This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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