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Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown
Andrew Churg1, Jin Dai, Hsin Tai
1Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
Abstract:
The role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of cigarette smoke-induced disease is controversial. We exposed mice with knocked-out p55/p75 TNF-alpha receptors (TNF-alpha-RKO mice) to cigarette smoke and compared them with control mice. Two hours after smoke exposure, increases in gene expression of TNF-alpha, neutrophil chemoattractant, macrophage inflammatory protein-2, and macrophage chemoattractant, protein-1 were seen in control mice. By 6 hours, TNF-alpha, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 gene expression levels had returned to control values in control mice and stayed at control values through 24 hours. In TNF-alpha-RKO mice, no changes in gene expression of these mediators were seen at any time. At 24 hours, control mice demonstrated increases in lavage neutrophils, macrophages, desmosine (a measure of elastin breakdown), and hydroxyproline (a measure of collagen breakdown), whereas TNF-alpha-RKO mice did not. In separate experiments, pure strain 129 mice, which produce low levels of TNF-alpha, showed no inflammatory response to smoke at 24 hours or 7 days. We conclude that TNF-alpha is central to acute smoke-induced inflammation and resulting connective tissue breakdown, the precursor of emphysema. The findings support the idea that TNF-alpha promoter polymorphisms may be of importance in determining who develops smoke-induced chronic obstructive pulmonary disease.
Insights
Tumor necrosis factor-alpha (TNF-alpha) drives acute inflammation and connective tissue breakdown from cigarette smoke exposure. Blocking TNF-alpha prevents these smoke-induced responses, suggesting its critical role in developing emphysema.
Area of Science:
- Pulmonary Medicine
- Immunology
- Toxicology
Background:
- The role of tumor necrosis factor-alpha (TNF-alpha) in cigarette smoke-induced lung disease remains debated.
- Cigarette smoke exposure is a primary risk factor for chronic obstructive pulmonary disease (COPD).
Purpose of the Study:
- To investigate the role of TNF-alpha in mediating acute inflammatory responses and connective tissue breakdown caused by cigarette smoke.
- To determine if blocking TNF-alpha signaling can prevent smoke-induced lung injury.
Main Methods:
- Exposure of p55/p75 TNF-alpha receptor knockout (TNF-alpha-RKO) mice and control mice to cigarette smoke.
- Measurement of inflammatory mediator gene expression (TNF-alpha, chemoattractants) at various time points post-exposure.
- Analysis of inflammatory cell counts (neutrophils, macrophages) and connective tissue breakdown markers (desmosine, hydroxyproline) in bronchoalveolar lavage fluid at 24 hours.
- Comparison with smoke response in low-TNF-alpha producing mice (strain 129).
Main Results:
- Control mice showed transient increases in inflammatory gene expression and significant increases in inflammatory cells and connective tissue breakdown markers (desmosine, hydroxyproline) 24 hours after smoke exposure.
- TNF-alpha-RKO mice exhibited no changes in inflammatory gene expression or lung tissue damage markers following smoke exposure.
- Low-TNF-alpha producing mice (strain 129) did not show an inflammatory response to cigarette smoke.
Conclusions:
- TNF-alpha is a critical mediator of acute inflammation and connective tissue degradation induced by cigarette smoke.
- These findings highlight TNF-alpha's central role in the pathogenesis of emphysema, a precursor to COPD.
- TNF-alpha promoter polymorphisms may influence susceptibility to developing smoke-induced COPD.