Gregory J Smith, Robert M Immormino, Martin T Ferris, Sarah A Lester, Timothy P Moran, Jack R Harkema, Samir N P Kelada
CC002/Unc was far more responsive to acute O3 than C57BL/6J, exhibiting significant inflammation following a single 0.4 ppm O3 exposure and greater inflammation and injury after 0.8 ppm O3. Enhanced sensitivity of CC002/Unc mice was associated with decreased breathing frequency and diminished hypothermic responses. Following repeated exposure, C57BL/6J lungs appeared normal, while CC002/Unc lungs had eosinophilic inflammation and centriacinar fibrosis. We identified five QTL for airway eosinophilia, including a large-effect QTL on chromosome 11 that accounts for 18% of phenotypic variation and contains genes with plausible links to aberrant immune responses.
BACKGROUND: Exposure to the ambient air pollutant ozone (O3) is associated with adverse respiratory health outcomes. Rodent models have been used to identify mechanisms of response to O3, but their utility has been questioned owing to species differences in physiologic response, most notably exposure-induced hypothermia, which renders rodents relatively resistant to O3 compared to humans.
OBJECTIVES: First, to test whether a recombinant inbred mouse strain from the Collaborative Cross population, CC002/Unc, provides a sensitive model of ozone response by benchmarking it to the most commonly used inbred strain, C57BL/6J. Second, to identify the genetic basis of CC002/Unc's sensitivity.
METHODS: We examined the responses of CC002/Unc and C57BL/6J mice to either acute (0.4 or 0.8 ppm O3 4 h) or repeated (0.8 ppm O3 × 4 h/day × 3 or 9 weekdays) O3 exposure. Then, we mapped quantitative trait loci (QTL) for responses to 9 days of O3 in a CC002/Unc × CC005/TauUnc (O3-resistant) backcross population.
RESULTS: CC002/Unc was far more responsive to acute O3 than C57BL/6J, exhibiting significant inflammation following a single 0.4 ppm O3 exposure and greater inflammation and injury after 0.8 ppm O3. Enhanced sensitivity of CC002/Unc mice was associated with decreased breathing frequency and diminished hypothermic responses. Following repeated exposure, C57BL/6J lungs appeared normal, while CC002/Unc lungs had eosinophilic inflammation and centriacinar fibrosis. We identified five QTL for airway eosinophilia, including a large-effect QTL on chromosome 11 that accounts for 18% of phenotypic variation and contains genes with plausible links to aberrant immune responses.
DISCUSSION: The CC002/Unc strain provides an improved model to study the effects of acute and repeated O3 exposure due to its enhanced sensitivity vs C57BL/6J and more human-like thermoregulatory response. Further genetic analysis to pinpoint causal genes underlying CC002/Unc's susceptibility will provide new insights into mechanisms of O3-induced lung disease.