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Annals of Clinical & Laboratory Science 33:451-458 (2003)
© 2003 Association of Clinical Scientists

Hydroxyethyl Starch Inhibits NF-{kappa}B Activation and Prevents the Expression of Inflammatory Mediators in Endotoxic Rats

Jie Tian1, Xin Lin2, Wei Zhou3 and Jianguo Xu1
1 School of Life Science, Nanjing University, and Department of Anesthesiology, Jinling Hospital
2 Emergency Department, Jinling Hospital
3 Medical School of Nanjing University, Nanjing, China

Address correspondence to Professor Jianguo Xu, Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, P. R. China; tel 86 25 482 7974; fax 86 25 480 8122; e-mail smarttian{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Hydroxyethyl starch (HES) has been shown to be beneficial in several inflammatory situations, but the mechanisms are unclear. The present study tested the hypothesis that HES has effects on nuclear factor kappa B (NF-{kappa}B) activation and the expression of inflammatory mediators induced by lipopolysaccharide. Sepsis was induced in male Wistar rats by injection of lipopolysaccharide (LPS, 6 mg/kg, ip). At 1 min after the LPS challenge, HES was infused via the right external jugular vein at the following doses: 3.75, 7.5, 15, or 30 ml/kg. NF-{kappa}B activation in peripheral blood mononuclear cells and neutrophils, plasma concentrations of tumor necrosis factor (TNF)-{alpha}, cytokine-induced neutrophil chemoattractant (CINC), expression of CD11b on the blood neutrophil cell surface, and neutrophil sequestration in multiple organs were examined 2 or 4 hr after the LPS challenge. Treatment of rats with HES (3.75 and 7.5 ml/kg) prevented LPS-induced NF-{kappa}B activation, and inhibited, in a dose-related manner, LPS-induced TNF-{alpha} and CINC expression. The 4 graded doses of HES decreased CD11b expression in a dose-dependent manner. HES significantly reduced neutrophil sequestration in lung, heart, and liver. These results suggest that HES has an anti-inflammatory effect in endotoxic rats. This effect is mediated by inhibition in the production pathways for inflammatory mediators, including NF-{kappa}B activation.

(received 28 March 2003; accepted 9 June 2003)

Keywords: hydroxyethyl starch, lipopolysaccharide, NF-{kappa}B, inflammatory mediators, neutrophils


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The sepsis syndrome is a life threatening complication of infection that is becoming increasingly common following the introduction of new, invasive procedures [1]. It is always accompanied by systemic inflammatory response syndrome, which induces the failure of multiple organs, including the lung, heart, and liver. The paradox of sepsis is that host immune responses are critical for the defense against infection, but excessive or dysregulated inflammation seems to result in neutrophil-mediated tissue injury and organ dysfunction [2–5]. In sepsis, neutrophilic inflammation appears to result from coordinated production and action of cytokines, chemokines, leukocyte-endothelial adhesion molecules, and enzymes, which are regulated by the ubiquitous transcription factor complex, nuclear factor kappa B (NF-{kappa}B). NF-{kappa}B is an important transcription factor, playing a fundamental role in regulating acute inflammation through activation of the cytokines and other mediators [6,7]. Elevation of NF-{kappa}B is a predictor of poor survival in septic patients and in a mouse model of endotoxemia [8]. Inhibition of NF-{kappa}B activation in the lungs after hemorrhage or endotoxemia is associated with decreased expression of proinflammatory cytokines and neutrophilic alveolitis [9,10].

Hydroxyethyl starch (HES) is a clinically well-tolerated complex polysaccharide. It is commonly used as a plasma expander, in part because of its therapeutic safety, stable effects on plasma volume, and low associated incidence of anaphylactic reactions. Several studies have shown that HES has beneficial effects, such as attenuation of capillary leakage, reduction of infarct size, or improved outcome in the treatment of severe inflammatory situations, such as sepsis, trauma, or other tissue injury [11–13]. However, the mechanistic basis for the beneficial effects of HES is unclear. Since neutrophil-mediated tissue injury contributes to many aspects of organ dysfunction in critical illnesses [14,15], the capability of HES to affect this process is a topic of current research.

