Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice

We investigated the mode of inheri-tance of susceptibility to nitrogen dioxide (NO₂)-induced lung injury in inbred mice. Susceptible C57BL/6J (B6) and resistant C3H/HeJ (C3) mice, as well as FI; F2, and backcross (BX) populations derived from them, were exposed to 15 parts per million NO₂ for 3 h. Six hours after exposure, animals were lavaged, and differential cell counts and cell viability (cytotoxicity) were measured. Statistically significant CP < 0.05) differences in numbers of lavageable macrophages, epithelial cells, and dead cells were found between inbred strains. Distributions of cellular responses in F₁ progeny overlapped both progenitors, and mean responses were intermediate. In C3:BX progeny, ranges of responses to NO₂ closely resembled C3 mice, and means were not significantly different between populations. Ranges of cellular responses to NO₂ in B6:BX and intercross progeny overlapped both progenitors; mean responses of both populations were intermediate to progenitors. Segregation analyses tested goodness of fit of phenotyping data with various inheritance models, and the highest likelihood for each cell response to NO₂ was for the hypothesis two-unlinked loci general. We conclude that there are likely two major unlinked genes that account for differential susceptibility to acute NO₂ exposure. The chromosomal location of the genes is not known.