Inhibition of lung defense by air pollutant particulates

描述（由申请人提供）：细颗粒空气污染与呼吸道感染和心血管疾病导致的死亡率增加有关。气道有许多机制来抑制环境中微生物的入侵和定殖，但人们对空气颗粒污染如何影响气道上皮的先天免疫宿主防御机制知之甚少。气道防御的一个组成部分是抗菌肽的产生，例如气管粘膜中的防御素。体外和体内实验表明，这些肽在先天宿主防御中发挥作用，既可以作为直接抗菌剂，也可以作为连接先天性和适应性免疫反应的趋化因子。细菌脂多糖 (LPS) 可以增加气管上皮细胞 (TEC) 中的防御素的产生，从而导致特定上游的 NF-(B 的激活和结合) (-防御素基因。我们最近发表的数据表明，低水平的空气污染物颗粒残留油飞灰 (ROFA) 抑制了培养的气道上皮细胞中 LPS 介导的 (-防御素基因表达的诱导。这种抑制归因于颗粒的 V2O5 成分。我们假设钒可能会损害气道的自然宿主防御能力，并导致细菌在气道的定植增加。我们的初步数据表明，低水平的钒(<2.5(g/cm2) 除了牛和人上皮细胞中的防御素外，还抑制 IL-8。由于这种体外观察是出乎意料的，考虑到较高浓度 (>10(g/cm2) 的刺激作用，我们认为在提出更深入的机制研究之前，在体内确认观察结果很重要。因此，我们假设这种对细菌诱导的先天免疫介质的抑制也发生在体内，并将导致革兰氏菌感染增加。在动物模型中证明空气污染物颗粒及其成分可以抑制肺部的抗菌防御，这将使我们能够开展更大规模的研究来检查抑制机制，并帮助进行风险评估。为了解决这一假设，我们建议：1）确定吸入钒对小鼠气道细菌数量和炎症的影响，并确定钒是否通过抑制先天免疫反应影响宿主抵抗感染的能力2）量化。我们研究的长期目标是更好地了解空气污染物颗粒对宿主防御的影响，这项初步研究的目的是通过体内感染模型证实我们的体外结果，将为更详细地研究污染对气道先天免疫防御的影响奠定基础。金属工人和锅炉制造商最近被认为是吸入空气污染物颗粒的有毒成分，这项研究研究了钒如何抑制最初的免疫反应，以防止肺部细菌感染。可以在呼吸道定殖并生长，这将有助于我们制定空气污染物法规，确定空气污染引起的感染风险并制定干预策略。

DESCRIPTION (provided by applicant): Fine particulate air pollution is associated with an increased mortality due to respiratory infection and cardiovascular disease. The airway has many mechanisms to inhibit invasion and colonization of microorganisms from the environment, yet it is poorly understood how particulate air pollution affects innate immune host defenses of airway epithelium. One component of airway defense is the production of antimicrobial peptides such as (-defensins in the tracheal mucosa. In vitro and in vivo experiments have indicated a role for these peptides in the innate host defense as both direct antimicrobial agents and as chemokines that can link the innate and adaptive immune responses. Production of (-defensins in tracheal epithelial cells (TEC) is increased by bacterial lipopolysaccharide (LPS), resulting in the activation and binding of NF-(B upstream from specific (-defensin genes. Our recently published data demonstrate that low levels of an air pollutant particle, residual oil fly ash (ROFA), inhibited the LPS-mediated induction of (-defensin gene expression in cultured airway epithelial cells. This inhibition was attributed to the V2O5 composition of the particle. We hypothesize that vanadium could impair the natural host defense capability of the airway, and allow for increased colonization of the airway with bacteria. Our preliminary data show that low levels of vanadium (<2.5(g/cm2) inhibit IL-8 in addition to (-defensins in bovine and human epithelial cells. Since this in vitro observation is unexpected, given the stimulatory effect of higher concentrations (>10(g/cm2), we feel it is important to confirm the observation in vivo, prior to proposing more in-depth studies on mechanisms. We therefore hypothesize that this inhibition of bacteria-induced innate immune mediators also occurs in vivo, and will result in increased infection with Gram(+) bacteria. Demonstration in an animal model that air pollutant particles and their components can inhibit the antibacterial defenses of the lungs will allow us to develop larger studies to examine the mechanisms of the inhibition, as well as to aid in risk assessment. To address this hypothesis we propose to: 1) Determine the effect of inhaled vanadium on bacterial numbers and inflammation of the mouse airway and determine whether vanadium affects the ability of the host to combat infection through suppression of an innate immune response 2) Quantify the effect of vanadium on innate immune gene expression in mouse airways in response to bacterial infection. The long-range goal of our research is to better understand the effect of air pollutant particles on host defense. The objective of this pilot study is to confirm our in vitro results with an in vivo infection model. Successful results from this study will provide the basis for a more detailed investigation into the mechanism of pollution effects on the innate immune defense of the airway. PUBLIC HEALTH RELEVANCE: Vanadium inhalation has long been associated with infectious lung diseases in metal workers and boilermakers and recently has been implicated as a toxic component of inhaled air pollutant particles. This research studies how vanadium inhibits the initial immune response to prevent bacterial infection in the lung. We will examine the effect on mice inhaling vanadium and then infected with airway pathogens that cause pneumonia, such as Streptococcus zooepidemicus and Staphylococcus aureus. This research will help determine the mechanism and levels of inhaled vanadium necessary to suppress the initial immune response such that bacteria can colonize the airways and grow. This will help us to devise regulations for air pollutants and to determine risk for infection caused by air pollution and to devise intervention strategies.