Published online before print September 30, 2002, doi: 10.1161/01.CIR.0000035651.72240.07
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(Circulation. 2002;106:2601.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Preoperative Glutamine Administration Induces Heat-Shock Protein 70 Expression and Attenuates Cardiopulmonary Bypass–Induced Inflammatory Response by Regulating Nitric Oxide Synthase Activity
From the Department of Surgery (Y.H., Y.S., H.M.), Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, Osaka; and the Second Department of Physiology (N.F., H.N.), Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Correspondence to Yoshitaka Hayashi, MD, PhD, Department of Surgery, Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, 2-2 Yamado-oka, Suita, Osaka 565-0871 Japan. E-mail hayashi{at}surg1.med.osaka-u.ac.jp
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Abstract |
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Background— Heat-shock protein 70 (HSP70) plays a major role in the pathophysiology of inflammation, and the induction of HSP70 before the onset of inflammation can reduce organ damage through a self-protective system. Glutamine is known to be an inducer of HSP70, and its preoperative administration seems useful in attenuating cardiopulmonary bypass (CPB)–induced inflammatory response.
Methods and Results— Adult male Sprague-Dawley rats (group G, received 100 mg/kg of glutamine via the right jugular vein 3 times per day for 1 week and just before the initiation of CPB; group C served as control) underwent CPB (60 minutes, 100 mL/kg per minute, 34°C) and were killed 3 hours after the termination of CPB. Group G showed significantly lower plasma concentrations of interleukin-6 and interleukin-8 after CPB termination. Myocardial and respiratory damages were significantly attenuated in group G, as evidenced by Langendorff perfusion, respiratory index, and neutrophil adherence. HSP70 expressions in the heart, lung, and liver were detected only in group G before CPB and were markedly stronger in group G 3 hours after CPB termination. Although plasma nitrate+nitrite concentrations were not significantly different between the groups, endothelial-constitutive nitric oxide synthase (NOS) activity was markedly preserved and inducible NOS activity was markedly attenuated in the tissues of group G.
Conclusions— These results suggest that preoperative glutamine administration induces HSP70 expression before CPB and attenuates CPB-induced inflammation by regulating NOS activity, which may be a prospective management for conferring tolerance to CPB-induced inflammatory response through a self-protective mechanism.
Key Words: cardiopulmonary bypass • inflammation • nitric oxide synthase • interleukins • proteins
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Introduction |
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Cardiopulmonary bypass (CPB) induces systemic inflammatory response characterized by abnormal production of chemotactic mediators such as proinflammatory cytokines.1–4 Although various kinds of antiinflammatory agents have been tried to attenuate CPB-induced inflammatory response,3,4 additional improvement is still required, especially in compromised patients. This is because the pathophysiology of CPB-induced inflammatory response is very complex,1,2 and the inflammatory response itself is considered one of the adaptive responses for self-protection.5 Building tolerance to perioperative damage during the unstressed condition may result in a more advanced method to attenuate CPB-induced inflammation, and exploiting a natural defense mechanism called stress response may be a potential approach to overcome this problem.
Heat-shock proteins (HSPs) are self-protective proteins that maintain cell homeostasis against various forms of stress as an adaptive response.6 These proteins are induced by a wide variety of stressors and have broad cytoprotective functions. The 70-kDa family of HSP (HSP70), in particular, plays a vital role in cellular protection and has been detected in various tissues subject to stress.7,8 HSP70 expression was demonstrated in cardiovascular surgery patients,9,10 and current experimental studies have demonstrated the efficacy of HSP70 induction before stress in reducing myocardial damage after ischemia-reperfusion.11,12 However, this novel approach through the self-protective system has not yet been applied to CPB-induced inflammatory response.
Various agents and gene-transfection techniques have been reported to induce HSP70 expression in the stressed or unstressed conditions13–18 as well as heat stress. For clinical applications, however, there are some problematic issues that require investigation, including too large amounts of dose, cytotoxicity, and induction efficiency. Glutamine, a nonessential amino acid, is thought to enhance cellular survival against a variety of stressful stimuli through HSP70 induction.19,20 Several clinical trials have demonstrated the efficacy of glutamine as a conditionally essential nutrient during serious injury or illness.21,22 Therefore, preoperative glutamine administration seems easily applied for clinical use in HSP70 induction.
CPB also enhances the production of nitric oxide (NO) in association with two isoforms of NO synthase (NOS) activation.23,24 CPB-induced mechanical stimulation of vascular wall activates endothelial-constitutive NOS (ecNOS) soon after the initiation of CPB.23 Even several hours after the termination of CPB, inducible NOS (iNOS) is still expressed in accordance with the continuance of inflammation.23,24 A link between HSP expression and NO production has been demonstrated,25–27 and thus, we performed this study to examine the hypothesis that preoperative glutamine administration can induce HSP70 expression before CPB and attenuate CPB-induced inflammatory response in association with NO production.
