Abstract：
Host-directed therapy (HDT) with vitamin D in tuberculosis (TB) is beneficial only if the subject is deficient in vitamin D. We investigated pulmonary delivery of 1,25-dihydroxy vitamin D3 (calcitriol) in mice infected with Mycobacterium tuberculosis (Mtb). We made two kinds of dry powder inhalations (DPI)- soluble particles or poly(lactide) (PLA) particles. We compared treatment outcomes when infected mice were dosed with a DPI alone or as an adjunct to standard oral anti-TB therapy (ATT). Mice infected on Day 0 were treated between Days 28-56 and followed up on Days 57, 71, and 85. Neither DPI significantly reduced Mtb colony forming units (CFU) in the lungs. Combining DPI with ATT did not significantly augment bactericidal activity in the lungs, but CFU were 2-log lower in the spleen. CFU showed a rising trend on stopping treatment, sharper in groups that did not receive calcitriol. Lung morphology and histology improved markedly in animals that received PLA DPI; with or without concomitant ATT. Groups receiving soluble DPI had high mortality. DPI elicited cathelicidin, interleukin (IL)-1 and induced autophagy on days 57, 71, and 85. Macrophage-targeted calcitriol is therefore bacteriostatic, evokes innate microbicidal mechanisms, and mitigates pathology arising from the host response to Mtb.
摘要：
只有当受试者缺乏维生素D时，结核病（TB）中的维生素D的宿主导向疗法（HDT）才是有益的。我们研究了感染结核分枝杆菌（Mtb）的小鼠中1,25-二羟基维生素D3（骨化三醇）的肺部递送。我们制备了两种干粉吸入剂（DPI）-可溶性颗粒或聚乳酸（PLA）颗粒。我们比较了当感染的小鼠单独使用DPI或作为标准口服抗结核治疗（ATT）的辅助剂量时的治疗结果。在第0天感染的小鼠在第28-56天之间进行治疗,并在第57、71和85天进行随访。DPI均未显著降低肺中的Mtb集落形成单位(CFU)。将DPI与ATT结合使用并没有显着增强肺部的杀菌活性，但脾脏中CFU低2-log。CFU在停止治疗时表现出上升趋势，在没有接受骨化三醇的组中更尖锐。在接受PLADPI的动物中,肺形态和组织学显著改善;有或没有伴随的ATT。接受可溶性DPI的组具有高死亡率。新闻部引发了卡萨利菌素，白细胞介素（IL）-1和在第57、71和85天诱导自噬。因此，针对巨噬细胞的骨化三醇具有抑菌性，唤起先天的杀菌机制，并减轻宿主对Mtb的反应引起的病理。
