α,β-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 α,β-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 μM each) found in CSE and fully prevented by 1 mM α,β-unsaturated aldehydes scavengers N-acetylcysteine (NAC) or sodium 2-mercaptoethanesulfonate. 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 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 α,β-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.

Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract

“…In this study, CSE released IL-8, and it was dependent on ERK activation. This is in accordance with previous reports that showed that the CS-induced inflammation cascade is mediated by activation of the mitogen-activated protein kinase (MAPK) pathway (18,19). CSE is frequently used as a surrogate for CS in in vitro experiments.…”

“…Production through ERK Pathway-It has been suggested that mitogenactivated protein kinases, especially p38 and ERK, play a role in CS-induced proinflammatory signaling (18,19). Therefore, we investigated the role of the mitogen-activated protein kinase pathway in CSE-induced cytokine production.…”

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

“…33,34 p38 MAPK has been observed in airway epithelial cells and macrophages responding to environmental stresses, and this pathway appeared to be important for the secretion of pro-inflammatory cytokines and chemokines. [35][36][37][38] Our findings observed that CS stimulated the activity of p38 MAPK and the release of TNF-α and IL-1β in airway epithelial cells and in a mouse model. In our previous study, we showed that the p38 MAPK inhibitor SB203580 effectively reduced acrolein (a component of CS)-induced TNF-α release in BALF and the lungs of mice.…”

Cigarette smoke and α,β‐unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts

“…Both NHLF and ASMC were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, antibiotics (50 U·mL -1 penicillin and 0.05 mg·mL -1 streptomycin) and 2 mM L-glutamine in an atmosphere of 95% air and 5% CO2 at 37°C. SAEC were cultured in small airways epithelial growth factor medium (SAGM; Lonza, Basel, CH) according to supplier's instructions, as previously described (Moretto et al, 2009). NHLF, ASMC and SAEC cultures were used between passage 1 and 6.…”

“…Culpitt et al, 2003;Walters et al, 2005;Demirjian et al, 2006;Yang et al, 2006) as well as from lung fibroblasts (Sato et al, 1999;Numanami et al, 2003;Li et al, 2007) and airway epithelial cells (Mio et al, 1997;Masubuchi et al, 1998;Kode et al, 2006). Recently we provided evidence that the a,b-unsaturated aldehydes acrolein and crotonaldehyde are the main components of smoke responsible for IL-8 release from macrophages (Facchinetti et al, 2007) as well as from airway epithelial cells and fibroblasts through the stimulation of both extracellular signal-regulated kinase type 1 and 2 (ERK1/2) and mitogen-activated protein kinase (p38 MAPK) intracellular pathways (Moretto et al, 2009).…”