title: alpha,beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases.
abstract: Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD), a syndrome characterized by pulmonary neutrophil infiltration, chronic inflammation, and progressive tissue destruction. We examined here the acute effect of aqueous cigarette smoke extract (CSE) and of two alpha,beta-unsaturated aldehydes (acrolein and crotonaldehyde) contained in CSE in cultured normal human lung fibroblasts and small airway epithelial cells. By examining a panel of 19 cytokines and chemokines, we found that IL-8 release was elevated by CSE as well as by acrolein, whereas other inflammatory mediators were mostly unaffected. CSE-evoked IL-8 release was mimicked by acrolein and crotonaldehyde at concentrations (3-60 microM each) found in CSE and fully prevented by 1 mM alpha,beta-unsaturated aldehydes scavengers N-acetylcysteine (NAC) or sodium 2-mercaptoethanesulfonate. Neither the saturated aldehyde acetaldehyde nor H(2)O(2) evoked IL-8 release. In addition, CSE or crotonaldehyde upregulated the release of IL-8 from alveolar macrophages from both COPD patients and healthy nonsmokers, indicating that this is a response common to cells involved in lung inflammation. CSE-evoked IL-8 release was accompanied by increased phosphorylation of p38 MAPK and ERK1/2. CSE-evoked p38 and ERK1/2 phosphorylation was mimicked by acrolein and inhibited by NAC. IL-8 release elicited by both acrolein and CSE was blocked by pharmacological inhibition of p38 and ERK1/2 phosphorylation. In summary, our data show that alpha,beta-unsaturated aldehydes-evoked phosphorylation of p38 and ERK1/2 underlies IL-8 release elicited by CSE, thus shedding light on the mechanisms through which cigarette smoke can initiate inflammation in the lung.
authors.affiliation: Department of Pharmacology, Chiesi Farmaceutici SpA, Via Palermo 26/A, 43100, Parma, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Thomas
authors.initials: T
authors.lastname: Southworth
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000447:Aldehydes / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015080:Mesna / Q000494:pharmacology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000447:Aldehydes; D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015080:Mesna; D000111:Acetylcysteine