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.
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.
Tsukagoshi
Hideo
H
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Kawata
Tadayoshi
T
Shimizu
Yuji
Y
Ishizuka
Tamotsu
T
Dobashi
Kunio
K
Mori
Masatomo
M
D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D000447:Aldehydes; D017077:Culture Media, Conditioned; D005353:Fibronectins; D007093:Imidazoles; D011725:Pyridines; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal; C093642:SB 203580; D000111:Acetylcysteine