Particle-induced Cardiopulmonary Injury In Mice: Genetic Susceptibility

由于颗粒物-气体暴露可能对公众健康产生影响，识别影响空气污染物易感性的宿主因素仍然是一个重要问题。尤其是对儿童、哮喘患者和老年人等潜在敏感亚群的关注。患有心肺疾病的人特别容易受到接触的影响。最近的证据表明，一些人可能在遗传上容易受到环境应激源的影响，包括氧化剂和颗粒。流行病学研究还表明，PM除了对肺部有影响外，还可能对心血管功能产生显著影响。在正在进行的研究中，我们已经开始测试这一假设，即遗传背景是一个重要的宿主因素，有助于个体之间对颗粒性免疫功能障碍(发病率的一个指标)和心率变异性(HRV)降低的反应性。 我们最初设计了一项研究，以确定吸入硫酸盐相关碳黑(CB)颗粒导致B6和C3近交系小鼠不同易感性肺泡巨噬细胞(AM)免疫功能障碍的易感基因。AM是宿主防御的重要组成部分，因此被选作研究对象，而宿主防御受损被认为是颗粒物致呼吸道疾病的重要因素。之所以选择B6和C3小鼠进行研究，是因为在所研究的8个品系中，菌株筛选发现它们最容易受到CBA/SO2诱导的吞噬功能障碍的影响。一个B6C3F2群体在147个SSLP标记上进行了基因分型，17号染色体上的一个QTL超过了通过排列检验经验确定的统计显著连锁的阈值。11号染色体上的一个QTL超过了暗示连锁的阈值。通过比较定位，确定了17号染色体QTL的候选易感基因，包括肿瘤坏死因子、LTA和CCL2(单核细胞趋化蛋白1)。重要的是，这两个QTL都与先前发现的由常见污染物臭氧、博莱霉素和辐射引起的肺损伤的易感性QTL重叠。这可能提示了肺损伤和炎症的共同调控部位。 我们还启动了一项研究，以调查接触金属钒导致慢性支气管炎表型易感性的机制，钒是工业化城市颗粒物的重要组成部分。我们已经确定了近交系小鼠在接触钒引起的肺表型上的显著差异，并启动了连锁分析和单倍型分析来确定导致这种差异的基因。单倍型分析已经确定了与两个染色体区域的显著连锁，候选基因已经确定，目前正在进行测试。 心率变异性(HRV)的变化与心血管疾病之间的联系已经确立。最近的研究表明，心率变异性与遗传因素有关。然而，使用近交系小鼠品系对心率(HR)和心率变异性(HRV)可能存在的差异进行全面评估尚未进行研究。此外，心率和心率变异性的遗传力还没有用近交系小鼠进行评估。我们已经开始使用广泛的近交系小鼠来研究HR和HRV的遗传贡献和遗传力。这些研究导致了目前正在研究的易感数量性状基因座(MS)和候选基因的鉴定。我们期待我们的研究将为HR和HRV的遗传决定因素以及这些基因在宿主对环境颗粒和其他环境应激源的反应中相互作用的机制提供有价值的见解。

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 and haplotype analyses to identify the genes responsible for this variation. The haplotype analyses have identified significant linkage to two chromosomal regions and candidate genes have been identified and are currently being tested. 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. The studies have led to identification of susceptibility quantitative trait loci (MS in revision) and candidate genes that are currently under investigation. 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 as well as other environmental stressors.