title: Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages.
abstract: Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen species (ROS), have been proposed to be responsible for the inflammatory process of COPD. However, this issue remains unsettled. By gas chromatography/mass spectrometry (GC/MS) we show that acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes, are contained in aqueous cigarette smoke extract (CSE) at micromolar concentrations and mimic CSE in evoking the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-alpha from the human macrophagic cell line U937. In addition, acrolein (10-30 microM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30-100 microM), an endogenous alpha,beta-unsaturated aldehyde that is abundant in lungs of patients with COPD, stimulated the release of IL-8 from U937 cells, whereas the saturated aldehyde, acetaldehyde, was ineffective. CSE-evoked IL-8 release was remarkably (> 80%) inhibited by N-acetyl-cysteine (0.1-3 mM) or glutathione monoethyl ester (1-3 mM). Both compounds, by forming covalent adducts (Michael adducts), completely removed unsaturated aldehydes from CSE. Our data demonstrate that alpha,beta-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, and suggest that they might contribute to pulmonary inflammation associated with cigarette smoke.
authors.affiliation: Department of Pharmacology, Chiesi Pharmaceuticals SpA, Parma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Amadei
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Tarantini
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Alberto
authors.initials: A
authors.lastname: Dragotto
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Gigli
authors.forename: Silvia
authors.initials: S
authors.lastname: Catinella
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
mesh_terms: D000447:Aldehydes / Q000009:adverse effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D000447:Aldehydes; D018836:Inflammation Mediators; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha