scholarly journals Modulation of Oxidative and Nitrosative Stress Attenuates Microvascular Hyperpermeability in Ovine Model of Pseudomonas Aeruginosa Sepsis

2021 ◽  
Author(s):  
Satoshi Fukuda ◽  
Yosuke Niimi ◽  
Yasutaka Hirasawa ◽  
Ennert R. Manyeza ◽  
C. Edwin Garner ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Pseudomonas Aeruginosa ◽  
Growth Factor ◽  
Lung Tissue ◽  
Interleukin 6 ◽  
Nitrosative Stress ◽  
Vascular Endothelial ◽  
Ovine Model ◽  
Organ Function ◽  
Endothelial Growth Factor

Abstract Background: Sepsis is one of the most frequent causes of death in the ICU, and microvascular hyperpermeability caused by oxidative/nitrosative stress plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. This study tested the efficacy of a novel compound R-107, a modulator of oxidative/nitrosative stress, in an ovine model of sepsis. We hypothesized that R-107 effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function.Methods: Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (1x1010 CFUs) for 60 minutes. After injury, animals were allocated into the following groups: 1) Control: intramuscular injection (IM) of saline, n=13; and 2) Treatment: IM of 50 mg/kg R-107, n=9. The IM treatment was given after the completion of the Pseudomonas aeruginosa injection. Animals were placed on a mechanical ventilator, fluid resuscitated, and monitored for 24 hours in a conscious state. Results: R-107 treatment attenuated 24-hour mortality (11 vs. 30%). R-107 significantly reduced fluid requirement (15 – 24 hours, p<0.05), net fluid balance (9 – 24 hours, p<0.05), and water content in lung, heart, and kidney (p=0.02, 0.04, and 0.01, respectively) compared to control. R-107 treatment significantly delayed the onset of positive qSOFA (3.3 vs. 6.8 hours, p=0.04), and significantly decreased lung injury score and modified sheep SOFA score at 24 hours (p=0.01 and 0.04). The R-107 treatment group had significantly lower arterial lactate (21 – 24 hours, p<0.05), shed syndecan-1 (3 – 6 hours, p<0.05), and interleukin-6 (6 – 12 hours, p<0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expression (p=0.03 and 0.002) compared to control. There was no adverse effect observed during R-107 treatment.Conclusions: Modulation of oxidative/nitrosative stress by R-107 reduced lung tissue vascular endothelial growth factor-A, plasma shed syndecan-1, and interleukin-6 and attenuated severe microvascular hyperpermeability resulting in improved multi-organ function and survival in Pseudomonas aeruginosa sepsis.

scholarly journals HSP22 (HSPB8) positively regulates PGF2α-induced synthesis of interleukin-6 and vascular endothelial growth factor in osteoblasts

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Gen Kuroyanagi ◽  
Go Sakai ◽  
Takanobu Otsuka ◽  
Naohiro Yamamoto ◽  
Kazuhiko Fujita ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Map Kinase ◽  
Interleukin 6 ◽  
Prostaglandin F2α ◽  
P38 Map Kinase ◽  
Vascular Endothelial ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor ◽  
Vegf Release

Abstract Background Heat shock protein 22 (HSP22) belongs to class I of the small HSP family that displays ubiquitous expression in osteoblasts. We previously demonstrated that prostaglandin F2α (PGF2α), a potent bone remodeling factor, induces the synthesis of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether HSP22 is implicated in the PGF2α-induced synthesis of IL-6 and VEGF and the mechanism of MC3T3-E1 cells. Methods MC3T3-E1 cells were transfected with HSP22-siRNA. IL-6 and VEGF release was assessed by ELISA. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was detected by Western blotting. Results The PGF2α-induced release of IL-6 in HSP22 knockdown cells was significantly suppressed compared with that in the control cells. HSP22 knockdown also reduced the VEGF release by PGF2α. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was attenuated by HSP22 downregulation. Conclusions Our results strongly suggest that HSP22 acts as a positive regulator in the PGF2α-induced synthesis of IL-6 and VEGF in osteoblasts.

scholarly journals Changes in Gene Expression in Rat Tissues during Toxoplasmosis

2021 ◽  
Vol 6 (2) ◽  
pp. 236-241
Author(s):  
E. S. Pashinskaya ◽  
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Lung Tissue ◽  
Rat Tissues ◽  
Vascular Endothelial ◽  
Epidermal Growth ◽  
Endothelial Growth Factor ◽  
Brain Tissues

The purpose of the study is to study changes in gene expression in rat tissues during toxoplasmosis. Materials and methods. The experiment was conducted on 70 Wistar females weighing 170-220 grams. To achieve this goal, the expression of the proto-oncogenes survivin (BIRC5), epidermal growth factor (ErbB-2/HER2-Neu), GLI, vascular endothelial growth factor (VEGF) and anti-oncogene TP53 was determined in comparison with the reference genes β-actin (ACTB) and GAPDH by PCR analysis in the tissues of 10 healthy female rats and 60 infected with toxoplasma. RNA isolation was performed by the column method using the ReliaPrep RNA Cell Miniprep System (Promega Corporation, USA). The quality of the isolated RNA was evaluated spectrophotometrically. Reverse transcription was performed using M-MuLV RT (New England BioLabs Inc, USA). Primers specific to the genes were prepared using Primer3 and the NCBI Nucleotide database. Amplification was performed on a Real-Time PCR Detection System CFX96 thermal cycler (Bio-Rad, USA), using a qPCRmix-HS SYBR PCR mixture (Eurogen, Russia). Comparative expression of the studied genes was carried out after normalization of each of the samples to the level of the control genes GAPDH and ACTIN-β. Expression analysis was performed by qbase+ and CFX Maestro. Statistical processing of the obtained data was carried out using the program Statistica 10.0. Results and discussion. Toxoplasma increases the expression of survivin (BIRC5) in lung tissue to 0.013 relative units, in liver – to 0.038 relative units, in spleen – to 0.061 relative units, and in brain – to 0.050 relative units. VEGF expression in lungs increased to 0.034 relative units, in liver – to 0.041 relative units, in spleen – to 0.063 relative units, in brain tissues – to 0.080 relative units. There was an increase in the expression of ErbB-2/HER2-Neu in lung tissue to 0.436 relative units, in liver – to 0.259 relative units, in spleen – to 0.271 relative units, and in brain – to 0.131 relative units. GLI expression in lung tissues after toxoplasma infection increased to 0.113 relative units, in liver – to 0.188 relative units, in spleen – to 0.388 relative units, and in brain tissues – to 0.459 relative units. An increase in the expression of the anti-oncogene TP53 in the tissues of the lungs to 0.171 relative units, liver – to 0.295, spleen – to 0.408, and brain – to 0.259 relative units was revealed. Conclusion. It has been shown that toxoplasma can cause an increase in the expression of the proto-oncogenes survivin (BIRC5), epidermal growth factor (ErbB-2/HER2-Neu), GLI and vascular endothelial growth factor (VEGF) with simultaneous enhancement of the anti-oncogene TP53

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