Savov Jordan D, Whitehead Gregory S, Wang Jianme, Liao Guochun, Usuka Jonathan, Peltz Gary, Foster W Michael, Schwartz David A
Department of Medicine, Duke University Medical Center and VA Medical Center, Durham, NC 27710, USA.
Am J Respir Cell Mol Biol. 2004 Jul;31(1):69-77. doi: 10.1165/rcmb.2003-0001OC. Epub 2004 Feb 19.
To determine if host factors influence the time course and extent of lung injury after acute inhalation of ozone (O3), we evaluated the physiologic and biologic response of nine genetically diverse inbred strains of mice (C57BL/6J, 129/SvIm, BTBR, BALB/cJ, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ) exposed to O3 (2.0 ppm x 3 h). Whole lung lavage determined that 129/Svlm, BTBR, DBA/2J, and FVB/NJ had a peak increase in polymorphonuclear cells (PMNs) at 6 h, whereas C57BL/6J and CAST/Ei had a peak increase at 24 h after exposure; airway PMNs were minimally elevated in A/J and C3H/HeJ; BALB/cJ had a predominant lymphocytic influx. Interleukin-6 concentration in the lavage fluid was associated with the influx of PMNs, whereas the total protein in the lavage fluid did not always correlate with lavage cellularity. Respiratory responses were monitored using whole body plethysmography and enhanced pause index. C57BL/6J, BALB/cJ, 129/SvIm, and BTBR were highly sensitive to O3 and exhibited significant increases in enhanced pause to methacholine aerosol stimulation at 6 and 24 h after exposure to O3. In contrast, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ strains had demonstrated increases in sensitivity to MCh at 6 h after exposure, but responses had returned to near baseline by 24 h after exposure to O3. Epithelial cell proliferation as assessed by proliferating cell nuclear antigen staining was evident at 24 h after exposure to O3. C57BL/6J and A/J showed 4% proliferating cell nuclear antigen-positive cells; 129/SvIm, DBA/2J, and FVB/NJ had 1-3%; and BTBR, BALB/cJ, CAST/Ei, and C3H/HeJ had < 1%. Phenotypic measurements in six inbred strains were used for an in silico genome analysis based on the Roche mouse database. Consistent loci on chromosomes 1, 7, and 15 were among those identified to have a significant association with the phenotypes studied. In aggregate, our approach has identified O3-resistant (C3H/HeJ and A/J) and -vulnerable (C57BL/6J and 129/SvIm) strains of mice, and determined novel genomic loci, suggesting a clear genetic basis for the lung response to inhaled O3.
为了确定宿主因素是否会影响急性吸入臭氧（O₃）后肺损伤的时间进程和程度，我们评估了9种基因不同的近交系小鼠（C57BL/6J、129/SvIm、BTBR、BALB/cJ、DBA/2J、A/J、FVB/NJ、CAST/Ei和C3H/HeJ）在暴露于O₃（2.0 ppm×3小时）后的生理和生物学反应。全肺灌洗结果显示，129/Svlm、BTBR、DBA/2J和FVB/NJ在暴露后6小时多形核细胞（PMN）数量达到峰值增加，而C57BL/6J和CAST/Ei在暴露后24小时达到峰值增加；A/J和C3H/HeJ气道中的PMN升高程度最小；BALB/cJ有主要的淋巴细胞流入。灌洗液中的白细胞介素-6浓度与PMN的流入相关，而灌洗液中的总蛋白并不总是与灌洗细胞数量相关。使用全身体积描记法和增强间歇指数监测呼吸反应。C57BL/6J、BALB/cJ、129/SvIm和BTBR对O₃高度敏感，在暴露于O₃后6小时和24小时对乙酰甲胆碱气雾剂刺激的增强间歇有显著增加。相比之下，DBA/2J、A/J、FVB/NJ、CAST/Ei和C3H/HeJ品系在暴露后6小时对乙酰甲胆碱的敏感性增加，但在暴露于O₃后24小时反应已恢复到接近基线水平。通过增殖细胞核抗原染色评估的上皮细胞增殖在暴露于O₃后24小时明显。C57BL/6J和A/J显示4%的增殖细胞核抗原阳性细胞；129/SvIm、DBA/2J和FVB/NJ有1%-3%；而BTBR、BALB/cJ、CAST/Ei和C3H/HeJ的比例<1%。基于罗氏小鼠数据库，对6个近交系的表型测量结果用于计算机基因组分析。在鉴定出的与所研究表型有显著关联的基因座中，位于染色体1、7和15上的一致基因座。总体而言，我们的方法鉴定出了对O₃有抗性的（C3H/HeJ和A/J）和易感性的（C57BL/6J和129/SvIm）小鼠品系，并确定了新的基因组位点，表明肺部对吸入O₃的反应有明确的遗传基础。
