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Department of Environmental Health Sciences, The Johns Hopkins University School of Public Health, Baltimore, Maryland 21205
We
tested the hypotheses that 1) inducible nitric oxide
synthase (iNOS) mediates ozone (O3)-induced lung
hyperpermeability and 2) mRNA levels of the gene for iNOS
(Nos2) are modulated by Toll-like receptor 4 (Tlr4) during O3 exposure. Pretreatment of O3-susceptible C57BL/6J mice with a specific inhibitor of
total NOS (NG-monomethyl-L-arginine)
significantly decreased the mean lavageable protein concentration (a
marker of lung permeability) induced by O3 (0.3 parts/million for 72 h) compared with vehicle control mice.
Furthermore, lavageable protein in C57BL/B6 mice with targeted disruption of Nos2 [Nos2(
/)] was 50% less
than the protein in wild-type [Nos2(+/+)] mice after
O3. To determine whether Tlr4 modulates
Nos2 mRNA levels, we studied C3H/HeJ (HeJ) and C3H/HeOuJ mice that differ only at a missense mutation in Tlr4 that
confers resistance to O3-induced lung hyperpermeability in
the HeJ strain. Nos2 and Tlr4 mRNA levels were
significantly reduced and correlated in resistant HeJ mice after
O3 relative to those in susceptible C3H/HeOuJ mice.
Together, the results are consistent with an important role for iNOS in
O3-induced lung hyperpermeability and suggest that
Nos2 mRNA levels are mediated through Tlr4.
innate immunity; epithelium; inflammation; polymorphism; knockout mouse
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