Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury (epidermal growth Communicated by Judah Folkman, January 4, 1993 (received for review January 3, 1992) ABSTRACTWound fluid was obtained from porcine partial-thickness excisional wounds and analyzed for heparinbinding growth factors. Two heparin-binding growth factor activities were detected, a relatively minor one that was eluted from a heparin affinity column with 0.65 M NaCi and a major one that was eluted with 1.1 M NaCI. These activities were not present in wound fluid 1 hr after injury but appeared 1 day after injury, were maximal 2-3 days after injury, and were not detectable by 8 days after injury. The heparin-binding growth factor eluted with 0.65 M NaCl was identified as a plateletderived growth factor (PDGF)-like activity by the use ofspecific anti-PDGF neutralizing antibodies. The heparin-binding growth factor eluted with 1.1 M NaCl was shown to be structurally related to heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) by several criteria, including binding to heparin affinity columns and elution with 1.1 M NaCl, competition with the binding of 125I-EGF to the EGF receptor, triggering phosphorylation of the EGF receptor, immunodetection on a Western blot, and stimulation of fibroblast and keratinocyte growth. It was concluded that HB-EGF is a major growth factor component of wound fluid and, since it is mitogenic for fibroblasts and keratinocytes, that it might play an important role in wound healing.
Copper plays a key role in angiogenesis and in the synthesis and stabilization of extracellular matrix skin proteins, which are critical processes of skin formation. We hypothesized that introducing copper into wound dressings would enhance wound repair. Application of wound dressings containing copper oxide to wounds inflicted in genetically engineered diabetic mice (C57BL/KsOlaHsd-Lepr(db)) resulted in increased gene and in situ up-regulation of proangiogenic factors (e.g., placental growth factor, hypoxia-inducible factor-1 alpha, and vascular endothelial growth factor), increased blood vessel formation (p<0.05), and enhanced wound closure (p<0.01) as compared with control dressings (without copper) or commercial wound dressings containing silver. This study proves the capacity of copper oxide-containing wound dressings to enhance wound healing and sheds light onto the molecular mechanisms by which copper oxide-impregnated dressings stimulate wound healing.
Summar yThe goal of this work was to determine the molecular basis for the induction of tumour vascularization and progression by injury. Magnetic resonance imaging (MRI) studies demonstrated that administration of wound fluid derived from cutaneous injuries in pigs reduced the lag for vascularization and initiation of growth of C6 glioma spheroids, implanted in nude mice, and accelerated tumour doubling time. The former effect can be attributed to the angiogenic capacity of wound fluid as detected in vivo by MRI, and in vitro in promoting endothelial cell proliferation. The latter effect, namely the induced rate of tumour growth, is consistent with the angiogenic activity of wound fluid as well as with the finding that wound fluid was directly mitogenic to the tumour cells, and accelerated growth of C6 glioma in spheroid culture. Of the multiple growth factors present in wound fluid, two key factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and platelet-derived growth factor (PDGF), were identified as the dominant mitogens for C6 glioma, and inhibition of their activity using specific neutralizing antibodies suppressed the mitogenic effect of wound fluid on DNA synthesis in C6 glioma. This study suggests that the stimulatory effect of injury on tumour progression can possibly be attenuated by therapeutic targeting directed against a limited number of specific growth factors.
Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-α induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-α and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-α, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-α levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-α serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.
