INTRODUCTION
Septic shock in the course of overwhelming microbial infection may proceed to multiple organ dysfunction syndrome (MODS), despite recent advances in intensive care therapy. Sequential MODS may herald an increase in mortality from 30% to 100% according to the number of organ systems involved (1 2 3 4, 5
The first step in cardiovascular resuscitation of septic shock is to restore and maintain adequate intravascular volume with a fluid challenge. Compared with crystalloid fluid, albumin seems to be more effective in expending intravascular volume and improves organ function in patients of critical ill, especially with hypoalbuminemia (6, 7 hyperoncotic albumin (HA) with furosemide improved oxygenation and cardiovascular stability in patients with sepsis-induced acute lung injury (8 9
It has been shown that albumin scavenges reactive oxygen intermediate, binds transition metal ion, and affords a variety of biological effects by replenishing plasma thiol concentrations (10 in vitro hemodiafiltration circuit is more effective in the clearance of TNF-α and IL-6 than saline dialysate (11 12
There are still some controversies regarding the impact of HA on outcome (8, 13-15 14 15
MATERIALS AND METHODS
Animals
Male Wistar rats (10-12 weeks old, 280-350 g) were purchased from BioLASCO Taiwan Co (Taipei, Taiwan). Rats were guaranteed free of particular pathogens. All animals were bred and maintained under a 12-h light-dark cycle at a controlled temperature (21°C ± 2°C) with free access to standard rat chow and tap water. All experimental procedures were approved by the institutional and local Committee on the Care and Use of Animals (National Defense Medical Center, Taipei, Taiwan, ROC) and provided assurance that all animals received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences.
Surgical procedures and experimental protocols
The experiments were performed on pairs of rats. Animals were anesthetized by intraperitoneal injection of sodium pentobarbital (40-50 mg/kg). The left carotid artery and the right jugular vein were cannulated and exteriorized to the back of the neck for hemodynamic measurements and drug administration, respectively. Afterward, the cannulated animals were allowed to recover to normal condition overnight and given ad libitum access to food and water. Rats were divided into two groups: septic and sham-operated (SOP) rats. After baseline (i.e., time 0) hemodynamic measurements and blood withdraw, sepsis was induced by cecal ligation and puncture (CLP), as described in our previous study (16 17
At baseline (i.e., time 0) and at 3, 9 and 18 h after CLP, mean arterial pressure (MAP) and heart rate were measured by a pressure transducer (P23ID, Statham, Oxnard, Calif) and displayed on a polygraph recorder (MacLab/4e; AD Instruments Pty Ltd, Castle Hill, Australia) in the conscious condition. Blood (0.5 mL) was drawn from carotid artery at 0, 3, 9, and 18 h after CLP to determine organ injury markers and cytokines. Extra arterial blood samples (0.2 mL) were drawn at time 0, 9, and 18 h for the measurement of hematocrit concentration (AVL OPTI Critical Care Analyzer; AVL Scientific, Roswell, Ga). Each volume of blood removed was immediately replaced by the injection of an equal volume of sterile saline. The total amount of blood removed was about 2.6 mL. Eighteen hours after CLP or sham operation, hepatic surface blood flow was determined under pentobarbital anesthesia. Subsequently, the animals were killed, and livers were immediately collected to measure tissue superoxide (O2 − ) level and iNOS protein expression and for histologic study.
Quantification of organ function and injury
Blood glucose was analyzed by a One-Touch II blood glucose monitoring system (Lifescan Inc, Milpitas, Calif) with 10 μL of whole blood. The remainder of blood samples was then immediately centrifuged at 7,500g for 2 min to obtain the plasma. About 60 μL of plasma was used to analyze biochemical markers of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, blood urea nitrogen (BUN), and creatinine by Fuji DRI-CHEM 3030 (Fuji Photo Film Co, Ltd, Tokyo, Japan).
Measurement of hepatic microvascular blood flow
After the final hemodynamics recording and blood sampling, local microcirculation was determined noninvasively by laser Doppler flowmetry (Moor DRT4, Wilmington, Del) under pentobarbital anesthesia. The laser Doppler flowmeter contains a glass fiber probe with resulting penetration depth of about 1 to 2 mm. A depth of 1 mm is usually sufficient to capillaries and arteriolar-venous shunts. Using this technique in the current study, we monitored the blood flow on the surface of the liver. After probe application, the rat was placed in a supine position under pentobarbital anesthesia for 5 min before recording. Each blood flow measurement lasted 40 s after a 5-min supine period and a 20-s stabilization. Two sites chosen randomly per tissue were studied, and the arithmetic means of these values were subjected to further statistical analysis.