We used the endotoxin-treated rat model in the present study to determine the effects of HES on NF-{kappa}B activation in peripheral blood mononuclear cells and neutrophils, plasma tumor necrosis factor (TNF)-{alpha}, cytokine-induced neutrophil chemo-attractant (CINC) concentrations, expression of CD11b on the blood neutrophil cell surface, and tissue neutrophil sequestration in multiple organs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal and experimental procedures.  Male Wistar rats were purchased from the Animal Center of the Chinese Academy of Science, Shanghai, China, divided into experimental groups in a random manner, and used for experiments when their body weights were between 250–300 g. All procedures were approved by the Institutional Animal Care Committee. The rats were anesthetized with urethane (1250 mg/kg, ip). A polyethylene catheter was implanted in the right external jugular vein for continuous infusion of solutions using a Razel Model WZ-50C syringe pump.

The rats were randomly assigned to 7 groups (6 rats/group): (a) controls; (b) LPS; (c, d, e, and f ) LPS plus HES (3.75, 7.5, 15, or 30 ml/kg); and (g) HES alone (30 ml/kg). Immediately after time 0, LPS (6 mg/kg, ip; lipopolysaccharide, Escherichia coli 055:B5, Sigma Chemical Co., St. Louis, MO) was given over 20 sec. Then HES (hydroxyethyl starch, medium molecular weight, low degree of substitution; HAES-steril 200/0.5, 6%, Fresenius Kabi) was infused, beginning at +1 min, with a rate of 0.2 ml/min. In the control and HES alone group, 0.9% saline vehicle (3 ml/kg, ip) was given instead of LPS at time 0. In the control and LPS group, 30 ml/kg saline was infused instead of HES beginning at the same time and with the same rate. In a pilot study, the blood pressure of rats was measured using a microtip manometer (Millar, Houston, TX) inserted into the femoral artery; the injection of HES did not produce any significant changes in systemic blood pressure.

The rats were exsanguinated either at 2 hr post LPS-challenge for blood cell isolation and electrophoretic mobility shift assay (EMSA), or at 4 hr post-LPS challenge for enzyme-linked immunosorbance assay (ELISA) and flow cytometic analysis. The lung, heart, and liver were collected at 4 hr post-LPS challenge for myeloperoxidase (MPO) analysis, frozen in liquid nitrogen, and stored at -80°C.

Isolation of peripheral blood mononuclear cells and neutrophils.  Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. After collection of mononuclear cells, residual red blood cells underwent hypotonic lysis using dextran sedimentation, and neutrophils were collected. Viability, as determined by trypan blue exclusion, was consistently >95%. Cell purity, determined by Wright’s stained cytospin preparations, was >98%. Blood cells were stored at -80°.

Nuclear protein extracts and EMSA.  Nuclear extracts of blood cells were prepared by hypotonic lysis followed by high salt extraction [16]. Briefly, cells were incubated in 0.5 ml ice-cold buffer A composed of 10 mM HEPES (pH 7.9), 10 mM KCl, 2 mM MgCl2, 0.1mM EDTA, 1 mM dithiothreitol (DTT), and 0.5 mM phenylmethylsulfonyl fluoride (PMSF) (all from Sigma) for 15 min, after which 50 µl NP-40 was added. After 30 sec, the mixture was centrifuged for 10 min (5000 g, 4°C). The pellet was then suspended in 50 µl ice-cold buffer B (50 mM HEPES (pH 7.9), 50 mM KCl, 300 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 0.5 mM PMSF, with 10% (v/v) glycerol) and incubated on ice for 30 min, with frequent mixing. After centrifugation (12,000 g, 4°C, 15 min) the supernatants were collected as nuclear extracts and stored at -80°C until use. Protein concentration was determined by the Bradford method [17].

