Inhibition of lung defense by air pollutant particulates

描述(申请人提供)：细颗粒物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。呼吸道有许多机制来抑制来自环境的微生物的入侵和定植，但颗粒性空气污染如何影响呼吸道上皮的天然免疫宿主防御机制却知之甚少。呼吸道防御的一个组成部分是在气管粘膜中产生抗菌肽，如(-防御素)。体外和体内实验表明，这些多肽在天然宿主防御中既是直接的抗菌剂，也是连接天然免疫和获得性免疫反应的趋化因子。细菌脂多糖(LPS)促进了气管上皮细胞(TEC)中(-Defensins)的产生，导致特定(-Defensin)基因上游的核因子-(B)的活化和结合。我们最近发表的数据表明，低水平的空气污染物残留油飞灰(ROFA)可以抑制内毒素诱导培养的呼吸道上皮细胞防御素基因的表达。这种抑制作用归因于颗粒的V2O5组成。我们假设，钒可以损害呼吸道的自然宿主防御能力，并允许增加呼吸道细菌的定植。我们的初步数据显示，低水平的钒(-lt；2.5(g/cm2))除了抑制牛和人上皮细胞的防御素外，还抑制IL-8。由于这种体外观察是意想不到的，考虑到更高浓度(&gt；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，确认体内观察是重要的。因此，我们假设这种对细菌诱导的天然免疫介质的抑制也在体内发生，并将导致更多的革兰氏(+)细菌感染。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，以检查这种抑制的机制，并帮助进行风险评估。为了解决这一假设，我们建议：1)确定吸入钒对小鼠呼吸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)量化钒对小鼠呼吸道先天免疫基因表达的影响，以应对细菌感染。我们研究的长远目标是更好地了解空气污染物颗粒对宿主防御的影响。这项先导性研究的目的是用体内感染模型来证实我们的体外结果。这项研究的成功结果将为更详细地研究污染对呼吸道天然免疫防御的影响机制提供基础。公共卫生意义：长期以来，吸入钒一直与金属工人和锅炉制造商的传染性肺部疾病有关，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初始免疫反应，以防止肺部细菌感染。我们将检查对吸入钒的小鼠的影响，然后感染引起肺炎的呼吸道病原体，如动物疫链球菌和金黄色葡萄球菌。这项研究将有助于确定吸入钒的机制和水平，以抑制最初的免疫反应，使细菌能够在呼吸道定居和生长。这将有助于我们制定有关空气污染物的法规，确定因空气污染而感染的风险，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.