Abstract
Sepsis is associated with an increase in reactive oxygen species (ROS), however, the precise role of ROS in the septic process remains unknown. We hypothesized that treatment with EUK-134 (manganese-3-methoxy N,N'-bis(salicyclidene)ethylene-diamine chloride), a compound with superoxide dismutase and catalase activity, attenuates the vascular manifestations of sepsis in vivo. Pigs were instrumented to measure cardiac output and blood flow in renal, superior mesenteric and femoral arteries, and portal vein. Animals were treated with saline (control), lipopolysaccharide (LPS; 10 µg·kg−1·h−1), EUK-134, or EUK-134 plus LPS. Results show that an LPS-induced increase in pulmonary artery pressure (PAP) as well as a trend towards lower blood pressure (BP) were both attenuated by EUK-134. Renal blood flow decreased with LPS whereas superior mesenteric, portal and femoral flows did not change. Importantly, EUK-134 decreased the LPS-induced fall in renal blood flow and this was associated with a corresponding decrease in LPS-induced protein nitrotyrosinylation in the kidney. PO2, pH, base excess and systemic vascular resistance fell with LPS and were unaltered by EUK-134. EUK-134 also had no effect on LPS-associated increase in CO. Interestingly, EUK-134 alone resulted in higher CO, BP, PAP, mean circulatory filling pressure, and portal flow than controls. Taken together, these data support a protective role for EUK-134 in the renal circulation in sepsis.
Highlights
Sepsis is a diffuse inflammatory response to an invading pathogen frequently associated with multi-organ injury and dysfunction [1,2], and characterized by inflammatory cell tissue infiltration, microthrombi and vascular leakage [3,4]
The major observation in this study is that EUK-134 alone (EUK)-134 blocked the LPS induced fall in renal blood flow and prevented the rise in pulmonary artery pressure
EUK-134 did not alter the fall in pH, base excess, and PO2 or the fall in systemic vascular resistance (SVR)
Summary
Sepsis is a diffuse inflammatory response to an invading pathogen frequently associated with multi-organ injury and dysfunction [1,2], and characterized by inflammatory cell tissue infiltration, microthrombi and vascular leakage [3,4]. Studies investigating a causal link between oxidative-injury and organ malfunction had inconsistent findings. Pretreatment with superoxide dismutase (SOD) improved survival in rodents with endotoxemia [7,8,9] and protected against cardiac dysfunction [10], but failed to reduce respiratory dysfunction in sheep, pigs, dogs, or rabbits [11,12,13,14]. Given alone or as adjuvant therapies, did reduce lung injury [12,15,16,17,18,19,20,21] and improved hemodynamics and survival in some but not all studies [19,22,23,24,25]
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