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Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

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Abstract

Exposures to the common air pollutant ozone (O3) cause decrements in pulmonary function and induce airway inflammation that is characterized by infiltration of polymorphonuclear neu-trophils (PMNs; refs 1–4). Because of the impact that O3 may have on public health, it is critical to identify susceptibility factors. Highly reproducible, significant inter-individual variations in human pulmonary function responses to O3 support the hypothesis that genetic background is an important determinant5,6. Initial analysis of PMN responses to O3 exposure in segregant populations derived from inflammation-prone (susceptible) C57BL/6J (B6) and inflammation-resistant C3H/HeJ (C3) inbred mice indicated that susceptibility was controlled by a locus we termed Inf2 (ref. 7). Subsequent analyses with recombinant inbred strains suggested that a more complex interaction of genes is involved8. In this report, we identify a quantitative trait locus (QTL) for O3 susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the gene encoding the pro-inflammatory cytokine tumour necrosis factor-α(Tnf). Antibody neutralization of the protein product of this putative candidate gene significantly protected against O3 injury in susceptible mice. These results strongly support linkage of O3 susceptibility to a QTL on chromosome 17 and Tnf as a candidate gene.

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Authors and Affiliations

  1. Departments of Environmental Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland, 21205, USA

    Steven R. Kleeberger, Liu-Yi Zhang & Malinda Longphre

  2. Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, 21205, USA

    Anne Jedlicka, Scott M. Eleff & Deborah DiSilvestre

  3. Magainin Institute of Molecular Medicine, Magainin Pharmaceuticals, Plymouth Meeting, Pennsylvania, 19462, USA

    Roy C. Levitt & Kenneth J. Holroyd

  4. Department of Pathology, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, 48824, USA

    Jack Harkema

Authors
  1. Steven R. Kleeberger
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  2. Roy C. Levitt
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  3. Liu-Yi Zhang
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  4. Malinda Longphre
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  5. Jack Harkema
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  6. Anne Jedlicka
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  7. Scott M. Eleff
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  8. Deborah DiSilvestre
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  9. Kenneth J. Holroyd
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Kleeberger, S., Levitt, R., Zhang, LY. et al. Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice. Nat Genet 17, 475–478 (1997). https://doi.org/10.1038/ng1297-475

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  • DOI: https://doi.org/10.1038/ng1297-475

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