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Effects of N -acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia

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ABSTRACT

Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n = 8 per group): (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). Fluid resuscitation was initiated at 120 min and maintained at fixed volume for 2 h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer’s solution (Volulyte) with or without supplementation with NAC (150 mg/kg/h). Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Results: Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p < 0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p < 0.01).

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

No MeSH data available.


Levels of biomarkers of oxidative stress and pro-inflammatory cytokines in renal tissue. Renal tissue TNF-α (a), IL-6 (b), hyaluronic acid (c), nitric oxide (d), MDA (e), and protein carbonyl (f). *p < 0.05, **p < 0.01, ***p < 0.001 versus control; +p < 0.05, ++p < 0.01 versus LPS group
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Fig4: Levels of biomarkers of oxidative stress and pro-inflammatory cytokines in renal tissue. Renal tissue TNF-α (a), IL-6 (b), hyaluronic acid (c), nitric oxide (d), MDA (e), and protein carbonyl (f). *p < 0.05, **p < 0.01, ***p < 0.001 versus control; +p < 0.05, ++p < 0.01 versus LPS group

Mentions: The levels of biomarkers of oxidative stress, pro-inflammatory cytokines, and products of glycocalyx degradation are represented in Fig. 4. The levels of TNF-α (3A) and IL-6 (3B) in kidney homogenates from the LPS group were significantly increased compared to the control group (528.1 ± 143.9 pg/mg protein versus 291.8 ± 99.1 pg/mg protein, p < 0.05; and 1246 ± 441 pg/mg protein versus 753.8 ± 122 pg/mg protein, p < 0.05, respectively). The same results were observed regarding hyaluronic acid (HA) (3C), nitric oxide (3D), and MDA (3E) after LPS infusion (p < 0.05). The addition of NAC to HES-RA during fluid resuscitation resulted in a significant lower level of HA and nitric oxide compared to the LPS group (p < 0.01). Infusion of HES-RA alone decreased the levels of MDA compared to LPS alone (p < 0.01) (3E). Protein carbonyl levels were not altered (3E).Fig. 4


Effects of N -acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia
Levels of biomarkers of oxidative stress and pro-inflammatory cytokines in renal tissue. Renal tissue TNF-α (a), IL-6 (b), hyaluronic acid (c), nitric oxide (d), MDA (e), and protein carbonyl (f). *p < 0.05, **p < 0.01, ***p < 0.001 versus control; +p < 0.05, ++p < 0.01 versus LPS group
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Fig4: Levels of biomarkers of oxidative stress and pro-inflammatory cytokines in renal tissue. Renal tissue TNF-α (a), IL-6 (b), hyaluronic acid (c), nitric oxide (d), MDA (e), and protein carbonyl (f). *p < 0.05, **p < 0.01, ***p < 0.001 versus control; +p < 0.05, ++p < 0.01 versus LPS group
Mentions: The levels of biomarkers of oxidative stress, pro-inflammatory cytokines, and products of glycocalyx degradation are represented in Fig. 4. The levels of TNF-α (3A) and IL-6 (3B) in kidney homogenates from the LPS group were significantly increased compared to the control group (528.1 ± 143.9 pg/mg protein versus 291.8 ± 99.1 pg/mg protein, p < 0.05; and 1246 ± 441 pg/mg protein versus 753.8 ± 122 pg/mg protein, p < 0.05, respectively). The same results were observed regarding hyaluronic acid (HA) (3C), nitric oxide (3D), and MDA (3E) after LPS infusion (p < 0.05). The addition of NAC to HES-RA during fluid resuscitation resulted in a significant lower level of HA and nitric oxide compared to the LPS group (p < 0.01). Infusion of HES-RA alone decreased the levels of MDA compared to LPS alone (p < 0.01) (3E). Protein carbonyl levels were not altered (3E).Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n&thinsp;=&thinsp;8 per group): (1) control group, (2) control&thinsp;+&thinsp;NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS&thinsp;+&thinsp;fluid resuscitation, and (5) LPS&thinsp;+&thinsp;fluid resuscitation&thinsp;+&thinsp;NAC (150&nbsp;mg/kg/h). Fluid resuscitation was initiated at 120&nbsp;min and maintained at fixed volume for 2&nbsp;h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer&rsquo;s solution (Volulyte) with or without supplementation with NAC (150&nbsp;mg/kg/h). Oxygen tension in the renal cortex (C&mu;PO2), outer medulla (M&mu;PO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Results: Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p&thinsp;&lt;&thinsp;0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p&thinsp;&lt;&thinsp;0.01).

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

No MeSH data available.