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Role of tumor necrosis factor in oxygen toxicity
J C Jensen1, H W Pogrebniak, H I Pass
1Surgical Metabolism and Thoracic Oncology Sections, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
mRNA from lungs of mice exposed to high-dose oxygen (greater than 95%) for 3 days demonstrated increased expression of the genes for tumor necrosis factor (TNF), interleukin-1, and interleukin-6 compared with mRNA from lungs of mice exposed to room air. Daily treatment of mice exposed to high-dose oxygen with an antibody to TNF improved survival compared with mice receiving a similar dose of control immunoglobulin G. Pretreatment of mice with repetitive sublethal intraperitoneal doses of recombinant human TNF for 3 days or a single intravenous dose followed by exposure to high-dose oxygen afforded a significant survival advantage compared with high-dose oxygen-exposed mice pretreated with vehicle or interleukin-1. The repetitive intraperitoneal TNF pretreatment reduced the development of interstitial pneumonitis, pulmonary edema, and lung weight gain associated with oxygen toxicity and enhanced expression of the gene for the free radical protective enzyme manganous superoxide dismutase in lung tissue, a gene that is augmented as mice are exposed to high-dose oxygen. Furthermore a single intravenous dose of TNF 24 h after oxygen exposure was still protective. The results suggest that the toxicity of oxygen therapy can be partially ameliorated by either treatment with anti-TNF antibody or pretreatment and early treatment with TNF. These findings are consistent with the hypothesis that oxygen exposure induces TNF, which causes part of the toxicity of high-dose oxygen, and that pretreatment or early treatment with TNF induces the gene for an enzyme that recently has been shown to be very effective in protecting mice from the toxicity of oxygen.
Insights
High-dose oxygen therapy increases tumor necrosis factor (TNF), contributing to lung injury. Blocking TNF or administering TNF early can protect against oxygen toxicity by enhancing protective enzymes.
Area of Science:
- Pulmonary Medicine
- Immunology
- Toxicology
Background:
- High-dose oxygen therapy, while critical, can cause lung injury (oxygen toxicity).
- Inflammatory mediators, including tumor necrosis factor (TNF), are implicated in oxygen-induced lung damage.
Purpose of the Study:
- To investigate the role of TNF in high-dose oxygen-induced lung toxicity.
- To evaluate the therapeutic potential of anti-TNF antibodies and TNF administration in mitigating oxygen toxicity.
Main Methods:
- Mice were exposed to high-dose oxygen, and lung mRNA expression for inflammatory genes was analyzed.
- Survival rates were assessed in mice treated with anti-TNF antibody or control immunoglobulin G.
- Mice were pretreated with recombinant human TNF or vehicle before oxygen exposure, and survival and lung pathology were evaluated.
Main Results:
- High-dose oxygen exposure increased lung expression of TNF, interleukin-1, and interleukin-6.
- Anti-TNF antibody treatment improved survival in oxygen-exposed mice.
- TNF pretreatment or early administration reduced lung injury, improved survival, and enhanced manganous superoxide dismutase gene expression.
Conclusions:
- Oxygen therapy-induced toxicity is partially mediated by TNF.
- Administering anti-TNF antibodies or TNF itself (pre- or early treatment) can ameliorate oxygen toxicity.
- TNF may induce protective enzymes, offering a novel therapeutic strategy against hyperoxia-induced lung injury.