VITAMIN D AND PULMONARY HOST DEFENSE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对于大多数人来说，肺具有处理各种吸入细菌的显着能力。 然而，有些人确实有反复的细菌感染，通常以急性或慢性支气管炎的形式，在某些情况下，肺炎。 众所周知，暴露于香烟烟雾和年龄的增加是更频繁的细菌性肺部感染的危险因素。 有趣的是，一些但不是所有的肺部疾病都与细菌感染增加有关。 例如，吸烟者（其中一些患有慢性阻塞性肺病（COPD））的细菌感染数量增加，而结节病（结节病）患者则不会（除非他们发生与支气管扩张相关的肺结构变化）。 在这些患者人群（尤其是COPD）中，细菌感染的发生率和严重程度仍存在差异。 对于其他健康受试者之间、不同类型的肺部疾病之间以及同一类型肺部疾病内细菌感染的这种差异性的原因知之甚少。 细菌感染易感性的变异性部分由感染因子暴露、遗传易感性和先天（或早期）免疫反应的差异来解释。 有趣的是，细菌感染的发生率和严重程度在冬季最高。 除了病毒感染，几乎没有什么变量会随季节而变化。 维生素D是一种已知的具有季节性周期性的免疫调节剂。 维生素D在皮肤中以非活性形式产生，通过连续的羟基化（一个在肝脏中，一个在肾脏或巨噬细胞中），导致活性酶1，25（OH）D3的循环水平。 活性维生素D通过与存在于许多细胞谱系中的维生素D受体相互作用来发挥转录作用。 在冬季，多种因素导致维生素D水平下降：1）阳光的持续时间和强度较短，2）大多数人在户外的时间较少（特别是老年人），3）在户外时皮肤覆盖增加。 所描述的维生素D的先天免疫作用包括增加巨噬细胞分化和功能能力以及增加巨噬细胞和上皮细胞分泌可溶性介质和抗菌肽。 COPD与感染增加有关，与相对维生素D缺乏和骨质疏松症有关。 相反，活动性类肉瘤（细菌感染没有增加）与维生素D状态增加有关，这是由于活化的巨噬细胞增加了活性维生素D的产生。 这些观察结果导致了一种假设，即维生素D水平是肺对吸入细菌的先天防御的重要决定因素。 这些研究人员进一步假设，维生素D对肺泡巨噬细胞和肺上皮细胞的先天免疫功能都有影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For most individuals the lung has a remarkable ability to deal with exposure to a variety of inhaled bacteria. Some individuals, however, do have recurrent bacterial infections, usually in the form of acute or chronic bronchitis and, in some instances, pneumonia. It is known that exposure to cigarette smoke and increasing age are risk factors for more frequent bacterial lung infections. Interestingly, some, but not all lung diseases, are associated with increased bacterial infections. For example, individuals who smoke (some of whom have chronic obstructive lung disease (COPD)) have increased numbers of bacterial infections while patients with sarcoidosis (sarcoid) do not (unless they develop the structural changes in the lung associated with bronchiectasis). Within these patient populations (especially COPD), there is still variability in the incidence and severity of bacterial infections. The reasons for this variability in bacterial infections between otherwise healthy subjects, between types of lung disease, and within the same type of lung disease are poorly understood. Variability in susceptibility to bacterial infections is partially explained by differences in exposure to infectious agents, genetic susceptibility and innate (or early) immune responses. It is of interest that the incidence and severity of bacterial infections is greatest during the winter months. Other than viral infections, there are few variables that change with season. Vitamin D is one known immune modulator with a seasonal periodicity. Vitamin D is produced in the skin as an inactive form that goes through sequential hydroxylations (one in the liver and one in the kidney or in macrophages) that results in circulating levels of the active enzyme, 1,25(OH)D3. Active vitamin D exerts transcriptional effects through interactions with the vitamin D receptor, present in many cell lineages. During the winter months a combination of factors leads to decreased vitamin D levels: 1) the duration and strength of sunlight is less, 2) most individuals spend less time outside (especially elderly populations) and 3) increased skin covering when outside. Described innate immune effects of vitamin D include increased macrophage differentiation and functional competence and increased secretion of soluable mediators and anti-bacterial peptides by macrophages and epithelial cells. COPD, associated with increased infections, is associated with relative vitamin D deficiency and osteoporosis. In contrast, active sarcoid (with no increase in bacterial infections) is associated with an increased vitamin D state due to increased production of active vitamin D by activated macrophages. These observations led to the hypothesis that levels of vitamin D are an important determinant of the innate defense of the lung against inhaled bacteria. These investigators further postulate that vitamin D has effects on the innate immune function of both alveolar macrophages and lung epithelial cells.