Genetic susceptibility to ozone-induced lung hyperpermeability. Role of Toll-like receptor 4

Steven R. Kleeberger, Sekhar Reddy, Liu Yi Zhang, Anne E. Jedlicka

Research output: Contribution to journalArticlepeer-review

145 Scopus citations


The pollutant ozone (O3) induces lung hyperpermeability and inflammation in humans and animal models. Among inbred strains of mice, there is a 3-fold difference in total protein (a marker of permeability) recovered in bronchoalveolar lavage (BAL) fluid after a 72-h exposure to 0.3 ppm O3. To determine the chromosomal locations of susceptibility genes, we performed a genome screen using recombinant inbred (RI) strains of mice derived from O3-susceptible C57BL/6J (B6) and O3-resistant C3H/HeJ (HeJ) progenitors. Each RI strain was phenotyped for O3-induced hyperpermeability, and linkage was assessed for 558 markers using Map Manager QTb27. A significant quantitative trait locus (QTL) was identified on chromosome 4. The likelihood ratio X2 statistic (16.6) for the peak of the QTL was greater than the significance threshold (16.3) determined empirically by permutation test. This QTL contains a candidate gene, Toll-like receptor 4 (Tlr4), that recently has been implicated in innate immunity and endotoxin susceptibility. The amount of the total trait variance explained by the QTL at Tlr4, the gene with the highest likelihood ratio statistic in the QTL, was approximately 70%. To test the role of Tlr4 in O3-induced hyperpermeability, BAL protein responses to O3 were compared in C3H/HeOuJ (OuJ) and HeJ mice that differ only at a polymorphism in the coding region of Tlr4. Significantly greater protein concentrations (430 ± 35 μg/ml) were found in OuJ mice compared with HeJ mice (258 ± 18 μg/ml) after exposure to O3. Furthermore, reverse transcriptase/polymerase chain reaction analysis demonstrated differential expression of Tlr4 message levels between HeJ and OuJ mice after O3 exposure. Together, results indicate that a QTL on mouse chromosome 4 explains a significant portion of the genetic variance in O3-induced hyperpermeability, and support a role for Tlr4 as a strong candidate susceptibility gene.

Original languageEnglish (US)
Pages (from-to)620-627
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Issue number5
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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