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

Abstract In sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&NS) plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. We hypothesized that a novel compound R-107, a modulator of O&NS, effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function in ovine sepsis model. Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (PA) (1x1010 CFUs). The animals were allocated into: 1) Control (n = 13): intramuscular injection (IM) of saline; and 2) Treatment (n = 9): IM of 50 mg/kg R-107. The treatment was given after the PA injection, and monitored for 24-hour. R-107 treatment 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/kidney (p = 0.02/0.04/0.01) compared to control. R-107 treatment significantly decreased lung injury score/modified sheep SOFA score at 24-hour (p = 0.01/0.04), significantly lowered arterial lactate (21–24 hours, p < 0.05), shed syndecan-1 (3–6 hours, p < 0.05), interleukin-6 (6–12 hours, p < 0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expressions (p = 0.03/0.002) compared to control. There was no adverse effect in R-107 treatment. In conclusion, modulation of O&NS by R-107 reduced hyperpermeability markers and improved multi-organ function.

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Modulation of oxidative and nitrosative stress attenuates microvascular hyperpermeability in ovine model of Pseudomonas aeruginosa sepsis

Scientific Reports ◽

10.1038/s41598-021-03320-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Satoshi Fukuda ◽

Yosuke Niimi ◽

Yasutaka Hirasawa ◽

Ennert R. Manyeza ◽

C. Edwin Garner ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Nitrosative Stress ◽

Lung Injury Score ◽

Vascular Endothelial ◽

Organ Function ◽

Oxidative And Nitrosative Stress ◽

Arterial Lactate ◽

Tissue Edema ◽

Fluid Requirement ◽

Endothelial Growth Factor

AbstractIn sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&NS) plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. We hypothesized that a novel compound R-107, a modulator of O&NS, effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function in ovine sepsis model. Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (PA) (1 × 1010 CFUs). The animals were allocated into: 1) Control (n = 13): intramuscular injection (IM) of saline; and 2) Treatment (n = 9): IM of 50 mg/kg R-107. The treatment was given after the PA injection, and monitored for 24-h. R-107 treatment significantly reduced fluid requirement (15–24 h, P < 0.05), net fluid balance (9–24 h, P < 0.05), and water content in lung/heart/kidney (P = 0.02/0.04/0.01) compared to control. R-107 treatment significantly decreased lung injury score/modified sheep SOFA score at 24-h (P = 0.01/0.04), significantly lowered arterial lactate (21–24 h, P < 0.05), shed syndecan-1 (3–6 h, P < 0.05), interleukin-6 (6–12 h, P < 0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expressions (P = 0.03/0.002) compared to control. There was no adverse effect in R-107 treatment. In conclusion, modulation of O&NS by R-107 reduced hyperpermeability markers and improved multi-organ function.

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

10.21203/rs.3.rs-421490/v1 ◽

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.

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