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Methods |
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Animal Care
Adult male Sprague-Dawley (SD) rats (Japan Animals, Co, Ltd, Toyonaka, Osaka, Japan) weighing 400 to 450 g were used in the present study. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the National Institutes of Health (NIH Publication No. 86-23, revised 1996).
Experimental Protocol
Forty rats were randomly divided into two groups according to the administration of glutamine before the initiation of CPB. Group G (n=20) received 100 mg/kg body weight of glutamine 3 times per day for 1 week and just before the initiation of CPB. Group C (n=20) served as control and received no glutamine.
Five rats from each group were killed for protein analysis before the initiation of CPB. The remaining 30 (15 rats from each group) underwent 60 minutes of CPB and were killed 3 hours after the termination of CPB. Ten rats from each group were used to evaluate cardiac performance and blood analysis. The remaining 10 (5 from each group) were used for protein analysis and neutrophil adherence.
Glutamine Administration
Glutamine (Ajinomoto) was prepared as a 3% solution dissolved in lactated Ringer’s (LR) solution immediately before use. An intravenous route via the right jugular vein was prepared for the administration of Glutamine solution (group G) or LR control (group C).
Surgical Procedure for Rat CPB
Experimental rat CPB was instituted with the use of a roller pump and a membrane oxygenator, according to the method we previously described (Figure 1).28 Anesthesia was introduced by intraperitoneal administration of sodium pentobarbital (50 mg/kg body weight), and respiration was maintained by lung ventilation via an 18-G tracheotomy tube. The bypass circuit was primed with the following solution without blood components: 12 mL plasma expander, 8 mL LR solution, 2 mL 7% sodium bicarbonate, 2 mL mannitol, 100 U heparin, and 1.5 mg Tobramycin. After systemic heparinization (300 U/kg body weight of heparin sulfate), siphon-dependent venous drainage was established with the use of two 16-G catheters, and oxygenated blood was returned using a 20-G catheter. Perfusion flow rate was maintained at 100 mL/kg per minute, and perfusate temperature was set at 34°C. Neither additional crystalloid solution nor blood component was infused throughout the experiment, and the CPB-remaining solution was infused gradually after the termination of CPB.
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Blood Analysis
Arterial blood (1.5 mL) was sampled at the following three times: (1) before the initiation of CPB; (2) at the termination of CPB; and (3) 3 hours after the termination of CPB. Plasma levels of proinflammatory cytokines (tumor necrosis factor-
[TNF-], interleukin [IL]-1ß, IL-6, and IL-8; as markers of the development of inflammation), nitrate+nitrite (NOx; as a marker of NO production), and nitrotyrosine (as an indicator of peroxynitrite formation) were measured.28 Respiratory index (RI) was calculated as a marker of lung damage.
Plasma levels of TNF-, IL-1ß, and IL-6 were measured by enzyme-linked immunosorbent assay, and the IL-8 level was measured by enzyme immunoassay. Plasma nitrate+nitrite was analyzed by an automated procedure based on the Griess reaction. Nitrotyrosine was measured as an index of nitration reaction of NO by a high-pressure liquid chromatography method with a C-18 reverse-phase column. Nitrotyrosine formation was expressed as the percentage ratio of nitrotyrosine to tyrosine (%NO2-Tyr). RI was calculated by arterial blood gas assay as follows: RI=alveolar-arterial oxygen tension gradient/arterial oxygen tension (AaDO2/PaO2).
Cardiac Function
Hearts were rapidly excised, and the coronary arteries were perfused with a modified Krebs-Henseleit buffer (in mmol/L, NaCl 120, KCl 4.5, NaHCO3 20, KH2PO4 1.2, MgCl2 1.2, CaCl2 2.5, and glucose 10; oxygenated with 95% O2 plus 5% CO2 to obtain pH 7.4 at 37°C) according to the Langendorff technique, at a perfusion pressure equal to 100 cm H2O. Each heart was housed in a controlled heart chamber that was maintained at 37°C. A thin-walled latex balloon-tipped catheter was inserted into the left ventricle through the left appendage to monitor left ventricular pressure. After 20 minutes of stabilization, heart rate (HR), left ventricular developed pressure (LVDP), maximal derivatives of left ventricular pressure (max dP/dt), and coronary flow rate (CF) were measured with the left ventricular end-diastolic pressure stabilized at 10 mm Hg.
