Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Antimicrob Agents Chemother. 2017 Sep 22;61(10). doi: 10.1128/AAC.01226-17. Print 2017 Oct.
The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is the most effective regimen for therapy of pneumonia (PCP). As many patients with PCP are allergic or do not respond to it, efforts have been devoted to develop alternative therapies for PCP. We have found that the combination of vitamin D (VitD3) (300 IU/kg/day) and primaquine (PMQ) (5 mg/kg/day) was as effective as TMP-SMX for therapy of PCP. In this study, we investigated the mechanisms by which vitamin D enhances the efficacy of PMQ. C57BL/6 mice were immunosuppressed by CD4 cell depletion, infected with for 8 weeks, and then treated for 9 days with the combination of VitD3 and PMQ (VitD3-PMQ) or with TMP-SMX or PMQ to serve as controls. The results showed that vitamin D supplementation increased the number of CD11c cells, suppressed the production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], and interleukin-6 [IL-6]) and inducible nitric oxide synthase (iNOS), and enhanced the expression of genes related to antioxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit), antimicrobial peptides (cathelicidin), and autophagy (ATG5 and beclin-1). These results suggest that the main action of vitamin D is enhancing the ability of the host to defend against infection.
复方磺胺甲噁唑（TMP-SMX）是治疗肺炎（PCP）最有效的方案。由于许多患有 PCP 的患者对此过敏或无反应，因此人们一直致力于开发治疗 PCP 的替代疗法。我们发现，维生素 D（VitD3）（300 IU/kg/天）和伯氨喹（PMQ）（5 mg/kg/天）联合治疗 PCP 的效果与 TMP-SMX 相当。在这项研究中，我们研究了维生素 D 增强 PMQ 疗效的机制。用 CD4 细胞耗竭使 C57BL/6 小鼠免疫抑制，用感染 8 周，然后用 VitD3 和 PMQ（VitD3-PMQ）联合或用 TMP-SMX 或 PMQ 治疗 9 天作为对照。结果表明，维生素 D 补充增加了 CD11c 细胞的数量，抑制了促炎细胞因子（肿瘤坏死因子-α[TNF-α]、γ干扰素[IFN-γ]和白细胞介素-6[IL-6]）和诱导型一氧化氮合酶（iNOS）的产生，并增强了与抗氧化（谷胱甘肽还原酶和谷氨酸-半胱氨酸连接酶修饰亚基）、抗菌肽（cathelicidin）和自噬（ATG5 和 beclin-1）相关的基因表达。这些结果表明，维生素 D 的主要作用是增强宿主抵御感染的能力。
