LINKAGE ANALYSIS OF SUSCEPTIBILITY TO OZONE-INDUCED LUNG INFLAMMATIONIN INBRED MICE

Exposures to the common air pollutant ozone (O-3) cause decrements in pulmonary function and induce airway inflammation that is characterize d by infiltration of polymorphonuclear neutrophils (PMNs; refs 1-4). B ecause of the impact that O-3 may have on public health, it is critica l 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 det erminant(5,6). Initial analysis of PMN responses to O-3 exposure in se gregant populations derived from inflammation-prone (susceptible) C57B L/6J (B6) and inflammation-resistant C3H/HeJ (C3) inbred mice indicate d 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 c hromosome 17. Candidate genes for the locus include Tnf, the gene enco ding the proinflammatory cytokine tumour necrosis factor-alpha (Tnf). Antibody neutralization of the protein product of this putative candid ate gene significantly protected against O-3 injury in susceptible mic e. These results strongly support linkage of O-3 susceptibility to a Q TL on chromosome 17 and Tnf as a candidate gene.