Role of Toll-like receptor 4 in hyperoxia-induced lung inflammation in mice.
OBJECTIVE
Prolonged exposure to hyperoxia causes lung inflammation, but the role of Toll-like receptor 4 (TLR4) in hyperoxia-induced signal transduction remains unclear.


METHODS
We evaluated neutrophil accumulation, signal transduction and cytokine production during hyperoxia, comparing TLR4 mutant (C3H/HeJ) and wild type (C3H/HeN) mice.


METHODS
The mice were exposed to 80% oxygen in a hyperoxic chamber for 0 (control), 48, or 96 h. After the exposure, bronchoalveolar lavage (BAL) was performed for differential cell counting and cytokine measurement. In lung homogenate, activation of NF-kappaB and STAT1 was also examined.


RESULTS
In C3H/HeJ mice, hyperoxia-induced neutrophil accumulation in BAL fluid was significantly decreased compared with C3H/HeN. Hyperoxia for 96 h caused NF-kappaB translocation in C3H/HeN mice, which was significantly attenuated in C3H/HeJ mice (p < 0.05). In contrast, STAT1 activation occurred as early as after 48 h of oxygen exposure, which did not differ between the two strains. The levels of TNF-alpha, IL-6, and KC in BAL fluid were increased after oxygen exposure, which was suppressed by the lack of TLR4 signaling.


CONCLUSIONS
These results suggest that TLR4-dependent NF-kB activation may be an important process of the upregulation of proinflammatory mediators and subsequent neutrophil accumulation into the lung during hyperoxia.
Ogawa
Y
Y
Division of Pulmonary Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Tasaka
S
S
Yamada
W
W
Saito
F
F
Hasegawa
N
N
Miyasho
T
T
Ishizaka
A
A
D000818:Animals; D016207:Cytokines / Q000032:analysis; D005260:Female; D000860:Hypoxia / Q000150:complications*; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D016207:Cytokines; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4