Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice.
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 pro-inflammatory cytokine tumour necrosis factor-alpha (Tnf). Antibody neutralization of the protein product of this putative candidate gene 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.
Kleeberger
S R
SR
Department of Environmental Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. srk@welchlink.welch.jhu.edu
Levitt
R C
RC
Zhang
L Y
LY
Longphre
M
M
Harkema
J
J
Jedlicka
A
A
Eleff
S M
SM
DiSilvestre
D
D
Holroyd
K J
KJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D005260:Female; D008040:Genetic Linkage; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010126:Ozone / Q000633:toxicity*; D019655:Quantitative Trait, Heritable; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone