Anesth Analg 2006;103:149-155
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000220906.74517.99
CRITICAL CARE AND TRAUMA
Hydroxyethyl Starch Exhibits Antiinflammatory Effects in the Intestines of Endotoxemic Rats
Ran Lv, MD,
Zhi-Qiang Zhou, MD,
Hai-Wei Wu, MD,
Yi Jin, MS,
Wei Zhou, MD, and
Jian-Guo Xu, MD
From the Department of Anesthesiology, Department of Cardiosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; Department of General Surgery, the Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Address correspondence and reprint requests to Prof Jian-Guo Xu, MD, Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, P.R. China. Address e-mail to nulvran{at}yahoo.com.cn.
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Abstract
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We performed the present in vivo study to investigate the effect of hydroxyethyl starch (HES) on intestinal production of inflammatory mediators and activation of transcription factors during endotoxemia. Rats with endotoxemia induced by lipopolysaccharide (LPS) (5 mg/kg, IV) were treated with HES (16 mL/kg, IV) or saline (64 mL/kg, IV). At 2, 3, or 6 h after the LPS challenge, the rat ileal tissues were collected. Various ileal inflammatory mediator levels (tumor necrosis factor-
, interleukin [IL]-6, cytokine-induced neutrophil chemoattractant-1, and IL-10), inflammatory mediator messenger RNAs (mRNAs), activities of nuclear factor (NF)-
B and activator protein (AP)-1, and ileal myeloperoxidase-positive cells were determined in each group. HES significantly reduced the increased intestinal levels of tumor necrosis factor-, IL-6, cytokine-induced neutrophil chemoattractant-1, and the mRNAs in the endotoxemic rats. Similarly, HES could decrease the myeloperoxidase-positive cells induced by LPS and also inhibit ileal NF-B and AP-1 activations. Our results suggest that during endotoxemia HES may down-regulate intestinal inflammatory mediator production, and this antiinflammatory effect of HES may act through suppression of NF-B and AP-1 activations.
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Introduction
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Severe Gram-negative infections associated with shock still cause frequent mortality rate in intensive care units despite substantial research in this field over several decades. Lipopolysaccharide (LPS) or endotoxin, a component of the outer cell wall of Gram-negative bacteria, is a powerful inducer of the systemic inflammatory response that plays an important role in the pathogenesis of septic shock (1).
Several studies have provided evidence that the gut is an active participant in the metabolic and inflammatory response to endotoxemia and sepsis. During both local and systemic inflammation, the intestine is increasingly being recognized as an important source of inflammatory mediators, including interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6 (2,3). In addition, Magnotti et al. (4) have reported that other yet-unidentified substances may influence not only the mucosa itself but also the function and integrity of remote organs and tissues. Indeed, the gut mucosa has been proposed to be the "motor" of multiple organ failure in critical illness (5).
Hydroxyethyl starch (HES) is a colloidal, synthetically modified polymer of amylopectin, a waxy starch derived from maize or sorghum. Clinically, HES is frequently used for intravascular volume replacement when attempting to maintain or improve tissue perfusion in patients experiencing sepsis, trauma, shock, or surgical stress (6,7). In addition to the effect on maintenance of stability of hemodynamic variables, several studies have shown that HES may exert antiinflammatory effects (8–10). Previous studies (11,12) in our laboratory demonstrated that during endotoxemia HES could induce a down-regulation of inflammatory mediators in the lung, heart, and liver. However, few studies have investigated the protective effect of HES on the inflammatory response in the gut.
Because all of the events that result in cytokine and chemokine expression involve activation of transcription factors, such as nuclear factor (NF)-B (13) and activator protein (AP)-1 (14), it seems possible that HES could regulate the expression of inflammatory mediators through the NF-B and/or AP-1 signaling pathway. As a result, in the present study we used the rat endotoxemia model to determine whether HES is able to exert an antiinflammatory effect in the gut through suppression of NF-B and/or AP-1 activation.
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METHODS
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Adult male Sprague-Dawley rats (350–400 g body weight) were obtained from Shanghai Animal Center, Shanghai, China, and kept in accordance with the Institutional Animal Care Committee guidelines. The study protocols were approved by the Institutional Animal Care Committee of Jinling Hospital. Animals were housed in a room with an ambient temperature of 22°C and a 12-h light/dark cycle. All rats were allowed at least 7 days to acclimatize. Before the experiment, the rats were fasted 12 h but were allowed free access to water. Animals were anesthetized by IP administration of 1250 mg urethane per 1 kg body weight. The right jugular vein was cannulated with a polyethylene catheter for IV administration of solutions. The macrohemodynamic variables, mean arterial blood pressure (MAP), and heart rate (HR) were measured through the left carotid artery, which was catheterized with a microtip transducer (Abbott Laboratories Ltd., Chicago, IL). The temperature was measured with a thermometer placed in the rectum and maintained at 37.0°C ± 0.5°C.
The rats were randomly divided into 4 groups (6 rats per group): LPS alone; LPS plus HES; HES alone; and saline control. Immediately after monitoring of baseline variables (0 min), LPS (5 mg/kg) (Escherichia coli O111: B4, Sigma Chemical CO, St. Louis, MO) was given for 30 min via the tail vein. In the HES-alone and saline control groups, 0.9% saline (3 mL/kg) was injected via the tail vein instead of LPS. One hour after the beginning of LPS injection, to test the influence of different solutions on LPS-induced changes, rats in the LPS-alone group were treated with 0.9% isotonic NaCl solution (64 mL/kg) and rats in the LPS and HES group were treated with HES (16 mL/kg) (HES, medium molecular weight, low degree of substitution; HAES-sterile 200/0.5, 6%; Fresenius Kabi, Bad Homburg, Germany), both via the right jugular vein. The rate of infusion was 0.4 mL/min. Similarly, HES (16 mL/kg) was infused in the HES-alone group and saline (64 mL/kg) in the saline controls. Ileums were collected either at 2 h after the beginning of LPS injection for determination of TNF- levels, TNF- mRNA expression, and NF-B, AP-1 activities or at 3 h after beginning LPS administration for IL-6, cytokine-induced neutrophil chemoattractant (CINC-1), IL-10 levels, and mRNA expression.
To exclude a contribution of cytokine expression by blood-borne elements, perfusion was performed in the following manner before removing the tissues: after thoracotomy, a cannula was placed in the left ventricle, and the right atrium was opened; 300 mL of 0.9% NaCl solution was perfused through the cannula at a pressure of 120 cm H2O; the intestinal samples were frozen in liquid nitrogen and stored at –70°C until analysis.
The intestinal levels of inflammatory mediators were quantified using enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions (TNF- from Diaclone Research, Besancon, France; IL-1ß, IL-6, and IL-10 from Biosource Europe SA, Niveiles, Belgium; and CINC-1 from Amersham Biosciences, Amersham, UK). Values were expressed as pg per mg protein.
To determine the mRNAs of inflammatory mediators, the intestinal samples were homogenized in TRIzol reagent (Roche Molecular Biochemicals, Indianapolis, IN, USA). Total RNA was extracted from the tissue according to the manufacturer's suggested protocol. Total RNA concentration was determined from spectrophotometric optical density measurement (260 and 280 nm). For each sample tested, the ratio between the spectrophotometric readings at 260 nm and 280 nm (A260/A280) was used to provide an estimate of the purity of the nucleic acid. The ratio in all samples ranged between 1.7 and 2.0. Reverse transcriptase reactions were then performed using the Reverse Transcription System Kit (Promega, Madison, WI). Each reaction tube contained 1 µg of total RNA in a volume of 20 µL containing 5 mmol/L MgCl2, 1
Reverse Transcription Buffer, 1 mmol/L of each dNTP, 1 U/µL of RNase inhibitor, 15 U/µg of AMV Reverse Transcriptase, 0.025 µg/µL of Oligo(dT)15 Primer, and DEPC-treated water to volume. Reverse transcriptase reactions were conducted in a DNA Thermal Cycler (MiniCycler PTC 150, MJ Research Inc., Waltham, MA) at 42°C for 60 min and 95°C for 5 min. The complementary DNA (cDNA) was then stored at –20°C.
Polymerase chain reaction (PCR) was performed using 0.5 U of Taq-polymerase (Promega, Madison, WI), 0.005 µmol dNTP, and 50 pmol of each primer (Sangon CO, Shanghai, China), in a total volume of 25 µL in a DNA Thermal Cycler. The primers, cycle numbers, and amounts of cDNA used are listed in Table 1. Each PCR cycle consisted of 30 s at 95°C, 30 s at 50°C, and 60 s at 72°C. The PCR products were electrophoresed on a 2% agarose gel stained with ethidium bromide. The gel was captured as a digital image and analyzed using Scion Image software (Scion Corp., Frederick, MD). The relative levels of cytokine mRNAs were normalized to ß-actin transcript from the same reaction.
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Table 1. Primers, Cycle Numbers, and Amounts of Complementary DNA (cDNA) Used for Semiquantitative Polymerase Chain Reaction (PCR)
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Nuclear protein was extracted and quantified as described previously (15). NF-B or AP-1 consensus oligonucleotide probe (5'-AGTTGAGGGGACTTTCCCAGGC-3' for NF-B and 5'-CGCTTGATGAGTCAGCCGGAA-3' for AP-1) was end-labeled with [
-32P] ATP (Free Biotech, Beijing, China). Nuclear protein extract and electrophoretic mobility shift assay (EMSA) experiments were performed using the procedure described by Sun et al. (15). For the supershift assay, polyclonal antibodies against NF-B (p50 and p65) and AP-1 (c-Jun, JunB, JunD, and c-Fos) subunits (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) were incubated with samples after the initial binding reaction between nuclear protein extracts and the consensus oligonucleotide.
Cellular aspects of intestinal inflammation were assessed immunohistochemically by staining for granulocytes (myeloperoxidase [MPO]) 6 h after injection of LPS using additional groups of rats. Segments of ileum were rinsed with 0.9% NaCl and fixed in 10% buffered formaldehyde solution at room temperature. After dehydration, intestine tissue was embedded in paraffin and sectioned (5 µm). Sections were preincubated with protein-blocking serum to prevent nonspecific binding and then incubated for 90 min at room temperature with anti-rat MPO antibody (Santa Cruz Biotechnology, Inc.; 1:200). Secondary reagents were made with the Vector Elite ABC kit (Vector Laboratories Inc., Burlingame, CA). NovaRed (Vector Laboratories Inc.) was used for color development. The total number of MPO-positive cells in 50 consecutive villi was counted, and this measurement was independently performed three times for each animal. In addition, villus height and crypt depth were also measured in a minimum of 10 consecutive villi for indication of damage to intestinal morphology.
All data are expressed as mean ± se and compared by analysis of variance and Student's t-test. Differences in values were considered significant at P < 0.05.
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RESULTS
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In all groups, MAP and HR were measured at baseline (0 min) and 15 min, 30 min, 1 h, 2 h, and 3 h after LPS injection via carotid artery catheters. The data showed that HR and MAP were comparable among the animal groups at baseline (P > 0.05) (Table 2). LPS exposure did not induce significant changes in HR and MAP over time. Accordingly, there were no significant differences between the experimental groups at the different time points studied (Table 2).
The ELISA results showed that endotoxemia in rats was associated with significant increases in the intestinal levels of TNF- (Fig. 1A), IL-6 (Fig. 1B), and CINC-1 (Fig. 1C) 2 h or 3 h after injection of LPS. In contrast, the endotoxin-induced increases in these mediators in the ileum were significantly blunted in rats treated with HES (P < 0.05). The levels of TNF-, IL-6, and CINC-1 did not differ between saline control and HES alone. Similarly, LPS significantly increased the intestinal level of IL-10 (Fig. 1D). Compared with LPS alone, however, infusion of HES only slightly up-regulated intestinal IL-10 in endotoxemic rats (P > 0.05).
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Figure 1. Intestinal inflammatory mediator levels in lipopolysaccharide (LPS) alone, LPS and hydroxyethyl starch (HES), HES alone, and control rats 2 or 3 h after injection of LPS or saline. The mean ± sem values of n = 6 rats per group are shown for tumor necrosis factor (TNF)- (A), interleukin (IL)-6 (B), cytokine-induced neutrophil chemoattractant (CINC)-1 (C), and IL-10 (D). * P < 0.05 versus LPS alone.
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The intestine baseline levels of the inflammatory mediator mRNAs were detected in control rats (Fig. 2). In contrast, 2 h or 3 h after injection of LPS, TNF- (Fig. 2A), IL-6 (Fig. 2B), CINC-1 (Fig. 2C), and IL-10 (Fig. 2D) mRNA levels markedly increased. Infusion of HES in endotoxemic rats was shown to significantly reduce the LPS-induced increases in TNF-, IL-6, and CINC-1 mRNA expressions (P < 0.05) and to slightly increase IL-10 mRNA expression (P > 0.05).