EMSA was performed using a commercial kit (Gel Shift Assay System; Promega, Madison, WI). The NF-{kappa}B consensus oligonucleotide probe (5'-AGTTGAGGGGACTTTCCCAGGC-3') was end-labeled with [{gamma}-32P]-ATP (Free Biotech, Beijing, China) with T4-polynucleotide kinase. Nuclear protein (30 µg) was preincubated in a total volume of 9 µl in a binding buffer, consisting of 10 mM Tris-HCl (pH 7.5), 4% glycerol, 1mM MgCl2, 0.5 mM EDTA, 0.5 mM DTT, 50 mM NaCl, and 0.05 mg/ml poly(di-dc)·poly(di-dc) for 10 min at room temperature. After addition of the 32P-labeled oligonucleotide probe, the incubation was continued for 20 min at room temperature. Reaction was stopped by adding 1 µl of gel loading buffer and the mixture was subjected to nondenaturing 4% polyacrylamide gel electrophoresis in 0.5 x TBE buffer (Tris-borate-EDTA). The gel was vacuum-dried and exposed to X-ray film (Fuji Hyperfilm) at -70°C with an intensifying screen.

Plasma TNF-a and CINC measurements.  Plasma TNF-{alpha}and CINC concentrations were quantified by enzyme-linked immunosorbance assays (ELISA) (rat TNF-{alpha}test kit: Diaclone, Besanson Cedex, France; rat GRO/CINC-1 test kit: Amersham, UK), according to the manufacturer’s instructions.

Flow cytometric analysis.  Blood samples were collected from each animal at 4 hr post-LPS challenge and prepared for cytometric analysis. After the lysing procedure, about 5 x 106 leukocytes were incubated with a PE-labeled mouse anti-rat CD11b antibody (Serotec, Oxford, UK) on ice for 30 min. After being washed, the samples were cold centrifuged, and the cell pellet was resuspended in 500 µl of phosphate buffered saline (PBS). The cells were analyzed with a Becton-Dickinson "FACS-Calibur" flow cytometer. Negative controls were incubated with PE-labeled mouse IgG2a (Serotec).

Assessment of tissue neutrophil accumulation.  Myeloperoxidase (MPO) activity was evaluated as an index of tissue neutrophil accumulation. MPO was extracted from lungs, hearts, and livers [18]. MPO activity in the supernatant was measured and calculated from the absorbance change at 460 nm resulting from decomposition of H2O2 in the presence of o-dianisidine.

Statistical analysis.  Data were expressed as means ± SE. Statistical significance was determined by one-way ANOVA followed by Tukey test; p <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
HES inhibits LPS-induced NF-kB activation.  EMSA experiments examined the effects of HES on the activation of NF-{kappa}B induced by LPS. The NF-{kappa}B bands were evaluated by densitometry. As shown in Fig. 1Go, NF-{kappa}B activity was detected at low levels in control mononuclear cells and neutrophils; it increased markedly after treatment with LPS. HES suppressed the LPS-induced NF-{kappa}B activity in a dose-related manner. The maximal inhibition was observed at a HES dosage of 7.5 ml/kg.



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  		Fig. 1. Inhibition by HES of LPS-induced NF-{kappa}B activation in peripheral blood cells of rats. Panels A and C show the EMSA autoradiogram and mean band intensity of EMSA in mononuclear cells; B and D show the EMSA autoradiogram and the mean band intensity of EMSA in neutrophils. Lane 1, controls; lane 2, LPS alone (6 mg/kg); lane 3, LPS & 3.75 ml/kg HES; lane 4, LPS & 7.5 ml/kg HES; lane 5, LPS & 15 ml/kg HES; lane 6, LPS & 30 ml/kg HES; lane 7, HES alone (30 ml/kg). Cells were isolated 2 hr after LPS injection. The bar graphs show the means ± SE; 6 rats/group; *p <0.05 vs LPS alone.

 
HES inhibits the increase of plasma of TNF-a.  TNF-{alpha} is an important cytokine in the generation of acute inflammatory responses. The TNF-{alpha} level was below the limit of detection in the control and HES-alone groups, but 4 hr after LPS challenge all animals displayed a significant increase in plasma TNF-{alpha}levels (Fig. 2Go). Treatment of the LPS-challenged animals with 3.75 or 7.5 ml/kg, but not 15 or 30 ml/kg, of HES caused decreased TNF-{alpha} levels, compared to rats treated only with LPS.