Measurement of plasma IL-1β, IL-6, and nitrite/nitrate concentrations
The plasma samples (150 μL) obtained at times 0, 3, 9, and 18 h were used. The plasma IL-1β and IL-6 were measured in duplicate with enzyme-linked immunosorbent assay kits (R&D Systems, Inc, Minneapolis, Minn) according to the manufacturer's instructions. It is noted that the plasma NO concentration depicted in the study is actually the total nitrite and nitrate concentration in plasma. With this method, nitrate is reduced to NO via nitrite. The nitrite/nitrate concentrations in all samples were measured using chemiluminescence by a Sievers Nitric Oxide Analyzer (Sievers 280 NOA; Sievers Inc, Boulder, Colo), as previously described (16
Measurement of liver O2 − production
Freshly collected liver tissue was cut into pieces (5 × 5 mm in size) and incubated with Krebs-HEPES buffer for the assay of O2 − as previously described (16 2 − activity was expressed as counts per second of milligram of organ dry weight.
Western blot analysis
At 18 h after CLP or sham operation, the liver was obtained and frozen at −80°C before assay. Frozen samples were thawed and homogenized on ice for protein assay (Bio-Rad Laboratories, Hercules, Calif) and Western blot analysis for iNOS protein expression, as previously described (16
Histologic studies
Parts of liver sections were fixed in 10% phosphate-buffered formaldehyde for more than 8 h. The fixed tissues were dehydrated and embedded in paraffin. Each paraffin block was processed into 4-μm-thick slices that were stained with hematoxylin and eosin. This histologic alteration was quantitatively analyzed as neutrophil infiltration index and scored 0 (absent) to 4 (maximal) by a pathologist in a blinded fashion as described previously (18
Statistical analysis
The data are presented as mean ± SEM of n determinations, where n represents the number of animals studied. Statistical evaluation was performed by using ANOVA or repeated measures of two-way ANOVA followed by Bonferroni correction as post hoc test. The score for tissue infiltration of neutrophils was compared by the Kruskal-Wallis rank test and presented as median (range). Survival data were analyzed using Fisher exact test. P < 0.05 was considered to be statistically significant.
RESULTS
Survival rate
The 9- and 18-h survival rates of CLP animals were 81.3 % (i.e., 39/48 animals) and 39.6 % (i.e., 19/48 animals), respectively. In contrast, the rats treated with HA had higher survival rates of 88.9 % (i.e., 24/27 animals) at 9 h and 66.7 % (i.e., 18/27 animals) at 18 h after CLP. Thus, HA significantly increased the 18-h survival rate of CLP rats (P < 0.05, vs. CLP group). In addition, no mortality was observed within 18 h in all SOP rats (survival rate = 100%, n = 12 in each group). Because of clot or kinking of arterial catheter, blood could not be withdrawn in some of rats in each group. Therefore, all subsequent data presented were on 10 animals in each group that survived the full 18 h of the experiment.
Systemic and microhemodynamic parameters
As results shown in Figure 1, A and B , the baseline values for MAP and heart rate were comparable in all groups. Cecal ligation and puncture led to a significantly substantial attenuation in MAP at 18 h (P < 0.01, vs. SOP group), whereas a significant and sustained increase in heart rate was observed from 3 h after CLP (P < 0.01, vs. SOP group). The treatment with HA significantly prevented the severe hypotension at 18 h after CLP (P < 0.01, vs. CLP group). However, the CLP-induced tachycardia was not attenuated in rats treated with HA. The SOP rats treated with saline or HA exhibited stable hemodynamic conditions during the experimental period, and there was no significant difference among groups.
Fig. 1: Changes in (A) MAP, (B) heart rate, (C) hematocrit concentration during the experimental period, and (D) hepatic blood flow at the end of experimental period in CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP) . Data are expressed as mean ± SEM. n = 10 in each group. **P < 0.01, *P < 0.05, all groups versus SOP; † P < 0.01, # P < 0.05, with versus without HA in CLP animals.
Baseline values of hematocrit were not significantly different among groups (Fig. 1 C). A time-dependent decrease in hematocrit concentration was observed in SOP animals treated with saline and HA, about 40% at 18 h after laparotomy. There was a significant increase in hematocrit concentration at 9 h after CLP (P < 0.01, vs. SOP group), whereas it descended to the level similar to the SOP group at 18 h after CLP. The increase in hematocrit concentration at 9 h after CLP was not changed by HA, but there was a lesser decrease at 18 h after CLP compared with the CLP group.
The microvascular blood flow was detectable in the liver of SOP and CLP rats (Fig. 1D ). A significant decrease in the level of blood flow was found at 18 h after CLP (P < 0.05, vs. SOP group). However, the treatment with HA rescued the decreasing hepatic blood flow at 18 h after CLP (P < 0.05, vs. CLP group), whereas HA had no effect on the change of hepatic blood flow in SOP rats.
