title: Resveratrol impairs the release of steroid-resistant inflammatory cytokines from human airway smooth muscle cells in chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS = S = COPD for IL-8 and NS = S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD.
authors.affiliation: Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Sibbing
authors.forename: David
authors.initials: D
authors.lastname: Jungck
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Lin
authors.forename: Katja
authors.initials: K
authors.lastname: Urban
authors.forename: Erich
authors.initials: E
authors.lastname: Stoelben
authors.forename: Justus
authors.initials: J
authors.lastname: Strauch
authors.forename: Andrea
authors.initials: A
authors.lastname: Koch
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology*; D000077185:Resveratrol; D012907:Smoking / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol