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Published ahead of print on June 28, 2007, doi:10.1165/rcmb.2007-0130OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 617-623, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2007-0130OC

{alpha},beta-Unsaturated Aldehydes in Cigarette Smoke Release Inflammatory Mediators from Human Macrophages

Fabrizio Facchinetti1, Francesco Amadei2, Pierangelo Geppetti3, Francesca Tarantini3, Claudia Di Serio3, Alberto Dragotto4, Paolo M. Gigli4, Silvia Catinella2, Maurizio Civelli1 and Riccardo Patacchini1

1 Department of Pharmacology, and 2 Department of Analytical Chemistry, Chiesi Pharmaceuticals SpA, Parma, Italy; 3 Department of Critical Care Medicine and Surgery, and 4 Department of Thoracic Surgery, University of Florence, Florence, Italy

Correspondence and requests for reprints should be addressed to R. Patacchini, Department of Pharmacology, Chiesi Pharmaceuticals SpA, Via Palermo 26/A, 43100, Parma, Italy. E-mail: r.patacchini{at}chiesigroup.com

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 µM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30–100 µM), 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.

Key Words: chronic obstructive pulmonary disease • IL-8 • TNF-{alpha} • U937 cells • THP-1 cells


CLINICAL RELEVANCE

This study provides new insights into the identity of the substances in cigarette smoke or generated in the lung, producing chronic inflammation. {alpha},beta-Unsaturated aldehydes may become new pharmacologic targets for anti-inflammatory drugs for chronic obstructive pulmonary disease.

 



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