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Early Treatment with Hydroxyethyl Starch 130/0.4 Causes Greater Inhibition of Pulmonary Capillary Leakage and Inflammatory Response than Treatment Instituted Later in Sepsis Induced by Cecal Ligation and Puncture in Rats

Address correspondence to: Jianguo Xu, M.D., Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, P. R. China; tel 86 25 8480 6839; fax: 86 25 8480 6839; e-mail leaflet1981{at}gmail.com.

	Abstract

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This study investigated the temporal profile of effects of hydroxyethyl starch (HES) 130/0.4 on pulmonary capillary leakage in a rat sepsis model induced by cecal ligation and puncture (CLP). Arterial blood pressure and heart rate were monitored during the experiment. Pulmonary capillary leakage was evaluated at 6, 12, 18, and 24 hr after CLP, and HES 130/0.4 was infused iv 2 hr prior to each time point. Myeloperoxidase (MPO) activity of lung homogenates and pulmonary levels of tumor necrosis factor alpha (TNF-), interleukin (IL)-6, IL-10, and nuclear factor-kappaB (NF-B) activity were measured. Infusion of HES 130/0.4 attenuated the pulmonary capillary leakage, reduced the elevations of MPO, TNF-, IL-6, and NF-B levels, and further increased the IL-10 level. Infusion of HES 130/0.4 at 4 or 10 hr after the septic insult resulted in the greatest decreases in inflammatory mediators, suggesting that HES 130/0.4 is more protective against pulmonary capillary leakage when given early rather than later during sepsis.

Keywords: hydroxyethyl starch, lung capillary leakage, NF-B, TNF-, IL-10

	Introduction

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Sepsis, the toxic condition arising from a deregulated systemic inflammatory response, is often the harbinger of multiple organ failure and constitutes the leading cause of mortality in intensive care units [1]. Capillary leakage, associated with trauma, sepsis, and multiple organ failure, is an early sign of inflammation after injury and is proportional to the severity of the insults [2,3]. Inflammatory cascade reactions including a variety of mediators (eg, tumour necrosis factor alpha (TNF-), inter-leukin (IL)-1ß, and IL-6), and activated cells (eg, neutrophils and endothelial cells) [4] that occur in sepsis induce increased capillary leakage, which in turn results in interstitial fluid accumulation, loss of protein, and tissue edema.

Pro-inflammatory and anti-inflammatory cytokines produced by a variety of cells including monocytes, macrophages, Kupffer, and endothelial cells [5] play dominant roles as local or systemic regulators in sepsis. The primary pro-inflammatory cytokine, TNF-, has been suggested to induce tissue damage and is considered a major initiator of inflammation as well. IL-6 is considered as a reliable marker indicating the severity of an inflammatory response [6]. Nuclear factor kappaB (NF-B) constitutes the unifying common pathway that links diverse inflammatory stimuli and responses [7]. NF-B activators include some cytokines whose genes are regulated by NF-B itself (IL-1, TNF-, and IL-6), inducing feed-forward activation and amplification of the inflammatory response [8].

Because of the intrapulmonary sequestration of neutrophils and the frequent occurrence of the acute respiratory distress syndrome in patients with sepsis, the link between overly exuberant neutrophil activation and organ injury was thought to affect the lungs in particular [9]. Neutrophils are activated by inflammatory markers released from cells, including TNF-, IL-6, and IL-8. In addition, activated neutrophils further activate a positive feedback loop to the ongoing inflammatory response by releasing more IL-1, TNF-, IL-6, and IL-8. Myeloperoxidase (MPO) activity is directly related to neutrophil number and serves as an index of neutrophil recruitment and activation [10].

