Pravastatin Improves Colonic and Hepatic Microcirculatory Oxygenation during Sepsis without Affecting Mitochondrial Function and ROS Production in Rats

Abstract

Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response, microcirculation, and mitochondrial function, possibly through their action on peroxisome proliferator-activated receptor alpha (PPAR-α). The aim of this study was to examine the effects of pravastatin on microcirculation and mitochondrial function in the liver and colon and the role of PPAR-α under septic conditions. This study was performed with the approval of the local animal care and use committee. Forty Wistar rats were randomly divided into 4 groups: sepsis (colon ascendens stent peritonitis, CASP) without treatment as control, sepsis + pravastatin, sepsis + PPAR-α-blocker GW6471, and sepsis + pravastatin + GW6471. Pravastatin (200 µg/kg s.c.) and GW6471 (1 mg/kg) were applied 18 h before CASP-operation. 24 h after initial surgery, a relaparotomy was performed, followed by a 90 min observation period for assessment of microcirculatory oxygenation (μHbO2) of the liver and colon. At the end of the experiments, animals were euthanized, and the colon and liver were harvested. Mitochondrial function was measured in tissue homogenates using oximetry. The ADP/O ratio and respiratory control index (RCI) for complexes I and II were calculated. Reactive oxygen species (ROS) production was assessed using the malondialdehyde (MDA)-Assay. Statistics: two-way analysis of variance (ANOVA) + Tukey’s/Dunnett’s post hoc test for microcirculatory data, Kruskal–Wallis test + Dunn’s post hoc test for all other data. In control septic animals µHbO2 in liver and colon deteriorated over time (µHbO2: −9.8 ± 7.5%* and −7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment μHbO2 remained constant (liver: µHbO2 pravastatin: −4.21 ± 11.7%, pravastatin + GW6471: −0.08 ± 10.3%; colon: µHbO2 pravastatin: −0.13 ± 7.6%, pravastatin + GW6471: −3.00 ± 11.24%). In both organs, RCI and ADP/O were similar across all groups. The MDA concentration remained unchanged in all groups. Therefore, we conclude that under septic conditions pravastatin improves microcirculation in the colon and liver, and this seems independent of PPAR-α and without affecting mitochondrial function.

Gemfibrozil Improves Microcirculatory Oxygenation of Colon and Liver without Affecting Mitochondrial Function in a Model of Abdominal Sepsis in Rats

“…The here-observed gemfibrozil-induced ameliorated microcirculation in the liver and colon under septic conditions is quite similar to results reported after pravastatin treatment. For pravastatin, we showed, most recently, a similar PPARα-independent improvement in µHbO 2 in the intestine and liver [ 44 ]. Mechanistically, statins have been described as being able to increase eNOS expression, resulting in vasodilatation and modulated inflammatory responses, as well as increased tight junction density via the Caveolin-1/eNOS pathway [ 45 , 46 ].…”

“…Regarding the results of the hepatic microcirculatory analysis, it is striking that GW 6471 also prevents microcirculatory impairment. As the previous dataset did not display this preventive effect, another approach is required to re-examine this finding [ 44 ].…”

Effect of statins on sepsis and inflammatory factors: A Mendelian randomization study

“…Although the inflammatory factors of statins acted on in our analysis were not completely consistent with previous studies, our study suggested that the overall effect of statins is to inhibit pro‐inflammatory factors, thereby preventing and treating sepsis. Many animal experiments have also proved the beneficial effect of statins on animal sepsis 31–33 . Therefore, statins may have a protective effect on sepsis and this may provide a new idea for the treatment of sepsis.…”

“…Many animal experiments have also proved the beneficial effect of statins on animal sepsis. [31][32][33] Therefore, statins may have a protective effect on sepsis and this may provide a new idea for the treatment of sepsis.…”

Effects of remote ischemic preconditioning on early markers of intestinal injury in experimental hemorrhage in rats

“…Since microcirculation and mitochondrial respiration represent the terminal stretch of regional tissue oxygenation, microvascular and mitochondrial measurements could serve as early, dynamic and possibly more accurate markers of intestinal tissue injury. Unfortunately, studies investigating microcirculation and mitochondrial respiration only exist for experimental animal models of abdominal sepsis 9 , 10 . Concordant trials with a simultaneous evaluation of microcirculatory and mitochondrial variables to investigate the local pathophysiology of hemorrhagic shock are missing.…”