Compared with saline control and HES alone, LPS activated NF-B and AP-1 in the rat intestine significantly 2 h after injection (Fig. 3). Activities of these two transcription factors in endotoxemic rats infused with HES decreased markedly (P < 0.05). Changes in intestinal activities of NF-B and AP-1 were parallel with those in intestinal proinflammatory mediator levels of TNF-, IL-6, and CINC-1.
To assess the specificity of the NF-B or AP-1 complex and to identify the contributing family members, supershift experiments were performed by adding antibodies against subunits to the nuclear extracts before EMSA. Protein-antibody recognition can be visualized by a decrease in the mobility of the DNA-protein complex and a diminution of the NF- or AP-1 complex. In the ileum of LPS-treated animals, both p50 and p65 were found as part of the NF-B complex. In contrast, HES could decrease LPS-induced activation of the NF-B complex, including p50 and p65 (P < 0.05) (Fig. 4A). The determination of the specificity of the AP-1 complex indicated that the AP-1 complex consisted mainly of c-Fos and, to a lesser extent, JunB, and JunD. Correspondingly, treatment with HES appeared to inhibit c-Fos to the greatest extent and JunB and JunD to a lesser extent (P < 0.05) (Fig. 4B).
The specificity of the DNA/protein was determined by competition reactions in which a 100-fold molar excess of unlabeled transcription factor (NF-B or AP-1) oligonucleotide (specific competitor) or unlabeled SP1 oligonucleotide (nonspecific competitor) was added to the binding reaction 10 min before the addition of a radiolabeled probe using LPS-induced positive rat nuclear extract (Fig. 5).
The immunohistochemical analysis showed that there were no lesions in the intestinal mucosa of the control rats, and the villi were regularly arranged. Six hours after injection of LPS, the morphologic structure of the ileum had changed. Mucosal ulcers appeared and marked neutrophil infiltration was observed, characterized by an increase in the number of MPO-positive cells. Villus height and crypt depth were significantly lower in LPS-challenged rats than in controls (Table 3). HES treatment reduced the number of MPO-positive cells in endotoxemic rats (P < 0.05) but did not markedly improve the villi structure (P > 0.05) (Table 3).
In the survival study no rats died.
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DISCUSSION
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Many studies have documented the antiinflammatory actions of HES under several pathological conditions. For instance, Kaplan et al. (16) confirmed the hypothesis that HES could attenuate increases in leukocyte adherence and vascular permeability in the cerebral vasculature after global cerebral ischemia induced by asphyxia, which they theorized might result from the propensity of HES to reduce or modulate the expression of adhesion molecules. Previous studies (11,12) in our laboratory also demonstrated that during endotoxemia HES could induce a down-regulation of inflammatory mediators in serum and some organs. However, it is still unknown whether HES has antiinflammatory effects in the gut. The present study was therefore performed to determine whether HES could exert antiinflammatory effects through down-regulation of proinflammatory mediators (e.g., TNF-, IL-6, and CINC-1) and/or up-regulation of antiinflammatory cytokines (e.g., IL-10) in intestinal tissues in a rat endotoxemia model. Changes in inflammatory mediators were used as inflammatory indexes in this study because exaggerated production of inflammatory mediators is one of the most obvious inflammatory responses induced by LPS. To increase the clinical relevance of the experimental protocol, a post-treatment mode of therapy, beginning 1 h after exposure, was chosen. The ratio of 1:4 between colloid and crystalloid (16 mL/kg and 64 mL/kg) was used to account for the higher acute volume effect of the colloid solution. In this way, we most closely simulated a typical clinical resuscitation protocol.
Our final results indicated that endotoxemia in rats was associated with increased concentrations of TNF- and IL-6 in the small intestine and that treatment with HES could significantly blunt the increases of these proinflammatory cytokines. This suggested that during endotoxemia HES participated in the down-regulation of proinflammatory cytokine production in the small intestine and therefore could have an antiinflammatory effect. In addition, from cellular aspects of intestinal inflammation, HES treatment could decrease the MPO-positive cells that are characteristic of neutrophil infiltration. This might be attributed to the decreased CINC-1, which plays an essential role in inducing neutrophil infiltration and activation in various types of acute inflammation (17). In contrast, the effect of HES on up-regulation of intestinal IL-10 was slight, which implied that the inhibition of intestinal proinflammatory mediators in our experiment was not a result of the increased antiinflammatory cytokine, IL-10. As we have shown, cytokines act predominantly as paracrine and autocrine messengers, not endocrine mediators. Thus, this study focused on local production of cytokines. To exclude the influence of blood on the levels of cytokines in the intestine, perfusion with 300 mL of saline was performed before the intestinal samples were collected. In addition, the concentrations of cytokine mRNAs in the intestinal tissues were determined. The finding that the changes of cytokine mRNA expressions were consistent with those of cytokine levels demonstrated that the increased intestinal TNF- and IL-6 levels after injection of LPS were the result of stimulated local production of the cytokines and that HES could reduce this local production through inhibition of mRNA expression.
