Mingchen Song

Science review: Extracellular acidosis and the immune response: clinical and physiologic implications

Metabolic acidosis is among the most common abnormalities seen in patients suffering from critical illness. Its etiologies are multiple and treatment of the underlying condition is the mainstay of therapy. However, growing evidence suggests that acidosis itself has profound effects on the host, particularly in the area of immune function. Given the central importance of immune function to the outcome of critical illness, there is renewed interest in elucidating the effects of this all too common condition on the immune response. In this review we concentrate on the effects of extracellular acids on production and release of inflammatory mediators, and we demonstrate that different acids produce different effects despite similar extracellular pH. Finally, we discuss potential clinical implications.

Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-κB DNA binding, and improves short-term survival in lethal endotoxemia

ObjectivesPrevious studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. DesignRandomized controlled laboratory experiment. SettingUniversity laboratory. SubjectsSixty-six adult Sprague-Dawley rats. InterventionsWe conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-&kgr;B DNA binding. Measurements and Main ResultsMean survival time among hemoadsorption-treated animals was 629 ± 114 vs. 518 ± 120 mins for sham-treated animals (p < .01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p < .05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-&kgr;B DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. ConclusionsHemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.

Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock.

The glycolytic intermediate, pyruvate, is capable of scavenging reactive oxygen species (ROS). However, this compound is relatively unstable and hence is not useful as a therapeutic agent. Ethyl pyruvate, a simple derivative of pyruvate, appears to be more stable, and when formulated in a calcium-containing Ringers-type balanced salt solution (REPS), has been shown to be salutary in rat models of two pathophysiological conditions—mesenteric ischemia/reperfusion and hemorrhagic shock/resuscitation—that are thought to be mediated, at least in part, by ROS. Because ROS also have been implicated in the pathogenesis of lipopolysaccharide (LPS)-induced shock, we carried out a series of experiments to determine if REPS is beneficial in this condition. Anesthetized rats were challenged with intravenous LPS (20 mg/kg). When mean arterial pressure (MAP) decreased to 60 mmHg, 3- to 5-mL boluses of either REPS (n = 10) or Ringers lactate solution (RLS; n = 10) were infused as needed to prevent MAP from decreasing further. By design, the maximal volume of fluid infused was 7 mL/kg. Resuscitation with REPS as compared with RLS prolonged survival time (498 ± 48 min vs. 362 ± 30 min;P = 0.0014). Resuscitation with REPS as compared with RLS also was associated with significantly lower circulating concentrations of nitrite/nitrate and interleukin (IL)-6 and higher plasma levels of IL-10. These data support the view that delayed treatment with REPS modulates the inflammatory response to LPS, and prolongs survival time in a lethal model of endotoxic shock.

Cytokine Removal with a Novel Adsorbent Polymer

Background/Aims: We sought to characterize a novel adsorbent polymer in terms of cytokine removal. Methods: We challenged 50 rats with lipopolysaccharide to obtain cytokine-rich blood and circulated this through cartridges containing polymer. In separate experiments, cell-free supernatants were passed through cartridges containing polymer. We measured tumor necrosis factor alpha, interleukin 10 and interleukin 6 concentrations under a variety of conditions to evaluate adsorption kinetics. Results: All three cytokines were rapidly removed from the blood with less than 50% of the initial concentrations present after 1 h of circulation through the cartridge. There was no significant difference in the effect across a range of blood flows and Ca2+ concentrations. Adsorption was decreased somewhat by extremely low temperature (4°C). Conclusion: The adsorbent polymer removes cytokines with high efficiency, and binding is relatively unaffected by a variety of physical conditions.

Hemoadsorption to Improve Organ Recovery from Brain-Dead Organ Donors: A Novel Therapy for a Novel Indication?

While brain-dead organ donors represent the majority of the organ donor pool, it appears that graft survival is adversely affected by brain death itself. Brain death has been shown to cause severe disturbances in the hormonal, hemodynamic and immunological homeostasis, which could in part be responsible for the inferior outcome of organs originating from brain-dead donors compared to living donors. Hemodynamic effects of brain death lead to a wide fluctuation in mean perfusion pressures, blood flow to the organs and systemic oxygen consumption, altering regional perfusion. In addition, a wide array of immunological changes has been shown to occur after brain death contributing to organ injury and hemodynamic instability. Recent studies have shown that brain death upregulates multiple lymphocyte- and macrophage-derived cytokines and the injured brain itself may be the source of proinflammatory factors such as S100B. This increased inflammatory response seen during and immediately after brain death has also been associated with poor allograft function. Furthermore, there is evidence to suggest that the massive inflammatory response seen in brain-dead donors could also lead to increased immunogenicity and accelerated allograft rejection after transplantation. Hence, we hypothesize that nonspecific downregulation of this inflammatory response by hemoadsorption could potentially lead to improved donor organ and allograft function. As a ‘proof of concept’ we tested the ability of a novel hemoadsorbent to remove S100B in vitro using two human glioblastoma cell lines. Our results indicate a >80% reduction in S100B after 2 h of circulation with the sorbent.

EFFECTS OF HYPERCHLOREMIC ACIDOSIS ON CIRCULATING CYTOKINES IN EXPERIMENTAL SEPSIS IN RATS: 506

Introduction: Hyperchloremic metabolic acidosis is a common feature of sepsis. Often the source of acidosis is partly iatrogenic, because saline solution resuscitaion if often used to treat shock. It is unknown if the acidosis itself has an effect on the levels of inflammatory mediators. Hypothesis: Hyperchloremic acidosis induced by dilute HCl infusion has a significant effect on circulating levels of inflammatory mediators in an experimental model of severe sepsis in the rat. Methods: We included 20 adult, male, Sprague-Dawley rats in this study. Eighteen hours after inducing lethal sepsis by cecal ligation and puncture, animals were randomized and classified in three groups. In group-2 and 3, we began an IV infusion of 0.1 HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L respectively. In group-1 we infused a similar volume of lactated Ringer solution. In all groups infusion continued 8 hours or until the animal died. we measured arterial blood gases, electrolytes, tumor necrosis factor (TNF) -α, interleukine (IL)-6, and IL-10 levels at 0h, 4h and 8h. Results: all measured cytokines showed steady trend of elevation at 4 and 8 h. this was true for IL-6 (rose from 106 ± 26 to 244 ±81 at 4h and 234±57 at 8h in group1 and from 36±12 to 345±125 at 4h and to 254 ±74 at 8h in group2 and from 56±5 to 400±97 at 4h and 581± 118 at 8h in goup3). Similar results obtained for IL10 (rose from 23±4 to 92±20 at 4h and to 101±23 at 8h for group1 and from 28±8 to 165±24 at 4h and to 124±14 at 8h for group2 and from 25±4 to 278± 67 at 4h and to 175±32 at 8h. TNF-α showed similar fashion of increase (Rose from 3.6±3.6 to 43±25 at 4h and 19±8 at 8h. for group 1 and from 7.8± 7.8 to 64±18 at 4h and to 14.2±3.7 at 8h for group 2 and from 41.6±31 to 108±18 at 4h and 31±12 at 8h for group3. Conclusions: moderate (SBE of −5to −10) and severe (SBE of −10 to −15) acidosis, induced by HCl infusion may increase circulating levels of IL-6, IL-10, and TNF-α in septic rats.