Pharmacological inhibition of epidermal growth factor receptor modulates cigarette smoke-induced CXCL8 release but not VEGF release

Cigarette smoke is the most important risk factor for the development of Chronic Obstructive Pulmonary Disease. A large body of evidence exists indicating that cigarette smoke is able to activate the Epidermal Growth Factor Receptor. We have previously established that aqueous cigarette smoke extract (CSE) stimulates CXCL8 and VEGF release from normal human lung fibroblasts (NHLF) and airways smooth muscle cells (ASMC) and that these effects are mediated by the α,β-unsaturated aldehydes contained in the CSE such as acrolein. Here we examined the effect of pharmacological inhibition of EGFR on CXCL8 and VEGF release induced by CSE and acrolein. We found that the EGFR inhibitors AG1478, gefitinib and PD153035 inhibit CSE- and acrolein-induced CXCL8 release in both NHLF and ASMC, but do not affect neither TNFα-induced CXCL8 release nor CSE-induced VEGF release. We have previously shown that CSE-evoked CXCL8 and VEGF release was accompanied by a rapid p38 MAPK phosphorylation mimicked by acrolein. Because p38 MAPK phosphorylation is one of the possible downstream pathway activated by EGFR, we examined the effects of EGFR inhibitors on p38 MAPK phosphorylation. We observed that all three EGFR inhibitors failed in modifying p38 MAPK phosphorylation evoked by CSE. In sum, pharmacological inhibition of EGFR suggests that EGFR is involved in CXCL8 release through a p38 MAPK independent mechanism. Given the pivotal role of CXCL8 and VEGF as neutrophil chemoattractant and angiogenic factor respectively, this study sheds light on the different mechanisms through which cigarette smoke can orchestrate inflammation and vascular remodeling in the lung.