Reciprocal congenic lines of mice capture the aliq1 effect on acute lung injury survival time.

Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene-environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F(2) populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multilocus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema after exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared with separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.

A genetic mouse model to investigate hyperoxic acute lung injury survival.

Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

Genetic analysis of hyperoxic acute lung injury survival in reciprocal intercross mice.

Acute lung injury (ALI) and its most severe presentation, acute respiratory distress syndrome, represent a full spectrum of a complex and devastating illness, with associated mortality that still hovers around 30-40%. Even supplemental O2, a routine and necessary therapy for such patients, paradoxically causes lung injury. The detrimental effects of O2 have established hyperoxic ALI (HALI) as a conventional model to study neonatal and adult forms of respiratory distress syndromes in experimental animals. To confront the high ALI mortality problem quite differently, we recently identified a mouse model (sensitive C57BL/6J and resistant 129X1/SvJ mice) to assess the genetic complexity of HALI and to identify genes affecting strain survival differences. Segregation analysis of 840 F2 mice generated from all four possible intercrosses between C57BL/6J and 129X1/SvJ mice demonstrated that survival time is a quantitative trait with decreased penetrance, and significant sex, cross, and parent-of-origin effects. Quantitative trait locus (QTL) analyses of the total F2 population identified three highly significant (named Shali1, Shali2 and Shali3, for Survival to hyperoxic acute lung injury) and one significant (Shali4) linkage. Analysis of F2 subpopulations further identified a male-specific QTL (Shali5). QTL allelic comparisons supported cross and sex effects and were consistent with imprinting. Genome-wide pairwise analysis predicted additive gene-gene interactions between the QTLs and also revealed a significant epistatic interaction with an otherwise unlinked region. QTL results confirmed that both parental strains contribute dominant resistance alleles to their offspring to determine individual HALI susceptibility.