VITAMIN D AND PULMONARY HOST DEFENSE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 对于大多数人来说，肺部具有处理各种吸入细菌的非凡能力。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出现，在某些情况下还会出现肺炎。众所周知，暴露在香烟烟雾中和年龄增加是导致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的增加有关。例如，吸烟的人(其中一些人患有慢性阻塞性肺疾病(COPD))会增加细菌感染的数量，而结节病(结节病)患者则不会(除非他们出现与支气管扩张症相关的肺部结构变化)。在这些患者群体中(尤其是COPD)，细菌感染的发生率和严重程度仍然存在差异。细菌感染在其他方面健康的受试者之间、不同类型的肺部疾病之间以及同一类型的肺部疾病内的这种差异的原因尚不清楚。 细菌感染易感性的差异部分是由于接触感染剂、遗传易感性和先天(或早期)免疫反应的差异。令人感兴趣的是，细菌感染的发生率和严重性在冬季最严重。除了病毒感染，几乎没有随季节变化的变量。维生素D是一种已知的免疫调节剂，具有季节性周期性。维生素D在皮肤中以不活跃的形式产生，经过一系列的羟化反应(一次在肝脏，一次在肾脏或巨噬细胞中)，导致循环中活性酶1，25(OH)D3的水平。活性维生素D通过与维生素D受体相互作用发挥转录效应，维生素D受体存在于许多细胞系中。在冬季，多种因素共同导致维生素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(尤其是老年人)，以及3)在户外时皮肤覆盖率增加。已描述的维生素D的先天免疫作用包括增加巨噬细胞的分化和功能，以及增加巨噬细胞和上皮细胞分泌可溶介质和抗菌肽。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。相比之下，活动性结节(细菌感染没有增加)与维生素D状态增加有关，这是由于激活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水平是肺部抵御吸入细菌的先天防御能力的重要决定因素。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天然免疫功能都有影响。

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.