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  		Fig. 2. Plasma TNF-{alpha} concentrations in control, LPS, LPS & HES, and HES alone rats. Blood was collected 4 hr after LPS injection. Means ± SE, 6 rats/group; *p <0.05 vs LPS alone.

 
HES inhibits the increase of plasma CINC.  We studied the effects of inhibiting NF-{kappa}B activation with HES on LPS-induced CINC expression. ELISA assays showed low CINC concentrations in control plasma (Fig. 3Go), which increased >2.0-fold in plasma of LPS-challenged animals. Treatment with 3.75, 7.5, or 15 ml/kg of HES significantly reduced the LPS-induced elevation of CINC levels, while HES alone had no effect on plasma CINC concentrations.



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  		Fig. 3. Plasma cytokine-induced neutrophil chemoattractant (CINC) concentrations in control, LPS, LPS & HES, and HES alone rats. Blood was collected 4 hr after LPS injection. Means ± SE, 6 rats/group; *p <0.05 vs LPS alone.

 
HES inhibits the increase of CD11b expression on neutrophils.  To determine whether HES affects the surface expression of ß2 adhesion molecules, CD11b levels were compared in different groups. As shown in Fig. 4Go, LPS caused >2.0-fold increase of the surface expression of CD11b. In rats given increasing doses of HES, the expression of CD11b was progressively decreased. Treatment of control rats with HES did not affect the CD11b level on neutrophils.



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  		Fig. 4. CD11b expression on neutrophils in control, LPS, LPS & HES, and HES alone rats. Blood was collected 4 hr after LPS injection. Means ± SE, 6 rats/group; *p <0.05 vs LPS alone.

 
HES reduces neutrophil sequestration.  The functional consequence of neutrophil influx into different tissues was assessed by assay of MPO activity. MPO activity increased markedly in 3 organs 4 hr after LPS challenge (Table 1Go). HES, at concentration of 3.75, 7.5, 15, and 30 ml/kg, respectively, reduced the LPS-induced tissue MPO activity by 25, 30, 16, and 10% in the lungs; by 31, 44, 23, and 20% in the hearts; and by 28, 32, 24, and 20% in the livers. Maximal inhibition of LPS-induced MPO activity was observed at a HES concentration of 7.5 ml/kg in all 3 organs, which correlated with the inhibition of LPS-induced NF-{kappa}B, TNF-{alpha}, and CINC expression at this concentration (Figs. 1Go–3Go).


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  		Table 1. HES suppression of LPS-induced increases of myeloperoxidase activity in rat tissues
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we used a third generation of hydroxyethyl starch with medium molecular weight and low degree of substitution (HES 200/0.5), determining its effects on the endotoxin-induced inflammatory response. We found that HES can suppress the LPS-induced NF-{kappa}B activation in both peripheral blood mononuclear cells and neutrophils, inhibit the increased plasma concentrations of TNF-{alpha} and CINC, suppress the increased expression of CD11b on neutrophils, and reduce the sequestration of neutrophils in lung, heart, and liver. We found that, except for the inhibition on CD11b expression, most of these effects of HES were significant at concentrations of 3.75 and 7.5 ml/kg, but not the higher concentrations of 15 and 30 ml/ kg. These results suggest an anti-inflammatory effect of HES that is not dose-dependent.