Numerous adjunctive treatments for severe sepsis and septic shock have been tested in clinical trials. Sufficient volume replacement is fundamental in treating patients undergoing sepsis, in order to maintain hemodynamic stability and to decrease the risk of hypovolemia and tissue malperfusion. Hydroxyethyl starch (HES) solutions are used as plasma substitutes in patients with sepsis, trauma, shock, or surgical stress [11–13]. Previous studies in our laboratory indicated that HES 200/0.5 can attenuate inflammatory responses in the lungs, heart, and liver during endotoxemia and sepsis [14,15]. We demonstrated that a novel HES solution (HES 130/0.4) can also exhibit anti-inflammatory effects on sepsis [16]. However, we did not determine whether an early phase or later phase of sepsis is the most efficacious period to administer HES 130/0.4. Therefore, the present study was performed to observe the temporal profile of effects of HES 130/0.4 on pulmonary capillary leakage, neutrophil infiltration, inflammatory cytokines (TNF-, IL-6, and IL-10), and NF-B in rats with sepsis induced by cecal ligation and puncture (CLP).

	Materials and Methods

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Animals.  Adult male Sprague-Dawley rats weighing 280–320 g were obtained from Nanjing Animal Centre (Nanjing, China) and maintained prior to surgery on standard laboratory chow and water ad libitum in a vivarium with a 12-hr light/12-hr dark diurnal cycle. One hundred rats were randomly assigned to 3 groups: (a) CLP with infusion of HES 130/0.4 (40 rats in the group, 10 rats for each time point), (b) CLP with infusion of saline (40 rats in the group, 10 rats for each time point), and (c) sham operation group as control (20 rats). All experiments were performed in accordance with the applicable national regulations and with the National Institutes of Health Guidelines regarding the care and use of animals for experimental procedures.

Surgical procedure.  Rats were anesthetized with 2% sodium pentobarbital in saline (40 mg/kg, ip). The left carotid artery was cannulated with a microtip transducer for continuous recording of macrohemodynamic parameters (ie, mean arterial pressure (MAP) and heart rate (HR)) during the experiment. A tail vein was catheterized in order to administer the specified infusions of HES 130/0.4 or saline. A thermo-regulated heating pad and overhead heating lamp were used to maintain the rats’ core body temperature at 37°C.

Baseline (0 min) hemodynamic parameters were recorded prior to the operation. CLP was performed utilizing a 20-gauge needle and double puncture technique as previously described [17], with minor modifications. Briefly, a 2 cm midline incision was made in the abdomen. Thee cecum was isolated carefully and ligated at about 20% of the total length just below the ileocecal valve to avoid bowel obstruction. Each animal’s total cecal length was measured and the cecal length ligated was based on a proportion to the length of the individual animal’s cecum. The cecum was punctured twice on the anti-mesenteric side with a sterile 20-gauge needle and was then gently squeezed to extrude the fecal material contained in the ligated cecal pouch into the peritoneal cavity. The cecum was placed back in the abdomen, and the incision was closed in two layers with sutures. The rats were then resuscitated with 1 ml of saline injected subcutaneously. Sham-operated controls were treated in a similar manner, but without cecal ligation and puncture. The entire process was executed within 8 min/rat.

We chose 6, 12, 18, and 24 hr after CLP as the investigation time points. Prior to each time point, the operation groups were treated by iv infusion of 15 ml/kg HES 130/0.4 (hydroxyethyl starch, medium molecular weight, low degree of substitution; HAES-steril 130/0.4, 6%, Fresenius Kabi, Germany) or 0.9% NaCl solution, respectively, via the tail vein described above, using a pump-driven constant infusion rate of 0.2 ml/min. Animals were sacrificed at given time points. The lungs were harvested for determining pulmonary capillary permeability, water mass fraction, MPO activity, cytokine levels (TNF-, IL-6, and IL-10), and NF-B activation.

Microvascular permeability in the lungs.  Pulmonary micro-vascular permeability was determined with the Evans blue dye extravasation method as described by Tian et al [14]. Evans blue (20 mg/kg; Sigma Chemical Co., St Louis, MO) was injected iv via the tail vein at 15 min before sacrifice. The lungs were excised and weighed. To each tissue sample, 4.0 ml of formamide was added and incubated at 37°C for 24 hr. If necessary, the incubation time was prolonged until the blue color of the samples completely disappeared. After filtration through a glass filter, the absorbance of the filtrate was measured by spectrophotometry at 620 nm. The total amount of dye was calculated by reference to a standard calibration curve. Pulmonary microvascular permeability was expressed as µg of Evans blue dye/mg of tissue.