Organ injury/dysfunction
Baseline values of plasma markers of liver injury/dysfunction were not significantly different among groups (Fig. 2 ). No significant changes in biochemical parameters were observed during the experimental period in SOP animals treated with saline or HA.
Fig. 2: Changes in (A) plasma ALT, (B) plasma AST, (C) plasma albumin, and (D) blood glucose levels in CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP) during the experimental period . Data are expressed as mean ± SEM. n = 10 in each group. **P < 0.01, *P < 0.05, all groups versus SOP; † P < 0.01, with versus without HA in CLP animals.
Hepatocellular injury was assessed by measurement of plasma levels of ALT and AST (Fig. 2 , A and B). Significant increases in plasma levels of ALT and AST were found at 9 h (P < 0.05) and 18 h (P < 0.01) after CLP compared with SOP group. The increases in plasma ALT and AST levels at 18 h after CLP were attenuated by HA (P < 0.01, vs. CLP group).
During the acute-phase response in sepsis, albumin synthesis and release by hepatocytes are greatly reduced, but this phenomenon may either be underestimated by the long half-life of this protein or be enhanced by associated events occurring during sepsis, such as hemodilution. Significant decreases in plasma levels of albumin were found at 9 and 18 h (P < 0.01, vs. SOP group; Fig. 2 C). The decrease in plasma albumin levels at 18 h after CLP was attenuated by HA (P < 0.01, vs. CLP group), yet the level was lower than that in SOP group.
In addition, the CLP surgery induced a biphasic changes in blood glucose, i.e., hyperglycemia at the early stage (3 h) and hypoglycemia at the late stage (18 h) (P < 0.01, vs. SOP group; Fig. 2D ). However, HA significantly ameliorated the hypoglycemia at 18 h after CLP (P < 0.01, vs. CLP group), yet the level was below baseline and SOP.
Renal injury was assessed by measurement of plasma levels of BUN and creatinine. Significant increases in plasma levels of BUN and creatinine were found at 18 h (P < 0.05) after CLP group (98.2 ± 5.6 and 0.29 ± 0.04 mg/dL, respectively) compared with SOP group (18.1 ± 1.3 and 0.2 ± 0 mg/dL, respectively). The increases in plasma BUN levels (52.1 ± 0.01 mg/dL) at 18 h after CLP were significantly attenuated by HA (P < 0.05, vs. CLP group), but not plasma creatinine levels (0.21 ± 0.01 mg/dL).
Plasma proinflammatory cytokine levels
The basal plasma levels of IL-1β and IL-6 were not significantly different between any of the experimental groups studied (Fig. 3 ). The CLP surgery led to significant increases in plasma IL-1β and IL-6 levels, reaching to a peak at 18 h (P < 0.01, vs. SOP group). The treatment of CLP rats with HA significantly inhibited the CLP-induced increases in plasma IL-1βand IL-6 levels at 18 h (P < 0.01, vs. CLP group). In the SOP group, no significant increases in plasma IL-1β and IL-6 levels were detectable during the experimental period. The treatment of SOP rats with HA alone had no significant effect on plasma level of IL-1β and IL-6.
Fig. 3: Changes in (A) plasma IL-1β and (B) plasma IL-6 levels in CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP) during the experimental period . Data are expressed as mean ± SEM. **P < 0.01, *P < 0.05, all groups versus SOP; † P < 0.01, with versus without HA in CLP animals.
Liver O2 − and plasma nitrite/nitrate levels
The basal production of O2 − was detectable in liver (Fig. 4A ) in SOP rats at the end of experiment. A significant increase in the liver O2 − level was observed in CLP rats (P < 0.01, vs. SOP group). However, the treatment of CLP rats with HA significantly inhibited the production of O2 − (P < 0.01, vs. CLP group), whereas HA itself had no effect on the change of liver O2 − level in SOP rats.
Fig. 4: A, Liver superoxide anion at the end of experimental period and (B) changes in plasma nitrite/nitrate levels during the experimental period in CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP). n = 10 in each group . **P < 0.01, all groups versus SOP; † P < 0.01, with versus without HA in CLP animals.
The basal plasma level of nitrite/nitrate was not significantly different among groups (Fig. 4B ). The CLP surgery led to a significant increase in plasma nitrite/nitrate level (P < 0.01, vs. SOP group), which reached a plateau at 9 h. The treatment of CLP rats with HA significantly inhibited the CLP-induced increase in plasma nitrite/nitrate level at 9 and 18 h (P < 0.01, vs. CLP group). In the SOP group, no significant increase in plasma nitrite/nitrate levels was detectable during the experimental period. The treatment of SOP rats with HA alone had no significant effect on plasma level of nitrite/nitrate.
