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Ozone-Induced Acute Pulmonary Injury in Inbred Mouse Strains

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center and VA Medical Center, Durham, North Carolina; and Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California

Address correspondence to: Jordan D. Savov, M.D., Ph.D., Duke University Medical Center, P.O. Box 2629, Durham, NC 27710. E-mail: jsavov{at}duke.edu

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.

Abbreviations: filtered air, FA • interleukin, IL • megabases, Mb • methacholine, MCh • proliferating cell nuclear antigen, PCNA • enhanced pause, Penh • polymorphonuclear cells, PMN • parts per million, ppm • single nucleotide polymorphism, SNP • tumor necrosis factor-, TNF-

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