The poor ability of mammalian central nervous system (CNS) axons to regenerate has been attributed, in part, to astrocyte behavior after axonal injury. This behavior is manifested by the limited ability of astrocytes to migrate and thus repopulate the injury site. Here, the migratory behavior of astrocytes in response to injury of CNS axons in vivo was simulated in vitro using a scratch-wounded astrocytic monolayer and soluble substances derived from injured rat optic nerves. The soluble substances, applied to the scratch-wounded astrocytes, blocked their migration whereas some known wound-associated factors such as transforming growth factor- 1 (TGF- 
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen and migration factor for vascular smooth muscle cells (SMC), promoted neovascularization in vivo in the rabbit cornea. MRI demonstrated quantitatively the angiogenic effect of HB-EGF when introduced subcutaneously into nude mice. HB-EGF is not directly mitogenic to endothelial cells but it induced the migration of bovine endothelial cells and release of endothelial cell mitogenic activity from bovine vascular SMC. This mitogenic activity was specifically blocked by neutralizing anti-vascular endothelial growth factor (VEGF) antibodies. In contrast, EGF or transforming growth factor-K K (TGF-K K) had almost no effect on release of endothelial mitogenicity from SMC. In addition, RT-PCR analysis demonstrated that VEGF ITS mRNA levels were increased in vascular SMC 4^10-fold by 0.35^2 nM of HB-EGF, respectively. Our data suggest that HB-EGF, as a mediator of intercellular communication, may play a new important role in supporting wound healing, tumor progression and atherosclerosis by stimulating angiogenesis.z 1998 Federation of European Biochemical Societies.
Angiogenesis, the growth of new capillary blood vessels by sprouting from established vessels, is a tightly controlled process. [1][2][3][4][5][6] The hypoxic induction of angiogenesis is a hallmark of pathological processes such as wound healing and solid tumor formation; it is strongly correlated with the disrupted circulation, rapid proliferation and growth characteristic of these states. Hypoxia causes secretion of vascular endothelial growth factor (VEGF), 7 an angiogenic/permeability factor that acts to increase the immediate availability of oxygen from capillaries through increased vascular permeability as well as induces formation of new vessels. Angiogenesis involves intense endothelial cell cytokine-dependent proliferation and hypoxia/reoxygenation. Cultured endothelial cells produce reactive oxygen species (ROS) spontaneously 8,9 and this is augmented by hypoxia/reoxygenation 10 -16 as well as by cytokines. 17 In vivo, oxygen radicals are produced as by-products of normal oxidative metabolism. 18 Hence, proliferating cells with a higher metabolism produce more oxygen radicals. ROS have been implicated in the mechanism of damage after reperfusion of ischemia 19 and vascular endothelial cells are the most vulnerable targets for free radicals produced at the time of organ reperfusion after cold preservation. 20 Angiogenesis is a continuos process of reoxygenation. The fact that ROS are produced by endothelial cells, especially under conditions of reoxygenation and the very high sensitivity of endothelial cells to ROS poses a physiological need to scavenge these toxic oxygen radicals, which other wise will lead to damage and apoptosis of the vasculature.SOD-1 is a key enzyme in the dismutation of the potentially toxic superoxide radicals into hydrogen peroxide and dioxygen. 21 Because angiogenesis is characterized by proliferating endothelial cells and reoxygenation, we have examined the possibility that altered activity of SOD-1 will effect the angiogenic process. This assumption is consistent with recent findings demonstrating that the anti-angiogenic compound 2-methoxyoestradiol 22 is a SOD-1 inhibitor. 23 We have speculated that upregulation of SOD-1 will increase the ability of endothelial cells to confront an increased level of ROS during angiogenesis, resulting in increased angiogenesis. Inhibition of SOD-1 will diminish this ability, resulting in inhibition of angiogenesis. Disulfiram (DSF), a chelator of heavy metals and the active ingredient of the drug Antabuse used in aversion therapy for chronic alcoholism, 24 is an inhibitor of SOD-1 in vivo. 25 Disulfiram administered in vivo is immediately reduced to diethyldithiocarbamate (DDC). DDC was shown to strongly inhibit vascular SOD-1 in isolated canine basilar arteries. 26 Here we demonstrate that transgenic mice over-expressing SOD-1 (Tg-SOD) have a higher angiogenic potential and that treatment with DSF induces apoptosis in endothelial cells in vitro and inhibits angiogenesis in vivo. Tumor growth is dependent upon the formation of new blood v...
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