in disruption of hematopoiesis and contribute ultimately to mortality in an experimental mouse model of topical NM exposure. Intervention with a single dose of 25-hydroxyvitamin D3 (25(OH)D) is capable of suppressing macrophage-mediated iNOS production resulting in mitigation of local skin destruction, enhanced tissue repair, protection from marrow depletion, and rescue from severe precipitous wasting. These protective effects are recapitulated experimentally using pharmacological inhibitors of iNOS or by compounds that locally deplete skin macrophages. Taken together, these data highlight a critical unappreciated role of the host innate immune system in exacerbating injury following exposure to NM and support the translation of 25(OH)D in the therapeutic use against these chemical agents.