Liver iNOS protein expression
The protein expression of iNOS protein was undetectable in liver homogenates obtained from all SOP rats (Fig. 5 ), whereas a significant induction of iNOS protein was observed in liver homogenates from the CLP rats (P < 0.01, vs. SOP group). The treatment of CLP rats with HA significantly reduced the expression of iNOS protein in the liver (P < 0.05, vs. CLP group).
Fig. 5: Expression of iNOS in livers from rats with sepsis induced by peritonitis at the end of experimental period . This figure depicts a typical display of iNOS protein expression (upper figure) and the statistical analysis of changes in iNOS protein expression (lower figure) in livers of CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP). Data are expressed as mean ± SEM, n = 3 in each group. **P < 0.01, *P < 0.05, all groups versus SOP; # P < 0.05, with versus without HA in CLP animals.
Histologic studies
Light microscopy showed no infiltration or sequestration of neutrophils in the liver in SOP rats (n = 6; Fig. 6 ), whereas more overt sequestration of neutrophils (2 [1-2], n = 6) and coagulative necrosis tissues of hepatic cords were found in the liver in CLP rats (Fig. 6 ). However, the neutrophil infiltrations (2 [1-2], n = 6) and liver necrosis were significantly reduced in CLP rats treated with HA (P < 0.05, vs. CLP group).
Fig. 6: Light microscopy showed liver sections of CLP or SOP rats that received 0.9% saline or 25% HA (3 mL/kg i.v. at 3 h after CLP or SOP) at the end of experimental period . Sections were stained with hematoxylin and eosin. N indicates necrosis. Each, original magnification ×400.
DISCUSSION
The polymicrobial sepsis-peritonitis model of CLP in the rat mimics many features of clinical peritonitis (19 17 20 2 − generation, and iNOS protein expression and hence leading to a lower mortality rate in rats with CLP-induced sepsis/septic shock.
The deteriorations in liver injury and dysfunction induced by a septic process usually occur after prolonged and severe compromised hepatic blood flow (21 22
Hepatic hypoperfused areas suffer from the directed effects of many inflammatory pathways triggered by endotoxin and sepsis, such as proinflammatory cytokines, oxygen deprivation, NO, activation of the coagulation factors and complement cascades, and other inflammatory mediators. Rapid and profound induction of inflammatory cytokines is seen in the liver and systemic circulation after endotoxin challenge, including TNF-α, IL-1β, IL-6, and IL-12 (23 24 25, 26 27 12 28
Because the liver is a major organ of endotoxin detoxification, an influx of neutrophils has been observed in the liver within 3 to 6 h after endotoxin administration (29 2 − generated by activated neutrophils. Moreover, activated neutrophils adhere to endothelial cells and induce endothelial cell injury at the site of inflammation. Treatment with superoxide dismutase and catalase significantly reduced the endotoxin-induced hepatic necrosis and mortality in Corynebacterium parvum -vaccinated rats, suggesting a direct involvement of O2 − in liver damage (30 10 31 2 − generation and plasma NO production, presumed partially through its free radical-scavenging effects. Hyperoncotic albumin also inhibited the neutrophil infiltration in the liver of CLP rats in the present study. It had been shown that ischemia-reperfusion injury is reduced by polynitroxylated albumin possibly through inhibition of neutrophil adhesion to endothelial cells (32
In addition to oxygen-derived radicals, the non-oxygen-derived radicals such as NO also mediate some of the cellular events and damage in the liver by inhibiting protein synthesis (33 2 − to form peroxynitrite (ONOO− ), a highly reactive oxidant species. ONOO− can deplete intracellular glutathione levels, inhibit mitochondrial superoxide dismutase, and oxidize mitochondrial proteins, leading to cascades that cause cellular apoptosis or necrosis in endotoxemia or sepsis (34 − (35 36
However, there are some limitations in our study. First, although the polymicrobial sepsis animal model reproduces well hemodynamic alterations of septic shock in human beings, the animals were initially healthy, and their response may be different from that in ill patients with compromised cardiorespiratory reserve. However, in this study, the medical intervention at 3 h after CLP that improves the clinical relevance may offer the early therapeutic applicability in septic animals with liver dysfunction; in particular, these animals were not sedated or pretreated. Second, different doses of HA, from 0.5 to 1.5 g/kg, have been used in high-risk neonates (37-39 40 14 15
Taking our findings together with the prevention of liver injury and the amelioration of hypoperfusion with small-volume resuscitation of HA, we suggest that 25% HA given at 3 h after CLP protects liver against injury caused by proinflammatory cytokines, NO and O2 − , which usually result from activation of neutrophils. Such an intriguing result could provide a wealth of information regarding the clinical application of HA therapy for critically ill patients and the relevant biological mechanisms in this population.
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