Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Herestraat 49, O&NI bis, Box 706, B-3000, Leuven, Belgium.
Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
Respir Res. 2022 Mar 29;23(1):76. doi: 10.1186/s12931-022-01997-9.
Evidence supports a critical role of vitamin D status on exacerbation in chronic obstructive pulmonary disease, indicating the need to avoid vitamin D deficiency in these patients. However, oral vitamin D supplementation is limited by the potential risk for hypercalcemia. In this study, we investigated if local delivery of vitamin D to the lungs improves vitamin D-mediated anti-inflammatory action in response to acute inflammation without inducing hypercalcemia.
We studied vitamin D sufficient (VDS) or deficient (VDD) mice in whom 1α,25(OH)D (0.2 μg/kg) or a vehicle followed by lipopolysaccharide (LPS 25 µg) were delivered to the lung as a micro-spray.
Local 1α,25(OH)D reduced LPS-induced inflammatory cells in bronchoalveolar lavage (BAL) in VDS (absolute number of cells: - 57% and neutrophils - 51% p < 0.01) and tended to diminish LPS-increased CXCL5 BAL levels in VDS (- 40%, p = 0.05) while it had no effect on CXCL1 and CXCL2 in BAL and mRNA in lung of VDS and VDD. It also significantly attenuated the increased IL-13 in BAL and lung, especially in VDD mice (- 41 and - 75%, respectively). mRNA expression of Claudin-18 in lung was significantly lower in VDS mice with local 1α,25(OH)D while Claudin-3, -5 and -8 mRNA levels remained unchanged. Finally, in VDD mice only, LPS reduced lung mRNA expression of adhesion junction Zona-occludens-1, in addition to increasing uric acid and total protein in BAL, which both were prevented by local 1α,25(OH)D.
Under normal levels of vitamin D, local 1α,25(OH)D nebulization into the lung efficiently reduced LPS induction of inflammatory cells in BAL and slightly attenuated LPS-increase in CXCL5. In case of severe vitamin D deficiency, although local 1α,25(OH)D nebulization failed to significantly minimize cellular inflammation in BAL at this dose, it prevented epithelial barrier leakage and damage in lung. Additional research is needed to determine the potential long-term beneficial effects of local 1α,25(OH)2D3 nebulization on lung inflammation.
有证据表明，维生素 D 状态对慢性阻塞性肺疾病（COPD）加重起关键作用，这表明需要避免这些患者出现维生素 D 缺乏。然而，口服维生素 D 补充剂受到高钙血症潜在风险的限制。在这项研究中，我们研究了局部向肺部输送维生素 D 是否可以改善维生素 D 介导的抗炎作用，而不会引起高钙血症。
我们研究了维生素 D 充足（VDS）或缺乏（VDD）的小鼠，用微喷雾器将 1α，25（OH）D（0.2μg/kg）或载体与脂多糖（LPS 25μg）一起递送到肺部。
局部 1α，25（OH）D 减少了 VDS 中 LPS 诱导的支气管肺泡灌洗液（BAL）中的炎症细胞（绝对细胞数减少 57%，中性粒细胞减少 51%，p<0.01），并倾向于降低 VDS 中 LPS 增加的 CXCL5 BAL 水平（减少 40%，p=0.05），而对 BAL 中的 CXCL1 和 CXCL2 以及 VDS 和 VDD 肺中的 mRNA 没有影响。它还显著减轻了 BAL 和肺中 IL-13 的增加，特别是在 VDD 小鼠中（分别减少 41%和 75%）。用局部 1α，25（OH）D 后，VDS 小鼠肺中的 Claudin-18 mRNA 表达明显降低，而 Claudin-3、-5 和 -8 mRNA 水平保持不变。最后，仅在 VDD 小鼠中，LPS 降低了肺中粘附连接 Zona-occludens-1 的 mRNA 表达，此外还增加了 BAL 中的尿酸和总蛋白，这些都被局部 1α，25（OH）D 所预防。
在正常维生素 D 水平下，将 1α，25（OH）D 局部雾化到肺部可有效减少 LPS 诱导的 BAL 中炎症细胞的产生，并略微减少 LPS 诱导的 CXCL5 增加。在严重维生素 D 缺乏的情况下，尽管局部 1α，25（OH）D 雾化在此剂量下未能显著减轻 BAL 中的细胞炎症，但它预防了肺上皮屏障的渗漏和损伤。需要进一步研究来确定局部 1α，25（OH）2D3 雾化对肺部炎症的潜在长期有益影响。
