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In sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&amp;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&amp;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 × 10 10  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  &lt; 0.05), net fluid balance (9–24 h,  P  &lt; 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  &lt; 0.05), shed syndecan-1 (3–6 h,  P  &lt; 0.05), interleukin-6 (6–12 h,  P  &lt; 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&amp;NS by R-107 reduced hyperpermeability markers and improved multi-organ function.

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