Ozone-induced acute lung injury: genetic analysis  of F2 mice generated from A/J and C57BL/6J strains

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.

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A genetic mouse model to investigate hyperoxic acute lung injury survival

Physiological Genomics ◽

10.1152/physiolgenomics.00232.2006 ◽

2007 ◽

Vol 30 (3) ◽

pp. 262-270 ◽

Cited By ~ 23

Author(s):

Daniel R. Prows ◽

Amanda P. Hafertepen ◽

William J. Gibbons ◽

Abby V. Winterberg ◽

Todd G. Nick

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Model ◽

Survival Time ◽

Therapeutic Potential ◽

Inbred Mouse ◽

Mouse Strains ◽

Genetic Mouse Model ◽

Genetic Components ◽

Survival Difference

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.

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Genetic susceptibility to irritant-induced acute lung injury in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.3.l575 ◽

2000 ◽

Vol 279 (3) ◽

pp. L575-L582 ◽

Cited By ~ 42

Author(s):

Scott C. Wesselkamper ◽

Daniel R. Prows ◽

Pratim Biswas ◽

Klaus Willeke ◽

Eula Bingham ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inbred Mouse ◽

Nickel Sulfate ◽

Lavage Fluid ◽

Mouse Strains ◽

Common Mechanism ◽

Recessive Trait ◽

Strain Sensitivity ◽

Sensitivity Pattern

Recent studies suggest that genetic variability can influence irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate (NiSO4), polytetrafluoroethylene, or ozone (O3), and survival time was recorded. The A/J (A) mouse strain was sensitive, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO4-induced acute lung injury. The B6AF1 offspring were also resistant. The strain sensitivity pattern for NiSO4 exposure was similar to that of polytetrafluoroethylene or ozone (O3). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 μg/m3 of NiSO4 produced 20% mortality. The strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A ≥ B6 > C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent arrays of genes). As in acute lung injury, B6C3F1 offspring exhibited phenotypes (lavage fluid proteins and neutrophils) resembling those of the resistant parental strain. Agreement of acute lung injury strain sensitivity patterns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a recessive trait.

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Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

Physiological Genomics ◽

10.1152/physiolgenomics.90392.2008 ◽

2009 ◽

Vol 38 (2) ◽

pp. 158-168 ◽

Cited By ~ 9

Author(s):

Daniel R. Prows ◽

Abby V. Winterberg ◽

William J. Gibbons ◽

Benjamin B. Burzynski ◽

Chunyan Liu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Survival Time ◽

Complex Disease ◽

Single Gene ◽

Clear Understanding ◽

Significant Qtls ◽

Parent Of Origin ◽

Origin Effects ◽

Trait Locus

Morbidity and mortality associated with acute lung injury (ALI) and acute respiratory distress syndrome remain substantial. Although many candidate genes have been tested, a clear understanding of the pathogenesis is lacking, as is our ability to predict individual outcome. Because ALI is a complex disease, single gene approaches cannot easily identify effectors that must be treated concurrently. We employed a strategy to help identify critical genes and gene combinations involved in ALI mortality. Using hyperoxia to induce ALI, a mouse model for genetic analyses of ALI survival time was identified: C57BL/6J (B) mice are sensitive (i.e., die early), whereas 129X1/SvJ (S) mice are significantly more resistant, but with low penetrance. Segregation analysis of reciprocal F2 mice generated from B and S strains revealed significant sex, cross, and parent of origin effects. Quantitative trait locus (QTL) analysis identified five chromosomal regions significantly linked to hyperoxic ALI survival time (named Shali1–Shali5). Further analyses demonstrated that both parental strains contribute resistance alleles to their offspring and that the phenotype demonstrated parent of origin effects. To validate earlier findings, we generated and tested mice from all eight possible B-S-derived backcrosses. Results from segregation and QTL analyses of 935 backcrosses, alone and combined with the previous 840 B-S-derived F2 population, further supported the highly significant QTLs on chromosomes 1 ( Shali1) and 4 ( Shali2) and confirmed that the sex, cross, and parent of origin all contribute to survival time with hyperoxic ALI.

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A comprehensive SNP-based genetic analysis of inbred mouse strains

Mammalian Genome ◽

10.1007/s00335-005-0001-7 ◽

2005 ◽

Vol 16 (7) ◽

pp. 476-480 ◽

Cited By ~ 31

Author(s):

Shirley Tsang ◽

Zhonghe Sun ◽

Brian Luke ◽

Claudia Stewart ◽

Nicole Lum ◽

...

Keyword(s):

Genetic Analysis ◽

Inbred Mouse ◽

Mouse Strains ◽

Inbred Mouse Strains

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Transmission-Ratio Distortion Through F1 Females at Chromosome 11 Loci Linked to Om in the Mouse DDK Syndrome

Genetics ◽

10.1093/genetics/142.4.1299 ◽

1996 ◽

Vol 142 (4) ◽

pp. 1299-1304

Author(s):

F Pardo-Manuel de Villena ◽

C Slamka ◽

M Fonseca ◽

A K Naumova ◽

J Paquette ◽

...