Water mass fraction in the lungs.  Water mass fraction was used as a marker of organ water accumulation after CLP. The lung tissues were removed and placed in a humidity chamber and the wet mass was measured immediately. The tissues were dried at 70°C to a constant mass for the determination of dry mass. Organ edema was determined by calculating the tissue water content according to the following formula: water mass fraction (%) = (1 - dry mass/wet mass) x 100.

Production of inflammatory cytokines in the lungs.  The levels of inflammatory cytokines in lung homogenates were quantified using enzyme-linked immunosorbent assay (ELISA) kits specific for various rat cytokines according to the manufacturer’s instructions (TNF- from Diaclone Research, France; IL-6 and IL-10 from Biosource Europe SA, Belgium). Results were expressed as pg/mg protein.

Pulmonary MPO activity.  MPO activity, a marker of tissue neutrophil accumulation, was determined as described previously [14]. Animals were anesthetized with 2% sodium pentobarbital in saline (40 mg/kg, ip). Lungs were removed, externally rinsed with saline, blotted dry, and separately weighed to prepare for the MPO assay. Lung tissue was homogenized for 30 sec in 4 ml of potassium phosphate buffer (20 mmol/L, pH 7.4) and centrifuged for 30 min at 40,000 g and 4°C. The pellet was resuspended in 4 ml of potassium phosphate buffer (50 mmol/L, pH 6.0) containing 0.5 g/dL of cetrimonium bromide. Resuspended pellets were frozen at –70°C until the MPO assay was performed. Frozen samples were thawed, sonicated for 90 sec, incubated in a 60°C water bath for 2 hr, and centrifuged for 10 min at maximum speed. Then 0.1 ml of supernatant was added to 2.9 ml of potassium phosphate buffer (50 mmol/L, pH 6.0) containing 0.167 mg/ml o-dianisidine and 5 x 10^–4 % hydrogen peroxide. The absorbance change at 460 nm was monitored for 3 min with a spectrophotometer (Beckman Instruments, Fullerton, CA).

The following equation was used to calculate MPO activity/g wet lung: MPO activity (units/g wet wt) = (A₄₆₀ x 13.5)/lung weight (g). A₄₆₀ is the change in absorbance of 460 nm light from 1 to 3 min after initiation of the reaction. The coefficient 13.5 was empirically determined so that 1 unit MPO activity is the amount of enzyme that will reduce 1 mmol peroxide/min.

Electrophoretic mobility shift assay (EMSA).  Nuclear protein was extracted and quantified and EMSA was performed using a commercial kit (Gel Shift Assay System; Promega, Madison, WI) as previously described by our laboratory [18].

Statistical methods.  The Kolmogorov-Smirnov test was applied to determine if the collected data were normally distributed. Data with normal distribution were expressed as mean ± SE. To investigate whether early treatment provides a greater effect than later treatment, the relative ratio of each parameter was calculated for each time point according to the formula: [mean data for CLP plus HES 130/0.4]/[mean data for CLP plus saline]. Statistical significance was determined by ANOVA for comparison among treated group (SPSS, version 10.0). The Bonferroni test was used for pairwise comparisons of the combinations of group pairs. Differences were considered statistically significant if p was <0.05.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgement References

 
Systemic hemodynamics.  MAP and HR were comparable at baseline in the 3 groups (data not shown). There were no significant differences in the monitored physiological variables (MAP and HR) during the experiment within groups, and all values were within the normal ranges for adult male rats. Neither of these parameters changed significantly at the specified time points between groups. This implies that the CLP model in the presence or absence of HES 130/0.4 treatment did not induce significant hemodynamic changes over time.

Effects of HES 130/0.4 on pulmonary microvascular permeability and water mass fraction.  Pulmonary microvascular permeability and water mass fraction, commonly used for assessment of pulmonary capillary leakage, were significantly increased following the operation, and peaked at 12 hr. Compared with the saline-treated CLP group, HES 130/0.4 markedly attenuated microvascular permeability at 6 hr (p <0.01), 12 hr (p <0.01), and 18 hr (p <0.05), and decreased the water mass fraction at 6 hr (p <0.01), 12 hr (p <0.01), 18 hr (p <0.05), and 24 hr (p <0.05). At 6 and 12 hr, HES 130/0.4 caused more reduction than at other time points in microvascular permeability (Fig. 1A) and water mass fraction (Fig. 1B) (Table 1).

