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Updated: Aug 15, 2026
Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure
Published on: August 25, 2017
Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes
Jerold A Last1, Kishorchandra Gohil, Vivek C Mathrani
1Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723, USA. jalast@ucdavis.edu
Abstract:
Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-kappaB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.
Insights
Acute ozone exposure causes significant weight loss in mice, impacting metabolism and immune responses. Gene expression analysis reveals liver metabolic gene down-regulation and potential interferon signaling between lung and liver.
Area of Science:
- Environmental toxicology
- Molecular biology
- Systemic physiology
Background:
- Ozone exposure causes rapid weight loss in rodents, but underlying mechanisms are unclear.
- Previous studies indicated lung inflammation and cachexia-like gene expression changes following ozone exposure.
- Systemic effects of ozone exposure on liver gene expression have not been investigated.
Purpose of the Study:
- To investigate the molecular mechanisms of systemic response to acute ozone exposure.
- To analyze global gene expression changes in the liver following ozone inhalation.
- To identify key metabolic pathways and signaling molecules affected by ozone exposure.
Main Methods:
- Global gene expression analysis (transcriptomics) of liver tissue from C57BL mice.
- Acute exposure of mice to high concentrations of ozone.
- Quantification of body weight loss and food consumption.
Main Results:
- Mice lost up to 14% body weight and decreased food consumption by 42%.
- Significant down-regulation of genes involved in lipid, fatty acid, and carbohydrate metabolism in the liver.
- Down-regulation of interferon-dependent genes and xenobiotic metabolism enzymes (cytochrome P450) in the liver.
Conclusions:
- Ozone exposure induces a systemic cachexia-like response, affecting liver metabolism.
- Interferon signaling may mediate communication between the lungs and liver after ozone exposure.
- Suppressed cytochrome P450 expression in the liver could explain altered drug metabolism observed previously.
