OZONE EFFECTS ON FUNCTION OF SURFACTANT PROTEIN VARIANTS

臭氧是光化学污染或烟雾的主要成分， 在美国有近7000万人，O3是一种强氧化剂， 蛋白质和脂质。 这导致肺部炎症和上皮细胞 损伤，并导致肺损伤和表面活性剂紊乱。 表面活性蛋白A（SP-A），两个基因（SP-A1和SP-A2）的产物 在人体中，被O3氧化，导致表面活性剂功能障碍。 然而，SP-A也在先天宿主防御中发挥作用，包括 巨噬细胞对促炎细胞因子表达的调节。 因此，O_3对SP-A的氧化作用可能在干扰寄主的过程中起一定作用 暴露于O3的肺部的防御，包括炎症和 易受某些病原体感染。 与所有这些 O3相关的反应，有很大的变异性之间的个人。 SP-A的许多遗传变异已被表征， 低水平SP-A mRNA和特定基因型之间的关系， 这解释了SP-A mRNA水平的高度变异性， 报道 该建议的核心假设是，一些SP-A 变体比其他变体更容易被O3氧化， 这种变异性导致了 不同的人到O3。 这一假设将通过暴露 SP-A变体由O3的两种基因产物组成，并研究其 调节巨噬细胞样THP-1中细胞因子表达的能力 细胞系（Aim 1）。 暴露于O3的SP-A变体结合 将测试甘露糖，以及这种结合对 SP-A对细菌的识别及其随后的 THP-1细胞（Aim 2）。 这些终点也将使用SP-A进行检验 由单个基因产物组成的变体（Aim 3）。 那么， 负责03诱导的SP-A变化的特定氨基添加物 功能将通过位点特异性诱变进行研究（目的4）。 的 拟议的研究将有助于阐明不同SP-A的特性 变种和这些O3暴露的差异反应。的 从这些研究中获得的知识将有助于我们理解 暴露在O3中的个体差异性很大， 处于O3诱导的肺病理学风险的个体，并建议 治疗策略，以防止由于O3暴露引起的问题。

Ozone, a major constituent of photochemical pollution or smog, affects nearly 70 million people in the U.S. O3, a potent oxidant, reacts with proteins and lipids. This leads to lung inflammation and epithelial damage, and contributes to lung injury and surfactant derangement. Surfactant protein A (SP-A), the product of two genes (SP-A1 and SP-A2) in humans, is oxidized by O3, contributing to surfactant dysfunction. However, SP-A also plays a role in innate host defense, including the regulation of proinflammatory cytokine expression by macrophages. Therefore, SP-A oxidation by O3 may play a role in disturbances of host defense in the O3-exposed lung, including inflammation and susceptibility to infection with certain pathogens. With all of these O3-related responses, there is great variability among individuals. Many genetic variants of SP-A have been characterized and an association between low levels of SP-A mRNA and a particular genotype have been made, explaining the high variability in SP-A mRNA levels that have been reported. The central hypothesis of this proposal is that some SP-A variants are more susceptible to oxidation by O3 than others and that this variability results in the marked response heterogeneity of different individuals to O3. This hypothesis will be tested by exposing SP-A variants comprised of both gene products to O3 and studying their ability to modulate cytokine expression in the macrophage-like THP-1 cell line (Aim 1). The ability of the O3-exposed SP-A variants to bind mannose will be tested, as will the effect or this binding on the recognition of bacteria by SP-A and their subsequent phagocytosis by THP-1 cells (Aim 2). These endpoints will also be tested with SP-A variants comprised of a single gene product (Aim 3). Then the role of the specific amino adds responsible for the 03-induced changes in SP-A function will be studied by site-specific mutagenesis (Aim 4). The proposed studies will help elucidate the properties of different SP-A variants and the differential response of these to O3 exposure. The knowledge from these studies will add to our understanding of the basis of the high individual variability to O3 exposure, help us identify individuals at risk for 03-induced lung pathology, and suggest therapeutic strategies to prevent problems due to 03 exposure.