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

ABSTRACT: 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 F(2) 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 F(2) 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.

SUBMITTER: Prows DR

PROVIDER: S-EPMC2712219 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Prows Daniel R DR Winterberg Abby V AV Gibbons William J WJ Burzynski Benjamin B BB Liu Chunyan C Nick Todd G TG

Physiological genomics 20090505 2

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 mortali ...[more]

PMID: 19417010

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Project description:Bronchopulmonary dysplasia (BPD) is characterized by a severe impairment in lung alveolarization and vascular development. We have previously shown that pulmonary angiogenesis is preserved in hyperoxia-exposed female mice accompanied by increased miR-30a expression, which is a proangiogenic miRNA. Also, miR-30a expression is decreased in human BPD. HIF-1α plays an essential role in postnatal lung development, especially in recovery from hyperoxic injury. Snai1 activation promotes pathological fibrosis through many mechanisms including Endo-MT, which may in turn adversely impact lung vascular development. Our objective was to test the hypothesis that higher miR-30a expression through HIF-1α decreases Snai1 expression in females and attenuates injury in the developing lung. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (P1-5, 0.95 FiO2) and euthanized on P21. Neonatal human pulmonary microvascular endothelial cells (HPMECs; 18-24-week gestation donors; 3/group either sex) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. Snai1 expression was measured in HPMECs in vitro and in neonatal mouse lungs in vivo. Also, Snai1 expression was measured in HPMECs after miR-30a mimic and miR-30a inhibitor treatment. To further establish the potential regulation of miR-30a by Hif-1α, miR-30a expression after Hif-1α inhibition was measured in HPMECs. In vivo, Snai1 expression was decreased in neonatal female lungs compared to males at P7. Increased Snai1 expression was seen in male HPMECs upon exposure to hyperoxia in vitro. Treatment with the miR-30a mimic decreased Snai1 expression in HPMECs, while miR-30a inhibition significantly increased Snai1 expression in HPMECs. siRNA-mediated loss of Hif-1α expression in HPMECs decreased miR-30a expression. Hif-1α may lead to differential sex-specific miR-30a expression and may contribute to protection from hyperoxic lung injury in female neonatal mice through decreased Snai1 expression.

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

Publications

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

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