Histological Analysis
Specimens of the heart, lung, and liver were immediately frozen in liquid nitrogen and stored at -80°C in preparation for immunohistological examination.
Western Immunoblot Analysis
After determination of protein concentration with the bicinchoninic acid method, 100 µg of protein extract in each sample was loaded onto a 10% SDS-PAGE system. The blots were transferred onto a PVDF membrane and then incubated in Tris-buffered saline/Tween20 (20 mmol/L Tris-HCl, pH 7.5, 150 mmol/L NaCl, 0.1% Tween20) containing 3% bovine serum albumin to block nonspecific absorption.
The inducible form of HSP70 (HSP72) expressions in the heart, lung, and liver tissues were analyzed to confirm HSP70 induction. The membrane was immunoreacted with a 1:1000 dilution of anti-HSP72 antibody (SPA-810; Stress Gen Biotechnologies Co, Victoria, Canada) and then incubated with a 1:7500 dilution of alkaline phosphatase–conjugated goat anti-mouse IgG antibody (Promega Co, Madison, Wis). NOS expressions were analyzed using the monoclonal mouse antiendothelial NOS antibody (Transduction Laboratories, N30020) at 1:2500 (vol/vol) dilution or the monoclonal anti-inducible NOS antibody (Transduction Laboratories, N39120) at 1:500 (vol/vol) dilution. Protein bands were visualized by use of the enhanced chemiluminescence substrate system (Amersham).
Neutrophil Adherence
Neutrophils in the myocardium and lung endothelium were selectively stained using a naphthol AS-D chloroacetate-esterase kit (Sigma Chemical, St Louis, Mo).28 The number of neutrophils was counted under light microscopy (magnification x100) in a blind manner; the cell count was performed in 10 fields in each of 10 individual sections. The number of neutrophils adhered into myocardium was expressed as cell number per section, and that into lung specimens was corrected by the number of pulmonary alveoli.
Statistical Analysis
All data are expressed as mean±SD. Time-dependent changes and comparisons between the groups were analyzed by two-way repeated-measures ANOVA and unpaired Student’s t test. All analysis was performed using the StatView v5.0 statistical package (Abacus Concepts Inc). P<0.05 was considered statistically significant.
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Results |
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There were no technical failures or operative deaths in the 40 consecutive rats used in the present study.
Blood Analysis
There were no significant differences in the hemoglobin level at any sampling point between the groups, and the degree of CPB-induced hemodilution was considered similar in the 2 groups.
Inflammatory Cytokines
In neither group did plasma levels of TNF- and IL-1ß reach minimum detectable levels at any sampling point during this experiment.
Before the initiation of CPB, plasma IL-6 level was below minimum detectable levels in both groups. After the termination of CPB, plasma IL-6 was detected and there were significant time-dependent changes in IL-6 in both groups (P<0.0001, ANOVA, treatment effect). Plasma IL-6 levels were significantly lower in group G than in group C both at the termination of CPB (47.3±9.8 versus 79.6±14.5 pg/mL, P<0.01) and 3 hours after the termination of CPB (74.6±18.3 versus 301.5±75.4 pg/mL, P<0.01) (Figure 2a).
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Plasma IL-8 levels before CPB were not significantly different between the groups (group G, 0.59±0.11, versus group C, 0.55±0.12 ng/mL). Similar to the pattern of IL-6, there were significant time-dependent changes in plasma IL-8 in both groups (P<0.0001, ANOVA, treatment effect), and there were significant differences in plasma IL-8 level between the groups both at CPB termination (2.24±0.61 versus 4.37±0.81 ng/mL, P<0.01) and 3 hours after CPB termination (5.14±1.06 versus 17.02±2.56 ng/mL, P<0.01) (Figure 2b).
Plasma Nitrate+Nitrite
There were time-dependent changes in plasma NOx levels in both groups (P<0.0001, ANOVA, treatment effect). There were no significant differences in plasma NOx level between the groups at any sampling point (before CPB: group G versus C, 25.5±3.3 versus 24.3±3.7 µmol/L; at CPB termination: group G versus C, 31.8±4.1 versus 32.6±4.0 µmol/L; 3 hours after CPB termination: group G versus C, 46.3±4.5 versus 51.2±5.1 µmol/L) (Figure 3a).
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Nitrotyrosine Formation
Nitrotyrosine was not detected in the supernatant fluid obtained before CPB in either group. There were time-dependent changes in %NO2-Tyr in both groups (P<0.0001, ANOVA, treatment effect). The %NO2-Tyr in group G (0.95±0.14%) was significantly lower than that in group C (1.46±0.23%, P<0.01) 3 hours after CPB termination, whereas there was no significant difference at CPB termination (group G versus C; 0.51±0.08% versus 0.57±0.09%) (Figure 3b).