There is strong evidence that prolonged and pronounced inflammatory stimulation is linked to organ failure and death after sepsis, trauma, or other tissue injury [19]. Fundamental to the acute inflammatory process are the local responses to leukocyte-endothelial cell interactions and the release of inflammatory mediators. Bacterial endotoxin (lipopolysaccharide, LPS) prompts the release of proinflammatory cytokines, such as TNF-{alpha} and interleukin (IL)-1, and chemokines, including IL-8 and CINC, from mononuclear cells and other cells [20,21]. These mediators act in concert to promote neutrophil sequestration by activating expression of integrins (CD11b/CD18) on the neutrophil cell surface and adhesion molecules on the endothelial cells. They induce neutrophil migration into the interstitium, propagating inflammation and injury through the release of reactive oxygen species (ROS) and proteolytic enzymes [22]. NF-{kappa}B exerts a broad influence on this network of mediators, affecting the transcription of many of these genes involved in their generation. There is increasing evidence that NF-{kappa}B is important in the pathobiology of diseases such as the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) [23,24]. Liu et al [25] showed that inhibition of NF-{kappa}B activation in vivo suppresses LPS-induced expression of CINC and intercellular adhesion molecule (ICAM), reduces neutrophil accumulation, and prevents capillary leakage in multiple organs. The restorative effect of HES on intravascular volume has been extensively studied, its effects on immune responses have not been as thoroughly investigated. Our study establishes the first in vivo linkage between HES treatment, NF-{kappa}B activation, inflammatory mediators expression, and neutrophil priming and sequestration, showing protective effects of HES in inflammatory cascades.

Studies have shown that HES can reduce leukocyte-endothelial cell interactions [26,27]. In a porcine model of global cerebral ischemia induced by asphyxia, pial venular leukocyte adherence was quantified by in situ fluorescence videomicroscopy through closed cranial windows. HES was found to reduce leukocyte adherence at 1 and 2 hr of reperfusion [27]. Another study has found that HES reduces the chemotaxis of neutrophils through endothelial cell monolayers [28]. However, few studies have addressed the basic mechanisms of the anti-adherent actions of HES. In vitro studies did not reveal any significant influence of HES on the expression of the adhesion molecules CD11b on neutrophils [29,30]. This is contrary to our in vivo finding that HES can inhibit CD11b expression in a dose-dependent manner. Differences in the experimental design (in vivo versus in vitro), stimulation types, assessment times, dosages, and intrinsic properties of the HES preparations may explain the apparent discrepancy.

Consistent with our findings, Nohe et al [31] noted that HES does not attenuate adhesion molecule expression, but has an immediate decreasing effect on neutrophil adhesion. They hypothesized that this may be due to HES inhibition of the interactions of neutrophilic ß2 integrins with their endothelial counter-receptors. Our studies extend these observations by showing that HES also inhibits increases of plasma TNF-{alpha}and CINC, which, as well as the inhibition of CD11b, are at least partially due to suppression of NF-{kappa}B activity, and are responsible for the subsequent reduction of neutrophil sequestration in multiple organs.

In our animal model, infusion of HES began as early as 1 min after LPS injection. The protective role of HES that we observed in inflammatory situations appears to depend critically on its early use. Once endothelial cell-leukocyte interactions have been well established, there would be little opportunity to prevent endothelial damage. A noteworthy observation in our experiment is that the maximal effect of HES occurred at a dose of 7.5 ml/kg in most cases, displaying a biphasic dose response. Numerous papers have reported such biphasic dose responses, especially of chemoattractants on target cell migration such as tumor cells, fibroblasts, and neutrophils [32]. That low and high concentrations of drugs have different effects on receptor affinity for chemoattractants, membrane fluidity, or mediator release may possibly account for U-, J-, or inverted U-shaped dose responses.

In our study, because expression of multiple inflammatory genes and neutrophil sequestration are mainly mediated by NF-{kappa}B [33], a central question is why higher concentrations (ie, 15 and 30 ml/kg) of HES produced less inhibition of NF-{kappa}B? NF-{kappa}B activation is mediated by several mitogen-activated protein kinases (MAPK) that were not measured in our experiment. Perhaps HES has different effects on the different kinases, so that the effects of higher doses may be partially offset by reverse effects. Further experiments are needed to delineate the various proinflammatory signaling pathways that HES influences.

In summary, this study shows an anti-inflammatory effect of HES in endotoxic rats. The possible mechanistic explanation for this effect is that HES inhibits LPS-induced NF-{kappa}B activation in a dose-related manner, preventing the elevations of plasma TNF-{alpha} and CINC, reducing CD11b expression on neutrophils, and subsequently, diminishing neutrophil sequestration in lung, heart, and liver.


   Acknowledgment
 
The authors thank Dr. Genbao Feng for technical assistance.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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