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

Exposures to the common air pollutant ozone (O-3) cause decrements in pulmonary function and induce airway inflammation that is characterized by infiltration of polymorphonuclear neutrophils (PMNs; refs 1-4). Because of the impact that O-3 may have on public health, it is critical to identify susceptibility factors. Highly reproducible, significant inter-individual variations in human pulmonary function responses to O-3 support the hypothesis that genetic background is an important determinant(5,6). Initial analysis of PMN responses to O-3 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 involved(8). In this report, we identify a quantitative trait locus (QTL) for O-3 susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the gene encoding the proinflammatory cytokine tumour necrosis factor-alpha (Tnf). Antibody neutralization of the protein product of this putative candidate gene significantly protected against O-3 injury in susceptible mice. These results strongly support linkage of O-3 susceptibility to a QTL on chromosome 17 and Tnf as a candidate gene.