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Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors
H Y Cho1, L Y Zhang, S R Kleeberger
1Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Abstract:
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.
Insights
Tumor necrosis factor (TNF) receptor signaling is critical for ozone-induced lung injury and airway hyperreactivity in mice. Blocking TNF receptors reduces inflammation and epithelial damage from ozone exposure.
Area of Science:
- Pulmonary Medicine
- Toxicology
- Immunology
Background:
- Ozone (O3) is a major air pollutant that causes lung injury.
- Tumor necrosis factor (TNF) is implicated in inflammatory responses.
- TNF receptors (TNFRs) mediate TNF signaling.
Purpose of the Study:
- To investigate the role of TNF receptor signaling in ozone-induced pulmonary injury and airway hyperreactivity.
- To determine how TNF receptor knockout affects lung responses to ozone exposure.
Main Methods:
- Exposure of wild-type and TNFR knockout mice (TNFR1-/-, TNFR2-/-, TNFR1/TNFR2-/-) to ozone (0.3 ppm for 48h or 2 ppm for 3h).
- Assessment of lung inflammation, epithelial damage, and airway hyperreactivity using bronchoalveolar lavage and other lung function tests.
- Analysis of TNFR1 and TNFR2 mRNA expression in lung tissue.
Main Results:
- All TNFR knockout mice showed significantly reduced ozone-induced lung inflammation and epithelial damage compared to wild-type mice.
- Lung hyperpermeability was not significantly different between knockout and wild-type mice.
- Ozone exposure modulated TNFR1 and TNFR2 mRNA levels in wild-type mice.
- Airway hyperreactivity induced by acute ozone exposure was diminished in knockout mice.
Conclusions:
- TNF receptor signaling plays a critical role in subacute ozone-induced pulmonary epithelial injury and inflammation.
- TNFR signaling is also important for acute ozone-induced airway hyperreactivity.
- Targeting TNF receptors may be a therapeutic strategy for ozone-induced lung damage.