Biomedical Engineering Reference
In-Depth Information
5.3 DBD Plasma Induced Secondary ROS
When growth factors such as FGF-2 bind to their receptors, ROS are produced by
NADPH oxidases [
187
]. This ROS signaling following growth factor stimulation
may enhance growth factor binding to receptors, induce receptor tyrosine kinase
phosphorylation, or signal along growth factor pathways [
58
,
82
,
188
]. In human
coronary endothelial cells, FGF-2 induced cell proliferation and migration through
ROS production by NADPH oxidase [
189
]. The NADPH oxidase inhibitor DPI
prevented secondary ROS formation and decreased cell proliferation. FGF-2
stimulation also increases FGF-2 expression in endothelial cells, smooth muscle
cells and cardiac myocytes. Using an in vitro scrape cell injury model, Ku et al.
showed that scrape-released FGF-2 induced a 4-10 fold increase in FGF-2 mRNA
levels [
72
]. This process may also be mediated by FGF-2 induced intracellular
ROS production [
74
-
76
,
190
]. In pulmonary arterial smooth muscle cells, FGF-2
expression following exogenous FGF-2 addition was associated with increased
intracellular ROS via NADPH oxidase activation. FGF-2 expression was attenu-
ated by the intracellular ROS scavenger N-acetyl cysteine [
78
]. FGF-2 release
caused by injury has also been shown to enhance FGF-2 expression in intestinal
epithelial stem cells and human lens cells [
68
,
191
].
We hypothesized that FGF-2 released by DBD plasma causes cell proliferation
through intracellular secondary ROS production. We measured longer term plasma
effects on intracellular ROS (up to 24 h after plasma). ROS levels increased
rapidly following plasma and returned to untreated control levels by 6 h. However,
at 24 h intracellular ROS peaked a second time. When cells were incubated with
an FGF-2 neutralizing antibody, the initial ROS peak was higher (40 % increase),
occurred later (3 h), and declined more slowly over time. No secondary ROS peak
was observed at 24 h with the FGF-2 antibody. When the secondary ROS peak
was blocked with sodium pyruvate, plasma no longer increased endothelial cell
proliferation. Finally, we were interested in observing the effect of multiple plasma
treatments, or essentially repeated oxidative stress. When endothelial cells were
plasma treated a second time either 48 or 72 h after the initial plasma treatment,
plasma-induced FGF-2 release increased significantly. This effect was also
blocked by an FGF-2 neutralizing antibody. These data show that initial oxidative
stress induces FGF-2 release, which then signals for cell proliferation via intra-
cellular secondary ROS production. The initial FGF-2 release induces FGF-2
production, so that any subsequent oxidative stress causes a larger FGF-2 release.
6 Conclusions
ROS modulation is an important therapeutic option for a wide variety of angiogenesis
dependent and independent diseases. However, current oxidant and anti-oxidant
therapies fail to incorporate the complexities of ROS type, dose, and timing.
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