Published ahead of print on February 19, 2004, doi:10.1165/rcmb.2003-0001OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 1, July 2004, 69-77 A more recent version of this article appeared on July 1, 2004
Submitted on January 3, 2003 O3-INDUCED ACUTE PULMONARY INJURY IN INBRED MOUSE STRAINSJordan D Savov1*,1 Pulmonary and Critical Care, Duke University Medical Center, Durham, NC, USA, 2 Genetics and Genomics, Roche Palo Alto, Palo Alto, CA, USA * To whom correspondence should be addressed. E-mail: jsavov{at}duke.edu.
To determine if host factors influence the time course and extent of lung injury following 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, C3H/HeJ) exposed to O3 (2.0 ppmx3 h). Whole lung lavage defined that: 129/Svlm, BTBR, DBA/2J, and FVB/NJ had a peak increase in PMNs at 6 h, whereas C57BL/6J and CAST/Ei at 24 h post-exposure; airway PMNs were minimally elevated in A/J and C3H/HeJ; BALB/cJ had a predominant lymphocytic influx. IL-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 (Penh). C57BL/6J, BALB/cJ, 129/SvIm, and BTBR were highly sensitive to O3 and exhibited significant increases in Penh to methacholine (MCh) aerosol stimulation at 6 h and 24 h post 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 post, but responses had returned to near baseline by 24 h post O3. Epithelial cell proliferation as assessed by proliferating cell nuclear antigen staining was evident at 24 h post O3. C57BL/6J and A/J showed 4% PCNA-positive cells; 129/SvIm, DBA/2J, and FVB/NJ had 1-3%; and BTBR, BALB/cJ, CAST/Ei, and C3H/HeJ had less than 1%. Phenotypic measurements in six inbred strains were used for an in silico genome analysis based on the Roche mouse database. Consistent loci on chromosome 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.
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