Ionizing irradiation is associated with an acute inflammatory reaction leading to pulmonary fibrosis, a significant medical problem. The radiosensivity of the lung limits the dose of radiation, which can be delivered to tumors in the thoracic region. The interaction between VEGF proinflamatory cytokine, the main mitogen for endothelial cells, and its soluble receptor sFLT, specific VEGF inhibitor, may play an important role in lung microvascular restoration during post-radiation inflammatory and fibrotic phases. We examined therapeutic nonviral, intramuscular gene transfer of human VEGF165 and sFLT1, in radiation-induced late pulmonary fibrosis in experimental animals. To investigate its antifibrotic activity we used pVEGF165 and psFLT1 expression vector, constructed in our laboratory. Therapeutic plasmids were previously tested in vitro and in vivo for its ability to cell transfection, gene expression and angiogenic and antiangiogenic potency. C57Bl/6J mice, well documented animal model for observation effects of thoracic irradiation were exposed to single dose 15Gy and randomly divided into three groups, which received intramuscular injection of plasmids as follows (1) control-“empty” plasmid, (2) plasmid encoding VEGF165 and (3) plasmid encoding sFLT. In this study DNA-plasmid was complexed with PEI (Polyethylenimine, 25kDa) and served in 30µg per mouse. To enhance the transfection efficiency the plasmid injections were repeated in two weeks intervals, for three months. Plasmid injections in group of animals receiving pVEGF were started two weeks later, because of possibility of its action as vascular permeability factor (VPF) in early post-radiation phase. For histopathologic changes examination some mice were euthanized at 1 or 2 months after irradiation. Remaining twenty four animals were observed, weighted and its survival time was noted. In conclusion, our data demonstrate that sFLT1 derived from plasmid transfection may inhibit endogenous VEGF and increase mortality rate irradiated C57Bl/6J mice and accelerate histopathologic changes in lungs. Obtained data suggest that VEGF is necessary for lung post-radiation damage reparation. Unexpectedly, in the same experiment the strategy depending on elevated VEGF level did not deliver promising data. and pVEGF165 transfection did not protect irradiation-induced pneumonitis and fibrosis.

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