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Departments of 1 Environmental Health, 3 Molecular and Cellular Physiology, and 4 Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0056; and 2 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142
Acute lung injury (or acute respiratory distress syndrome) is a devastating and often lethal condition. This complex disease (trait) may be associated with numerous candidate genes. To discern the major gene(s) controlling mortality from acute lung injury, two inbred mouse strains displaying contrasting survival times to 10 parts/million ozone were identified. A/J (A) mice were sensitive [6.6 ± 1 (SE) h] and C57BL/6J (B) were resistant (20.6 ± 1 h). The designation for these phenotypes was 13 h, a point that clearly separated their survival time distributions. Our prior segregation studies suggested that survival time to ozone-induced acute lung injury was a quantitative trait, and genetic analysis identified three linked loci [acute lung injury-1, -2, and -3 (Ali1-3, respectively)]. In this report, acute lung injury in A or B mice was characterized histologically and by measuring lung wet-to-dry weight ratios at death. Ozone produced comparable effects in both strains. To further delineate genetic loci associated with reduced survival, a genomewide scan was performed with F2 mice generated from the A and B strains. The results strengthen and extend our initial findings and firmly establish that Ali1 on mouse chromosome 11 has significant linkage to this phenotype. Ali3 was suggestive of linkage, supporting previous recombinant inbred analysis, whereas Ali2 showed no linkage. Together, our findings support the fact that several genes, including Ali1 and Ali3, control susceptibility to death after acute lung injury. Identification of these loci should allow a more focused effort to determine the key events leading to mortality after oxidant-induced acute lung injury.
acute respiratory distress syndrome; oxidative stress; pulmonary edema; quantitative trait; quantitative trait locus
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