Particle-induced Cardiopulmonary Injury In Mice: Genetic

由于颗粒气体暴露可能对公众健康产生影响，确定影响对空气污染物敏感性的宿主因素仍然是一个重要问题。特别关注的是潜在的敏感亚组，如儿童，哮喘患者和老年人。患有心肺疾病的人特别容易受到辐射的影响。最近的证据表明，有些人可能在遗传上容易受到环境压力的影响，包括氧化剂和颗粒。流行病学研究还表明，PM除了对肺部的影响外，还可能对心血管功能产生重大影响。在正在进行的研究中，我们已经开始测试的假设，遗传背景是一个重要的主机因素，有助于个体间的反应，颗粒诱导的免疫功能障碍（发病率的指标）和降低心率变异性（HRV）。 我们最初设计了一项研究，以确定易感基因的肺泡巨噬细胞（AM）的免疫功能障碍诱导吸入硫酸盐相关的炭黑（CB）颗粒在不同易感性B6和C3近交系小鼠。选择AM进行研究是因为它们代表了宿主防御的重要组成部分，并且已经假设受损的宿主防御是颗粒物诱导的呼吸道疾病的重要因素。选择B6和C3小鼠进行研究，因为菌株筛选确定它们在研究的8个菌株中对CBA/SO2诱导的吞噬功能障碍最敏感。一个B6 C3 F2群体在147个SSLP标记处进行基因分型，并且第17号染色体上的QTL超过了由排列检验凭经验确定的统计学显著连锁的阈值。第11号染色体上的QTL超过了暗示连锁的阈值。通过比较作图确定了17号染色体QTL中的候选易感基因，包括Tnf、Lta和Ccl 2（单核细胞趋化蛋白1）。重要的是，这两个QTL重叠以前确定的易感性QTL的肺损伤引起的常见污染物臭氧，以及博莱霉素和辐射。这可能提示肺损伤和炎症的共同调控位点。 我们还开展了一项研究，探讨暴露于金属钒（已知是工业化城市颗粒物的重要组成部分）引起的慢性支气管炎表型易感性的机制。我们已经发现近交系小鼠之间因暴露于钒而诱导的肺表型存在显着变异，并启动了连锁分析以确定导致这种变异的基因。 心率变异性（HRV）的变化和心血管疾病之间的联系已经建立。最近的研究表明，遗传因素对心率变异性有影响。然而，尚未研究使用近交系小鼠品系对心率（HR）和HRV可能差异的全面评估。此外，尚未使用近交系小鼠评估HR和HRV的遗传性。我们已经开始调查的遗传贡献和遗传性的HR和HRV使用广泛的近交系小鼠品系。我们预计我们的调查将提供有价值的洞察力的HR和HRV的遗传决定因素，以及这些基因相互作用的机制，在主机响应环境颗粒物。

Because of the impact that particle-gas exposures may have on public health, identification of host factors that influence susceptibility to airborne pollutants remains an important issue. Particular concern has arisen about potentially sensitive sub-groups such as children, asthmatics, and the elderly. Individuals with cardiopulmonary disease are at particular risk to the effects of exposure. Recent evidence has suggested that some individuals may be genetically predisposed to environmental stressors, including oxidants and particles. Epidemiological studies have also suggested that PM may produce significant changes in cardiovascular function in addition to its pulmonary effects. In ongoing studies, we have began to test the hypothesis that genetic background is an important host factor that contributes to interindividual responsivity to particulate-induced immune dysfunction (an indicator of morbidity) and decreased heart rate variability (HRV). We initially designed a study to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon black (CB) particles in differentially susceptible B6 and C3 inbred mice. AMs were chosen for study because they represent in important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. B6 and C3 mice were chosen for investigation because a strain screen identified them as the most differentially susceptible to CBA/SO2-induced phagocytic dysfunction among eight strains studied. A B6C3F2 cohort was genotyped at 147 SSLP markers and a QTL on chromosome 17 exceeded the threshold value for statistically significant linkage as determined empirically by permutation test. A QTL on chromosome 11 exceeded the threshold for suggestive linkage. Candidate susceptibility genes in the chromosome 17 QTL were identified by comparative mapping and included Tnf, Lta, and Ccl2 (monocyte chemoattractant protein 1). Importantly, both QTLs overlap previously identified susceptibility QTLs for lung injury induced by the common pollutant ozone, as well as bleomycin and radiation. This may suggest common regulatory loci for injury and inflammation in the lung. We have also initiated a study to investigate the mechanisms of susceptibility to chronic bronchitis phenotypes induced by exposure to the metal vanadium which is known to be an important component of particulates in industrialized cities. We have identified significant variation among inbred strains of mice in the lung phenotypes induced by exposure to vanadium, and have initiated linkage analyses to identify the genes responsible for this variation. A link between changes in heart rate variability (HRV) and cardiovascular disease has been established. Recent studies have suggested a genetic component to heart rate variability. However, a full assessment of possible differences in heart rate (HR) and HRV using inbred mouse strains has not been studied. Furthermore, the heritability of HR and HRV has not been assessed using inbred mice. We have begun to investigate the genetic contribution and the heritability of HR and HRV using a wide range of inbred mouse strains. We anticipate our investigations will provide valuable insight to the genetic determinants of HR and HRV, and the mechanisms through which these genes interact in host response to environmental particulates.