title: Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown.
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.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
authors.forename: Andrew
authors.initials: A
authors.lastname: Churg
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Hsin
authors.initials: H
authors.lastname: Tai
authors.forename: Changshi
authors.initials: C
authors.lastname: Xie
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Wright
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003720:Densitometry; D003895:Desmosine / Q000032:analysis; D015870:Gene Expression; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects* / Q000473:pathology; D007507:Therapeutic Irrigation; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D019402:Macrophage Inflammatory Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003895:Desmosine