PMID- 10783135
OWN - NLM
STAT- MEDLINE
DCOM- 20000609
LR  - 20220311
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 22
IP  - 5
DP  - 2000 May
TI  - Genetic susceptibility to ozone-induced lung hyperpermeability: role of toll-like 
      receptor 4.
PG  - 620-7
AB  - The pollutant ozone (O(3)) 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 O(3). To 
      determine the chromosomal locations of susceptibility genes, we performed a 
      genome screen using recombinant inbred (RI) strains of mice derived from 
      O(3)-susceptible C57BL/6J (B6) and O(3)-resistant C3H/HeJ (HeJ) progenitors. Each 
      RI strain was phenotyped for O(3)-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 chi(2) 
      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 
      O(3)-induced hyperpermeability, BAL protein responses to O(3) 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 
      microg/ml) were found in OuJ mice compared with HeJ mice (258 +/- 18 microg/ml) 
      after exposure to O(3). Furthermore, reverse transcriptase/polymerase chain 
      reaction analysis demonstrated differential expression of Tlr4 message levels 
      between HeJ and OuJ mice after O(3) exposure. Together, results indicate that a 
      QTL on mouse chromosome 4 explains a significant portion of the genetic variance 
      in O(3)-induced hyperpermeability, and support a role for Tlr4 as a strong 
      candidate susceptibility gene.
FAU - Kleeberger, S R
AU  - Kleeberger SR
AD  - Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene 
      and Public Health, Baltimore, Maryland 21205, USA.
FAU - Reddy, S
AU  - Reddy S
FAU - Zhang, L Y
AU  - Zhang LY
FAU - Jedlicka, A E
AU  - Jedlicka AE
LA  - eng
GR  - ES03819/ES/NIEHS NIH HHS/United States
GR  - R01HL57142/HL/NHLBI NIH HHS/United States
GR  - R29HL58122/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Drosophila Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - 66H7ZZK23N (Ozone)
SB  - IM
MH  - Air Pollution/*adverse effects
MH  - Animals
MH  - Bronchoalveolar Lavage Fluid/chemistry
MH  - Capillary Permeability/genetics
MH  - Chromosome Mapping
MH  - *Drosophila Proteins
MH  - Gene Expression Regulation
MH  - Genetic Linkage
MH  - Genetic Predisposition to Disease
MH  - Lung Diseases/*etiology/genetics
MH  - Membrane Glycoproteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Neutrophils/metabolism
MH  - Ozone/*adverse effects
MH  - Phenotype
MH  - Polymorphism, Genetic
MH  - RNA, Messenger/metabolism
MH  - Receptors, Cell Surface/genetics/*metabolism
MH  - Time Factors
MH  - Toll-Like Receptor 4
MH  - Toll-Like Receptors
EDAT- 2000/04/27 09:00
MHDA- 2000/06/17 09:00
CRDT- 2000/04/27 09:00
PHST- 2000/04/27 09:00 [pubmed]
PHST- 2000/06/17 09:00 [medline]
PHST- 2000/04/27 09:00 [entrez]
AID - 10.1165/ajrcmb.22.5.3912 [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2000 May;22(5):620-7. doi: 10.1165/ajrcmb.22.5.3912.