Linkage analysis was performed on 307 (C57BL/6J x A/J) x A/J backcross animals to identify QTLs affecting nickel-induced acute lung injury. Parental strain A/J is sensitive to nickel-induced acute lung injury (as measured by mean survival time (MST) after exposure to nickel sulfate) whereas C57BL/6J is resistant. Significant linkage was detected at 26.5 cM on mouse Chromosome 6 near D6Mit183 with a LOD score of 3.0. This locus maps from 12 cM - 38 cM and was named Aliq4, acute lung injury QTL 4. C57BL/6J-derived alleles at Aliq4 confers increased mean survival time of animals exposed to nickel sulfate. Aliq4 also appears to interact additively with other loci on chromosomes 12, 16 and 9. Animals of haplotype H-H-H-AA at D6Mit183, D12Mit112, D16Mit152, and D9Mit299, respectively, exhibit a 52 hour MST longer than animals of haplotype AA-AA-AA-H. Positional candidate gene approach identified the following genes mapping near Aliq4 as potential candidate genes: Aqp1, Crhr2, Sftpb, Pecam, and Tgfa. Aliq4 alsomaps near a QTL for bronchial hyperresponsiveness, Bhr5, spanning 55 cM - 95 cM on mouse Chromosome 6.