Cigarette smoking is the major risk factor for 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 ,-unsaturated aldehydes (acrolein, crotonaldehyde) contained in CSE, in cultured normal human lung fibroblasts (NHLF) and small airway epithelial cells (SAEC). By examining a panel of 19 cytokines and chemokines we found that IL-8 release was elevated by CSE as well as by acrolein while other inflammatory mediators were mostly unaffected. CSE-evoked IL-8 release was mimicked by acrolein and crotonaldehyde at concentrations (3-60 µM each) found in CSE, and fully prevented by 1 mM of ,-unsaturated aldehydes scavengers N-acetylcysteine (NAC) or 2-mercaptoethane-sulfonate (MESNA). Neither the saturated aldehyde acetaldehyde nor H₂O₂ evoked IL-8 release. In addition, CSE or crotonaldehyde upregulated the release of IL-8 from alveolar macrophages from both COPD patients and healthy non smokers, 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 mitogen-activated protein kinase (MAPK) and extracellular-regulated kinases 1 and 2 (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 ,-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.