View larger version (34K): [in this window] [in a new window]   Fig. 1. Pulmonary microvascular permeability (A) and water mass fraction (B) at 6, 12, 18, and 24 hr after CLP. Although there were still significant differences between the HES-treated and control groups, HES 130/0.4 significantly inhibited the increase of microvascular permeability and lung water mass fraction (mean ± SE for 6 rats at each time point for the operation groups and 12 for the control group).

View larger version (37K): [in this window] [in a new window]   Fig. 2. Pulmonary MPO activity at 6, 12, 18, and 24 hr after CLP. Compared to saline-treated CLP group, HES 130/0.4 markedly attenuated the elevation of MPO activity (mean ± SE for 6 rats at each time point for the operation groups and 12 for the control group). * p <0.05, ** p <0.01 vs control group; # p <0.05, ## p <0.01 vs HES-treated CLP group.

View larger version (30K): [in this window] [in a new window]   Fig. 3. Levels of TNF- (A) and IL-6 (B) in the lungs at 6, 12, 18, and 24 hr after CLP. TNF- was up-regulated after CLP, peaked at 6 hr, and returned to baseline at 24 hr. Compared to saline-treated CLP group, HES 130/0.4 reduced TNF- level at each time point. IL-6 was up-regulated after CLP, being maximal at 12 hr. Compared to saline-treated CLP group, HES 130/0.4 reduced the IL-6 level at each time point (mean ± SE for 6 rats at each point for CLP groups and 12 for the control group). * p <0.05, ** p <0.01 vs control group; # p <0.05, ## p <0.01 vs HES-treated CLP group.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Lung IL-10 level increased after CLP, being maximal at 24 hr. HES 130/0.4 induced IL-10 levels compared to the saline-treated CLP group at 6, 12, and 18 hr (mean ± SE for 6 rats at each point for CLP groups, 12 for controls). * p <0.05, ** p <0.01 vs controls; # p <0.05, ## p <0.01 vs HES-treated.

Effects of HES 130/0.4 on NF-B activation in the lungs.

View larger version (46K): [in this window] [in a new window]   Fig. 5. Activation of NF-B in the lungs. A: Bands with different intensity representative of NF-B activation. Lanes 1 and 2 represent CLP groups treated with saline or HES 130/0.4, respectively, at 6 hr; lanes 3 and 4 represent CLP groups treated with saline or HES 130/0.4 at 12 hr; lanes 5 and 6 represent CLP groups treated with saline or HES 130/0.4 at 18 hr; lanes 7 and 8 represent CLP groups treated with saline or HES 130/0.4, respectively, at 24 hr; lane 9 represents the sham-operated control group. B: Pulmonary NF-B activity was detectable at low level in the control group and was markedly elevated after CLP, being maximal at 6 hr. Compared to the saline-treated group, HES 130/0.4 suppressed NF-B activity level at each time point (mean ± SE for 6 rats at each time point for CLP groups and 12 for the control group. * p <0.05, ** p <0.01 vs control group; # p <0.05, ## p <0.01 vs HES-treated CLP group.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgement References

 
The primary aim of this study was to test pulmonary capillary leakage, as assessed by microvascular permeability and water mass fraction, in sepsis induced by CLP in groups of rats treated with HES 130/0.4 or saline during the first 24 hr after operation. In addition, we measured pulmonary TNF-, IL-6, and IL-10 levels and MPO activity as inflammatory indices to determine the effects of HES 130/0.4 on inflammatory cytokines, neutrophil infiltration, and NF-B activity.

CLP is a clinically relevant model of intra-abdominal sepsis, which develops slowly and progressively and simulates the polymicrobial enteric insult that occurs in patients with colonic perforations; the CLP model has been a mainstay of basic research on sepsis [19].