Our findings corresponded well with the results of experimental studies on hemorrhagic shock (18) demonstrating that HES could reduce the hemorrhage-induced increase in plasma IL-6 concentrations. Schmand et al. (18), however, could not exclude that the decreased IL-6 concentrations might only reflect a more rapid shock reversal and, thus, an improved macrohemodynamic profile. To allow investigation of the effect of HES on inflammatory mediators in the gut without the development of shock, a smaller dose of LPS, 5 mg/kg, was specifically chosen. The final data showed that there were no significant differences in macrohemodynamic variables among the experimental groups at the different time points studied. This implied that the observed changes in concentrations of the inflammatory mediators in the intestine were not primarily mediated by endotoxin-induced hypotension or endotoxemic shock but were more likely caused by a direct effect of endotoxin on the cells which may produce the inflammatory mediators. On the other hand, this finding suggested that HES could exert its antiinflammatory effect during endotoxemia independent of its action on macrohemodynamics.
In inflammation, NF-B appears to be one of several particularly important transcription factors; it is activated extracellularly and binds to the promoter region of "inflammatory" genes to increase their rate of transcription (19,20). Several studies (2,21) have also demonstrated that LPS may activate NF-B in the intestine. Thus we postulated that HES might exert its antiinflammatory effects in the gut during endotoxemia and down-regulate proinflammatory mediators TNF-, IL-6, and CINC-1 through the NF-B signaling pathway. This hypothesis was confirmed by our results, which showed that HES reduced NF-B activity and decreased TNF-, IL-6, and CINC-1 levels in the small intestine.
NF-B is composed of homo- or heterodimers of subunits. p50–p65 is the most frequently described form of NF-B involved in the inflammation response and is activated in inflammatory processes (22). The determination of the specificity of the NF-B complex indicated that in the rat ileum, LPS could activate both p50 and p65 subunits, and correspondingly, HES could significantly inhibit the increased activations.
AP-1 designates another class of transcription factors that mediate inflammatory responses through various cytokines, growth factors, and other agents that induce oxidative stress (14,23). Studies have shown that several inflammatory mediator genes (e.g., IL-6 and IL-1ß) contain one or more AP-1 binding sites in their promoter regions (14). In this study, HES significantly suppressed LPS-induced activation of AP-1, including JunB, JunD, and c-Fos subunits, suggesting that in addition to NF-B, other transcription factors, such as AP-1, were also involved in anti-inflammatory actions of HES.
As to how HES inhibited the transcription factors and down-regulated the proinflammatory mediators, two possible modes of action should be considered. One potential mechanism is the direct inhibitory effect of HES on cells, which may release proinflammatory mediators during endotoxemia. The other is that HES could regulate the interactions between LPS and cell-surface receptors, decrease the inflammatory response induced by LPS, and thus indirectly reduce the levels of inflammatory mediators.
A major limitation of the study is the small sample size. It is possible that further differences among the groups may have gone undetected because of the lack of statistical power.
It has to be emphasized that our findings with a third generation of HES (HES 200/0.5) cannot be extended to other HES preparations that clearly differ in concentration, degree of substitution, and molecular weight distribution. The molecular weight and the range of the respective HES fraction determine renal excretion and volume effect, as well as tissue deposition and hemostatic changes, and may also be critical for specific antiinflammatory effects during acute inflammation.
Currently, HES is often used for intravascular volume support during inflammatory disorders. Our results illustrate that in endotoxemic rats, HES may play a beneficial role in down-regulating proinflammatory mediators in parallel with inhibition of NF-B and AP-1 activities in the intestine. However, it must be pointed out that the inflammatory responses in the HES-treated rats were still greater than the responses in controls; thus the present documentation of an antiinflammatory action of HES reveals an adjunct effect to fluid resuscitation.
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ACKNOWLEDGMENTS
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The authors thank Dr. Genbao Feng for technical assistance.
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Footnotes
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Accepted for publication March 1, 2006.
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Abstract
Introduction
