Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
J Steroid Biochem Mol Biol. 2019 Mar;187:42-51. doi: 10.1016/j.jsbmb.2018.10.021. Epub 2018 Nov 3.
Chronic obstructive pulmonary disease (COPD), which is characterized by an excessive inflammatory response of the airways, is often complicated by exacerbations. Vitamin D deficiency has been associated with an increased risk for COPD and may predispose COPD patients to a higher exacerbation rate, particularly during smoking. In the current study, we investigated the effect of vitamin D deficiency and cigarette smoke (CS)-exposure on lung inflammation and bacterial clearance after an acute infection with Nontypeable Haemophilus influenzae (NTHi). Vitamin D deficient or sufficient mice were exposed to nose-only CS or ambient air for 6 weeks and oropharyngeally instilled with 10 NTHi. Residual viable NTHi were measured at different time points post-infection. Mechanisms of bacterial clearance (e.g. phagocytosis, pattern recognition receptors, antimicrobial peptides, surfactant proteins and mucin) and lung remodeling (e.g. metalloproteinases, MMP's) were assessed. Although smoking resulted in reduced phagocytosis capacity of macrophages and neutrophils, bacterial clearance was similar to control mice. By contrast and independent of smoking, bacterial clearance was significantly accelerated in vitamin D deficient mice already from 24 h post-infection (p = 0.0087). This faster and complete eradication was associated with a more rapid resolution of cytokines and neutrophils 72 h post-infection and dominated by an upregulation of cathelicidin-related antimicrobial peptide (CRAMP) mRNA during infection (p = 0.026). However, vitamin D deficiency also resulted in more MMP12 protein in broncho-alveolar lavage and a shift in mRNA expression of MMP12/TIMP1 (p = 0.038) and MMP9/TIMP1 (p = 0.024) ratio towards more protease activity. Overall, vitamin D deficient mice resolved NTHi infection faster with a faster resolution of local lung inflammation, possibly through upregulation of CRAMP. This was associated with a disruption of the protease/anti-protease balance, which may potentially scale towards a higher extracellular matrix breakdown.
慢性阻塞性肺疾病（COPD）的特征是气道过度炎症反应，常伴有恶化。维生素 D 缺乏与 COPD 风险增加有关，可能使 COPD 患者恶化率更高，尤其是在吸烟时。在目前的研究中，我们研究了维生素 D 缺乏和香烟烟雾（CS）暴露对非典型流感嗜血杆菌（NTHi）急性感染后肺部炎症和细菌清除的影响。维生素 D 缺乏或充足的小鼠仅暴露于鼻腔 CS 或环境空气中 6 周，并经口咽部滴注 10 个 NTHi。在感染后不同时间点测量残留的活菌 NTHi。评估了细菌清除的机制（例如吞噬作用、模式识别受体、抗菌肽、表面活性剂蛋白和粘蛋白）和肺重塑（例如金属蛋白酶、MMP）。尽管吸烟导致巨噬细胞和中性粒细胞吞噬能力下降，但细菌清除与对照小鼠相似。相比之下，与吸烟无关，维生素 D 缺乏小鼠的细菌清除速度从感染后 24 小时开始明显加快（p=0.0087）。这种更快、更彻底的消除与感染后 72 小时细胞因子和中性粒细胞更快的消退有关，并由感染期间 cathelicidin-related antimicrobial peptide（CRAMP）mRNA 的上调主导（p=0.026）。然而，维生素 D 缺乏也导致支气管肺泡灌洗液中 MMP12 蛋白增加，MMP12/TIMP1（p=0.038）和 MMP9/TIMP1（p=0.024）mRNA 表达的比值向更多蛋白酶活性转移。总的来说，维生素 D 缺乏小鼠更快地解决了 NTHi 感染，局部肺部炎症更快消退，这可能是通过上调 CRAMP 实现的。这与蛋白酶/抗蛋白酶平衡的破坏有关，可能会导致细胞外基质的分解增加。
