Signal Transduction Pathways of Tumor Necrosis Factor-mediated Lung Injury Induced by Ozone in Mice

• Published in: American journal of respiratory and critical care medicine Vol. 175; no. 8; pp. 829 - 839
• Main Authors: Cho, Hye-Youn, Morgan, Daniel L, Bauer, Alison K, Kleeberger, Steven R
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.04.2007; American Lung Association; American Thoracic Society
• Subjects: Air pollution; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Asthma; Biological and medical sciences; Blood and lymphatic vessels; Blood coagulation. Blood cells; Cardiology. Vascular system; Cytokines; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dosimetry; E. Environmental and Occupational Lung Disease; Fundamental and applied biological sciences. Psychology; General aspects, investigation methods, hemostasis, fibrinolysis; Histopathology; Human subjects; Inflammation; Intensive care medicine; Kinases; Laboratories; Lavage; Lungs; Medical sciences; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - physiology; Molecular and cellular biology; NF-kappa B - physiology; Outdoor air quality; Ozone; Ozone - adverse effects; Pathogenesis; Proteins; Respiratory Distress Syndrome, Adult - chemically induced; Signal transduction; Signal Transduction - physiology; TNF Receptor-Associated Factor 2 - physiology; Toxicity; Transcription Factor AP-1 - physiology; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factor-TNF; knockout; nuclear factor-KB; Lung disease; Intensive care; Respiratory disease; Enzyme; activator protein-1; Cytokine; Rodentia; Mitogen-activated protein kinase; tumor necrosis factor receptor; Ozone; Signal transduction; Vertebrata; Mammalia; Mouse; Tumor necrosis factor; Animal; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200509-1527OC

Increasing evidence suggests that tumor necrosis factor (TNF)-alpha plays a key role in pulmonary injury caused by environmental ozone (O(3)) in animal models and human subjects. We previously determined that mice genetically deficient in TNF response are protected from lung inflammation and epithelial injury after O(3) exposure. The present study was designed to determine the molecular mechanisms of TNF receptor (TNF-R)-mediated lung injury induced by O(3). TNF-R knockout (Tnfr(-/-)) and wild-type (Tnfr(+/+)) mice were exposed to 0.3 ppm O(3) or air (for 6, 24, or 48 h), and lung RNA and proteins were prepared. Mice deficient in p50 nuclear factor (NF)-kappaB (Nfkb1(-/-)) or c-Jun-NH(2) terminal kinase 1 (Jnk1(-/-)) and wild-type controls (Nfkb1(+/+), Jnk1(+/+)) were exposed to O(3) (48 h), and the role of NF-kappaB and mitogen-activated protein kinase (MAPK) as downstream effectors of lung injury was analyzed by bronchoalveolar lavage analyses. O(3)-induced early activation of TNF-R adaptor complex formation was attenuated in Tnfr(-/-) mice compared with Tnfr(+/+) mice. O(3) significantly activated lung NF-kappaB in Tnfr(+/+) mice before the development of lung injury. Basal and O(3)-induced NF-kappaB activity was suppressed in Tnfr(-/-) mice. Compared with Tnfr(+/+) mice, MAPKs and activator protein (AP)-1 were lower in Tnfr(-/-) mice basally and after O(3). Furthermore, inflammatory cytokines, including macrophage inflammatory protein-2, were differentially expressed in Tnfr(-/-) and Tnfr(+/+) mice after O(3). O(3)-induced lung injury was significantly reduced in Nfkb1(-/-) and Jnk1(-/-) mice relative to respective control animals. Results suggest that NF-kappaB and MAPK/AP-1 signaling pathways are essential in TNF-R-mediated pulmonary toxicity induced by O(3).