Reactive oxygen species as mediators of membrane-dependent signaling induced by ultrafine particles.
Cell-membrane-dependent proliferative signal transduction activated by ultrafine carbon particles in lung epithelial cells involves the specific induction of Akt and ERK1/2 phosphorylation. Particle-induced generation of reactive oxygen species (ROS) and oxidative stress are regarded as initial molecular mechanisms leading to the induction of diverse cellular responses. Therefore, we aimed to analyze the ROS dependence of the induced activation of the Akt/ERK1/2 signaling pathway upon exposure to ultrafine particulate matter (UPM). For this, ultrafine carbon black (ufCB) and ferric sulfate (FS) were used as a model representing the carbonaceous core and a nonparticulate Fenton-reactive transition metal salt often found in combustion-derived UPM. Cell-free as well as intracellular particle-induced ROS generation was assessed and related to the induced Akt and ERK1/2 phosphorylation by inhibiting oxidative stress with catalase, superoxide dismutase, and N-acetylcysteine. We show here that the activation of this signal transduction pathway was mainly due to intracellular, rather than extracellular, ROS production induced by both ufCB and FS. Further inhibitor studies on the role of cell membrane receptors pointed to the epidermal growth factor receptor as a common mediator for particle- as well as transition metal-induced signaling, whereas integrin-dependent Akt and ERK1/2 activation seems to be particle-specific.
Weissenberg
Alexander
A
Molecular Toxicology Group, Institut für Umweltmedizinische Forschung, 40225 Düsseldorf, Germany.
Sydlik
Ulrich
U
Peuschel
Henrike
H
Schroeder
Peter
P
Schneider
Maren
M
Schins
Roel P F
RP
Abel
Josef
J
Unfried
Klaus
K
D000818:Animals; D002244:Carbon / Q000737:chemistry*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry; D018384:Oxidative Stress; D010316:Particle Size; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D005290:Ferric Compounds; D017382:Reactive Oxygen Species; C024823:ferric sulfate; D002244:Carbon; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases