title: Genome-wide association mapping of acute lung injury in neonatal inbred mice.
abstract: Reactive oxygen species (ROS) contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia (BPD), a respiratory condition that affects preterm infants. However, the mechanisms of susceptibility to oxidant stress in neonatal lungs are not completely understood. We evaluated the role of genetic background in response to oxidant stress in the neonatal lung by exposing mice from 36 inbred strains to hyperoxia (95% O2) for 72 h after birth. Hyperoxia-induced lung injury was evaluated by using bronchoalveolar lavage fluid (BALF) analysis and pathology. Statistically significant interstrain variation was found for BALF inflammatory cells and protein (heritability estimates range: 33.6-55.7%). Genome-wide association mapping using injury phenotypes identified quantitative trait loci (QTLs) on chromosomes 1, 2, 4, 6, and 7. Comparative mapping of the chromosome 6 QTLs identified Chrm2 (cholinergic receptor, muscarinic 2, cardiac) as a candidate susceptibility gene, and mouse strains with a nonsynonymous coding single-nucleotide polymorphism (SNP) in Chrm2 that causes an amino acid substitution (P265L) had significantly reduced hyperoxia-induced inflammation compared to strains without the SNP. Further, hyperoxia-induced lung injury was significantly reduced in neonatal mice with targeted deletion of Chrm2, relative to wild-type controls. This study has important implications for understanding the mechanisms of oxidative lung injury in neonates.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; Curriculum in Toxicology, Center for Environmental Medicine, Asthma, and Lung Biology, and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Nichols
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA;
authors.forename: Wesley
authors.initials: W
authors.lastname: Gladwell
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA;
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Verhein
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA;
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Oscar
authors.initials: O
authors.lastname: Suzuki
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; kleeber1@niehs.nih.gov.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D018496:Hyperoxia / Q000235:genetics*; D055370:Lung Injury / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011014:Pneumonia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D043585:Receptor, Muscarinic M2 / Q000235:genetics*
chemical_list: D043585:Receptor, Muscarinic M2
keywords: bronchopulmonary dysplasia; cardiac; cholinergic receptor; inflammation; muscarinic 2; quantitative trait locus