Toll-like receptor 4 variants reduce airway response in human subjects at high endotoxin levels in a swine facility.
BACKGROUND
Toll-like receptor 4 (TLR4) variants have been shown to reduce the respiratory responses to inhaled LPS in controlled experiments among healthy volunteers.


OBJECTIVE
We sought to investigate whether naive subjects with TLR4 variants showed reduced respiratory response to a complex aerosol including endotoxin as a major constituent.


METHODS
Twenty-nine nonsmoking, nonatopic healthy subjects with TLR4 299/399 polymorphisms and 29 age- and sex-matched, wild-type TLR4 control subjects were exposed for 5 hours each in a noncontaminated environment (baseline day) and in a swine confinement facility (exposure day). There were 16 men and 13 women in each of the 2 age- and sex-matched groups.


RESULTS
TLR4 polymorphic subjects who were exposed to high endotoxin levels (>or=1550 EU/m(3)) had less reduction in the percentage across-shift change in FEV(1) from baseline than did wild-type subjects exposed to similar endotoxin levels. Among subjects exposed to higher endotoxin levels, the mean differences in the percentage across-shift changes between baseline and exposure days were significantly less in TLR4 polymorphic subjects compared with those seen in wild-type subjects in FEV(1) (-8.48% +/- 1.52% [mean +/- SE] vs -11.46% +/- 1.79%, P = .001), forced expiratory flow between 25% and 75% of forced vital capacity (-18.30% +/- 1.99% vs -24.14% +/- 3.28%, P = .009), and FEV(1)/forced vital capacity ratio (-5.40% +/- 0.56% vs -8.53% +/- 1.51%, P = .04). These patterns were not observed in IL-6 levels from serum and nasal lavage fluid, IL-8 levels from nasal lavage fluid, white blood cell counts, or blood differential counts.


CONCLUSIONS
The association between TLR4 variants and reduced airway responsiveness to inhaled particulate was observed at high endotoxin concentrations, creating the possibility of certain threshold phenomena for the apparent protective effect of TLR4 variants.
Senthilselvan
Ambikaipakan
A
Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada. sentil@ualberta.ca
Dosman
James A
JA
Chénard
Liliane
L
Burch
Lauranell H
LH
Predicala
Bernardo Z
BZ
Sorowski
Randine
R
Schneberger
David
D
Hurst
Tom
T
Kirychuk
Shelley
S
Gerdts
Volker
V
Cormier
Yvon
Y
Rennie
Donna C
DC
Schwartz
David A
DA
D000395:Air Pollutants, Occupational / Q000276:immunology*; D000485:Allergens / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000276:immunology*; D005260:Female; D006799:Housing, Animal; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D019570:Inhalation Exposure; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D034421:Sus scrofa; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
D000395:Air Pollutants, Occupational; D000485:Allergens; D016207:Cytokines; D004731:Endotoxins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4