Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

Steven R. Kleeberger; Roy C. Levitt; Liu Yi Zhang; Malinda Longphre; Jack Harkema; Anne Jedlicka; Scott M. Eleff; Deborah DiSilvestre; Kenneth J. Holroyd

doi:10.1038/ng1297-475

Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

Steven R. Kleeberger, Roy C. Levitt, Liu Yi Zhang, Malinda Longphre, Jack Harkema, Anne Jedlicka, Scott M. Eleff, Deborah DiSilvestre, Kenneth J. Holroyd

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

161 Scopus citations

Abstract

Exposures to the common air pollutant ozone (O₃) cause decrements in pulmonary function and induce airway inflammation that is characterized by infiltration of polymorphonuclear neutrophils (PMNs; refs 1-4). Because of the impact that O₃ may have on public health, it is critical to identify susceptibility factors. Highly reproducible, significant inter-individual variations in human pulmonary function responses to O₃ support the hypothesis that genetic background is an important determinant. Initial analysis of PMN responses to O₃ exposure in segregant populations derived from inflammation-prone (susceptible) C57BL/6J (B6) and inflammation- resistant C3H/HeJ (C3) inbred mice indicated that susceptibility was controlled by a locus we termed Inf2 (ref. 7). Subsequent analyses with recombinant inbred strains suggested that a more complex interaction of genes is involved. In this report, we identify a quantitative trait locus (QTL) for O₃ susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the gene encoding the prop-inflammatory cytokine tumour necrosis factorα (Tnf). Antibody neutralization of the protein product of this putative candidate germ significantly protected against O₃ injury in susceptible mice. These results strongly support linkage of O₃ susceptibility to a QTL on chromosome 17 and Tnf as a candidate gene.

Original language	English (US)
Pages (from-to)	475-478
Number of pages	4
Journal	Nature genetics
Volume	17
Issue number	4
DOIs	https://doi.org/10.1038/ng1297-475
State	Published - 1997

ASJC Scopus subject areas

Genetics

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title = "Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice",

abstract = "Exposures to the common air pollutant ozone (O3) cause decrements in pulmonary function and induce airway inflammation that is characterized by infiltration of polymorphonuclear neutrophils (PMNs; refs 1-4). Because of the impact that O3 may have on public health, it is critical to identify susceptibility factors. Highly reproducible, significant inter-individual variations in human pulmonary function responses to O3 support the hypothesis that genetic background is an important determinant. Initial analysis of PMN responses to O3 exposure in segregant populations derived from inflammation-prone (susceptible) C57BL/6J (B6) and inflammation- resistant C3H/HeJ (C3) inbred mice indicated that susceptibility was controlled by a locus we termed Inf2 (ref. 7). Subsequent analyses with recombinant inbred strains suggested that a more complex interaction of genes is involved. In this report, we identify a quantitative trait locus (QTL) for O3 susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the gene encoding the prop-inflammatory cytokine tumour necrosis factorα (Tnf). Antibody neutralization of the protein product of this putative candidate germ significantly protected against O3 injury in susceptible mice. These results strongly support linkage of O3 susceptibility to a QTL on chromosome 17 and Tnf as a candidate gene.",

author = "Kleeberger, {Steven R.} and Levitt, {Roy C.} and Zhang, {Liu Yi} and Malinda Longphre and Jack Harkema and Anne Jedlicka and Eleff, {Scott M.} and Deborah DiSilvestre and Holroyd, {Kenneth J.}",

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AU - Kleeberger, Steven R.

AU - Levitt, Roy C.

AU - Zhang, Liu Yi

AU - Longphre, Malinda

AU - Harkema, Jack

AU - Jedlicka, Anne

AU - Eleff, Scott M.

AU - DiSilvestre, Deborah

AU - Holroyd, Kenneth J.

PY - 1997

Y1 - 1997

N2 - Exposures to the common air pollutant ozone (O3) cause decrements in pulmonary function and induce airway inflammation that is characterized by infiltration of polymorphonuclear neutrophils (PMNs; refs 1-4). Because of the impact that O3 may have on public health, it is critical to identify susceptibility factors. Highly reproducible, significant inter-individual variations in human pulmonary function responses to O3 support the hypothesis that genetic background is an important determinant. Initial analysis of PMN responses to O3 exposure in segregant populations derived from inflammation-prone (susceptible) C57BL/6J (B6) and inflammation- resistant C3H/HeJ (C3) inbred mice indicated that susceptibility was controlled by a locus we termed Inf2 (ref. 7). Subsequent analyses with recombinant inbred strains suggested that a more complex interaction of genes is involved. In this report, we identify a quantitative trait locus (QTL) for O3 susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the gene encoding the prop-inflammatory cytokine tumour necrosis factorα (Tnf). Antibody neutralization of the protein product of this putative candidate germ significantly protected against O3 injury in susceptible mice. These results strongly support linkage of O3 susceptibility to a QTL on chromosome 17 and Tnf as a candidate gene.

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Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

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