Sepsis can increase pulmonary capillary permeability [20]. Zikria and Bascom [21] established the role that capillary leakage plays in the systemic inflammatory response syndrome and the development of multiple organ failure. Because an increase in trans-capillary leakage of fluid and proteins is often seen in patients in the intensive care unit [22,23], therapeutic measures to reduce the increased permeability may be of value to counteract tissue edema and hypovolemia. Reduced capillary leakage after the colloid infusion would cause more hemodynamic stability and less edema. Previous evidence showed that HES has a capillary sealant effect, which reduces capillary leakage [24]. Our previous study showed that HES 130/0.4 can attenuate capillary leakage in a sepsis model, which was confirmed by the present data. However, we only investigated the effects of HES 130/0.4 on capillary leakage within 6 hr before sacrifice. The current study shows that HES 130/0.4 is effective at various time points during 24 hr after CLP and that attenuation of capillary leakage is greater at 6 and 12 hr than at later periods (18 and 24 hr).

The influence of resuscitation fluids in inflammatory response and leukocyte function has been assessed in several studies. A clinical study by Boldt et al [25] showed that volume replacement regimen using HES 130/0.4 was more able to decrease inflammatory response and endothelial injury and activation in elderly patients suffering from major abdominal surgery than administration of crystalloids. A clinical study by Lang et al [26] showed that volume replacement with HES 130/0.4 may reduce the inflammatory response associated with elective major abdominal surgery more than administration of crystalloids. In patients undergoing minor urological surgery, the administration of various HES preparations was not associated with negative effects on neutrophil phagocytic activity [27]. Lawrence et al [28] demonstrated in an experimental setting that cell-mediated immunity was unaffected after the treatment of HES. Shatney et al [29] found no deleterious effects of HES on reticuloendothelial function or host resistance to sepsis. Our studies support these findings. Evidence from our ongoing studies indicates that HES 130/0.4 exerts anti-inflammatory effects in multiple organs during endotoxemia and sepsis [14–16]. In the present study, HES 130/0.4 inhibited TNF-, IL-6, IL-10, NF-B activation, and MPO activity not only at 6 hr, but throughout 24 hr after CLP. In addition, the effects of TNF-, IL-6, IL-10, NF-B activation, and MPO activity after HES 130/0.4 treatment were consistent with the attenuation of pulmonary capillary leakage, which supports our previous hypothesis that HES 130/0.4 attenuates pulmonary capillary leakage by modulation of inflammatory mediators and NF-B activation.

Studies have indicated that 2–10 hr after CLP is an early, hyperdynamic period, while 20–30 hr following CLP is a late, hypodynamic phase of sepsis [30]. Our data demonstrate that HES 130/0.4 treatment in the early stage causes greater reduction than in the late stage in inflammatory response and pulmonary capillary leakage. Hence, it is important to treat sepsis with HES 130/0.4 early, in order to ameliorate the outcome.

In the present study, relevant macrohemo-dynamic changes were excluded by repeated measurements of hemodynamics in the 3 experimental groups. This indicates that the effects of HES 130/0.4 were not caused by reversal of hemodynamic disturbances. Various mechanisms, such as the electrical charge of the molecules, structural changes in the interstitial matrix, and possible formation of vesicular trans-membrane channels, have been proposed to explain how synthetic colloids affect increased capillary leakage [31]. Despite our current findings, we cannot rule out possible roles of such mechanisms or of alternate signaling pathways in the inhibitory effect of HES 130/0.4 on capillary leakage.

In conclusion, HES 130/0.4 when administered iv at various time points during 24 hr after CLP inhibits pulmonary capillary leakage, production of pro-inflammatory cytokines, neutrophil activation, NF-B activation, and up-regulation of anti-inflammatory cytokines in septic rats. Infusion of HES 130/0.4 may attenuate pulmonary capillary leakage by modulating inflammatory responses in the lungs. In addition, HES 130/0.4 showed greater inhibitory effects at 6 hr than at later time points. Thus, we envision that early use of HES 130/0.4 may be most effective during sepsis.

	Acknowledgement

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The authors thank Dr. Genbao Feng for invaluable advice and technical assistance.

	References

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgement References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Feng, X. Articles by Xu, J. Search for Related Content PubMed PubMed Citation Articles by Feng, X. Articles by Xu, J.