Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors.
This study was designed to investigate the mechanisms through which tumor necrosis factor (Tnf) modulates ozone (O(3))-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type (wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [TNFR1(-/-)], the p75 TNF receptor [TNFR2(-/-)], or both receptors [TNFR1/TNFR2(-/-)] were exposed to 0.3 parts/million O(3) for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(-/-) mice had significantly less O(3)-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O(3) elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(-/-) and TNFR1(-/-) mice, respectively. Airway hyperreactivity induced by acute O(3) exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wt mice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O(3)-induced pulmonary epithelial injury and inflammation and in acute O(3)-induced airway hyperreactivity.
Cho
H Y
HY
Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Zhang
L Y
LY
Kleeberger
S R
SR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D010126:Ozone; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
D015703:Antigens, CD; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D010126:Ozone