Keyword(s):

Genetic Model ◽

Inbred Mouse ◽

Transmission Ratio Distortion ◽

Transmission Ratio ◽

F1 Hybrids ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Chromosome 11 ◽

Ratio Distortion

Abstract We determined the genotypes of >200 offspring that are survivors of matings between female reciprocal F1 hybrids (between the DDK and C57BL/6J inbred mouse strains) and C57BL/6J males at markers linked to the Ovum mutant (Om) locus on chromosome 11. In contrast to the expectations of our previous genetic model to explain the “DDK syndrome,” the genotypes of these offspring do not reflect preferential survival of individuals that receive C57BL/6J alleles from the F1 females in the region of chromosome 11 to which the Om locus has been mapped. In fact, we observe significant transmission-ratio distortion in favor of DDK alleles in this region. These results are also in contrast to the expectations of Wakasugi's genetic model for the inheritance of Om, in which he proposed equal transmission of DDK and non-DDK alleles from F1 females. We propose that the results of these experiments may be explained by reduced expression of the maternal DDK Om allele or expression of the maternal DDK Om allele in only a portion of the ova of F1 females

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Comparison and Functional Genetic Analysis of Striatal Protein Expression Among Diverse Inbred Mouse Strains

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00128 ◽

2019 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Cory Parks ◽

Francesco Giorgianni ◽

Byron C. Jones ◽

Sarka Beranova-Giorgianni ◽

Bob M. Moore II ◽

...

Keyword(s):

Genetic Analysis ◽

Protein Expression ◽

Inbred Mouse ◽

Mouse Strains ◽

Inbred Mouse Strains

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Construction Of Reciprocal Congenic Mouse Lines Containing QTLs That Affect Survival Time To Hyperoxic Acute Lung Injury

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2160 ◽

2010 ◽

Author(s):

Daniel R. Prows ◽

Benjamin B. Burzynski ◽

William J. Gibbons, Jr

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Survival Time ◽

Congenic Mouse ◽

Mouse Lines

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Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00223.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. L685-L703 ◽

Cited By ~ 52

Author(s):

Alison K. Bauer ◽

Alvin M. Malkinson ◽

Steven R. Kleeberger

Keyword(s):

Lung Cancer ◽

Lung Injury ◽

Wound Repair ◽

Lung Tumor ◽

Inbred Mouse ◽

Human Lung Cancer ◽

Mouse Lung ◽

Mouse Strains ◽

Molecular Characteristics ◽

Anatomic Site

Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation ( Inf1, Inf2), O3-induced acute lung injury ( Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.

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A GENETIC STUDY OF SUSCEPTIBILITY TO EXPERIMENTAL TUBERCULOSIS IN MICE INFECTED WITH MAMMALIAN TUBERCLE BACILLI

Journal of Experimental Medicine ◽

10.1084/jem.121.6.1051 ◽

1965 ◽

Vol 121 (6) ◽

pp. 1051-1070 ◽

Cited By ~ 28

Author(s):

Clara J. Lynch ◽

Cynthia H. Pierce-Chase ◽

Rene Dubos

Keyword(s):

Survival Time ◽

Experimental Infection ◽

Inbred Strains ◽

New Combination ◽

Mouse Strains ◽

Survival Times ◽

Significant Difference ◽

Hereditary Factors ◽

The Difference ◽

Parental Level

A study has been made of the genetic aspects of the difference between two inbred strains of mice (C57B1/6 and Swiss) in response to experimental infection with mammalian tubercle bacilli. Males and females, 4 to 6 weeks of age were inoculated intravenously with 0.2 ml of a 1/50 culture dilution of Mycobacterium tuberculosis var. bovis (Vallée strain) grown in tween albumin medium. Mean survival time for C57B1 animals was 28.1 ± 0.6 days and for Swiss, 55.3 ± 0.6 days postinfection. The characteristic survival time of the two strains was reversed in mice receiving a smaller infective dose. The age of mice at the time of inoculation also affected the results of infection: both C57B1 and Swiss, inoculated at 12 months of age, died at the same rate, but when inoculated at older ages, C57B1 survived slightly longer. Bacteriologic studies demonstrated that there was no significant difference between the two mouse strains with regard to the numbers of viable units of tubercle bacilli recovered from various organs during the 2 week period following infection with a 10–3 culture dilution of Vallée. Moreover, the standard infective inoculum (1/50 culture dilution) did not activate corynebacterial pseudotuberculosis in C57B1 mice, a strain known to be latently infected with Corynebacterium kutscheri, rapid multiplication of tubercle bacilli occurred, but no corynebacteria were recovered. When C57B1 and Swiss strains were crossed, survival tests after infection with the standard inoculum demonstrated that mice of the F1 generation were more resistant than either parent. Whether the overdominance was due to a new combination of parental genes for resistance or to heterosis was not determined. The increased litter size of the F1 mice, an evidence of increased vigor, supports the view that heterosis was involved. In backcrosses to the resistant strain (Swiss), survival time gradually became stabilized at approximately the parental level. In the 1st backcross to the susceptible strain (C57B1), survival times fell into two classes indicating segregation of genes, with perhaps dominance of genes from the Swiss. After repeated backcrosses to C57B1, mice of the 4th backcross generation had a survival time essentially the same as that of the original parental strain. On the basis of having obtained progeny characterized by the original parental susceptibilities after genetic tendencies had been intermingled by crossbreeding, it was concluded that hereditary factors influenced the response of mice to experimental infection with M. tuberculosis. The number of genes was not determined.

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