4-Hydroxy-2-Nonenal Enhances Fibronectin Production by IMR-90 Human Lung Fibroblasts Partly via Activation of Epidermal Growth Factor Receptor-Linked Extracellular Signal-Regulated Kinase p44/42 Pathway

Abstract

To elucidate the underlying mechanisms in oxidative stress-related airway remodeling observed in chronic inflammatory pulmonary diseases such as asthma, we studied the effects of a thiol antioxidant, N-acetylcysteine (NAC), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG-1478, and tyrphostin-1 as a negative control for AG-1478 on an aldehydic product of lipid peroxidation 4-hydroxy-2-nonenal (HNE)-induced secretion of fibronectin by IMR-90 human lung fibroblasts. We also studied signal transduction pathways involved in the secretion of fibronectin evident after exposure of IMR-90 cells to HNE. Twenty-five-micromole HNE treatments of IMR-90 cells activated extracellular signal-regulated kinase p44/42 (Erk1/2) with little activation of p38 mitogen-activated protein kinase (p38MAPK) and no activation of c-Jun NH 2-terminal kinase. HNE-induced secretion of fibronectin was inhibited by U-0126, an inhibitor of the Erk1/2 pathway, while no significant inhibition by SB-203580, an inhibitor of p38MAPK pathway, was observed. NAC and AG-1478, but not tyrphostin-1, inhibited HNE-induced fibronectin secretion accompanied by a pallarel inhibition of Erk1/2 activation. These data suggest that pulmonary oxidative stress-related lipid peroxidation may play an important role in developing airway remodeling through activating lung fibroblasts to further produce extracellular matrices, such as fibronectin, partly via activation of an EGFR-linked Erk1/2 signal transduction pathway, and that the antioxidant NAC and the EGFR tyrosine kinase inhibitor AG-1478 can be potentially useful in pulmonary diseases involving airway remodeling.