Mitogen-activated protein kinases mediate peroxynitrite-induced cell death in human bronchial epithelial cells.
Peroxynitrite, formed by the reaction of nitric oxide (NO. ) with superoxide anions (O(2)(-).), may play a role in the pathophysiology of inflammation. The effects of 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, on the human bronchial epithelial cell line BEAS-2B, were examined. SIN-1 exposure resulted in cell death in a time- and dose-dependent manner. Depletion of intracellular glutathione increased the vulnerability of the cells. Pretreatment with Mn(III)tetrakis(N-methyl-4'-pyridyl)porphyrin (MnTMPyP) or hydroxocobalamin (HC), O(2)(-). and NO. scavengers, respectively, reduced significantly SIN-1-induced cell death (18.66 +/- 3.57 vs. 77.01 +/- 14.07 or 82.20 +/- 9.64, % cell viability SIN-1 vs. MnTMPyP or HC). Moreover, the mitogen-activated protein kinases (MAPK) p44/42 (ERK), p38, and p54/46 (JNK) were also activated in a time- and concentration-dependent manner. PD-98059 and SB-239063, specific inhibitors of ERK and p38 MAPK pathways, failed to protect cells against 1 mM SIN-1. However, PD-98059 partially inhibited (60% cell survival) SIN-1 effects at < or =0.25 mM, and this was increased with the inclusion of SB-239063. Therefore, MAPKs may mediate signal transduction pathways induced by peroxynitrite in lung epithelial cells leading to cell death.
Nabeyrat
Elodie
E
Thoracic Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London SW3 6LY, United Kingdom.
Jones
Gina E
GE
Fenwick
Peter S
PS
Barnes
Peter J
PJ
Donnelly
Louise E
LE
D001980:Bronchi / Q000166:cytology* / Q000201:enzymology*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D020030:Nitric Oxide Donors; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one