Respiratory Index
RI before CPB did not differ significantly between the groups (group G versus C, 0.33±0.11 versus 0.34±0.08), and there were significant time-dependent changes in RI value in both groups (P<0.0001, ANOVA, treatment effect). Group G showed significantly lower RI values than did group C, both at CPB termination (0.59±0.11 versus 0.90±0.21, P<0.01) and 3 hours after CPB termination (0.70±0.10 versus 1.53±0.23, P<0.01).
Cardiac Function
Group G showed significantly higher LVDP (87±15 versus 63±8 mm Hg, P<0.01), max dP/dt (1391±205 versus 1025±134 mm Hg/s, P<0.01), and CF (16.5±1.3 versus 11.2±0.8 mL/min, P<0.01) than group C did (Figure 4), whereas there was no significant difference in HR (group G versus C; 313±29 versus 297±35 beats/min) between the groups.
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Histological Analysis
Western Immunoblot Analysis
HSP72
Before the initiation of CPB, HSP72 expression (a band with a molecular weight of 72 kDa) was identified only in group G. Three hours after the termination of 60 minutes of CPB, markedly stronger expressions of HSP72 were indicated in group G than in group C (Figure 5).
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ecNOS
In both groups, a band with a molecular weight of 140 kDa (corresponding to the expected size of ecNOS) was identified to the same degree before the initiation of CPB. Three hours after the termination of CPB, however, ecNOS expression in group G was markedly stronger than that in group C (Figure 6a).
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iNOS
A band with a specific molecular weight of 130 kDa (corresponding to the expected size of iNOS) was not identified in either group before CPB. Both groups showed iNOS expression 3 hours after CPB termination, and iNOS expression in group G was weaker than that in group C (Figure 6b).
Neutrophil Adherence
Cytohistochemical staining showed significant blockage of neutrophil adherence into the specimens of heart and lung in group G compared with group C. The amount of neutrophil adherence into the heart was significantly smaller in group G (1.3±0.5 counts/field) than in group C (5.6±1.2 counts/field, P<0.01). That into the lung was also significantly smaller in group G (group G versus C; 0.4±0.1 versus 4.8±0.5 counts/alveoli, P<0.01) (Figure 7).
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Discussion |
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Glutamine has been reported to enhance HSP70 expression in the stressed and unstressed conditions, although it has not been applied to the field of cardiovascular surgery. This is partially because most studies aimed to elucidate the role of glutamine in the digestive organs, especially in intestinal-epithelial cells.19,20 Another reason is that there is a difference in the efficiency of HSP induction according to organ, and induction efficiency in the heart and lung is thought to be poor compared with that in other organs.29 Oral administration or peripheral venous infusion was done in the previous studies, and thus, we decided on central venous infusion of glutamine to provide a higher degree of HSP induction. The regular administration for 1 week was based on assumed preoperative hospitalization and patient management. The present study demonstrates that a high degree of HSP induction is achieved without critical complications during experiments and indicates that glutamine is a nontoxic agent inducing HSP70 expression in vital organs such as heart, lung, and liver. Furthermore, the dose of glutamine we chose seems safe for human administration. Denno et al30 demonstrated that a continuous infusion of 0.57 g/kg per day of glutamine did not induce renal and liver dysfunction without producing significant elevations in ammonia and glutamate levels.
In the present study, pretreatment with glutamine attenuated CPB-induced inflammation, as evidenced by the reduction of abnormal increase in proinflammatory cytokines. IL-6 and IL-8 are produced in the early phase of CPB-induced inflammatory response,10 and the present study is considered to simulate a clinical circumstance of CPB. However, earlier indicators useful for predicting and evaluating the degree of subsequent inflammation may emphasize the results of the present study. Nannizzi-Alaimo et al31 have demonstrated that soluble CD40L level increases during the first hour of CPB and peaks at 2 hours after CPB, which would be interesting to elucidate the relationship between glutamine-mediated HSP and CPB-induced inflammatory response.
Although Chu et al32 have demonstrated that the manipulation of HSP expression attenuates the production of proinflammatory cytokines, the detail mechanism has not yet been demonstrated. Martin et al33 previously demonstrated that the liver plays a crucial role in deleting proinflammatory cytokines in the plasma, and these results, that HSP70 was highly expressed in liver tissue, may suggest the possible mechanism of HSP for attenuating a burst of proinflammatory cytokines. Enhanced HSP expression in liver tissue may be largely associated with the lower plasma concentrations of proinflammatory cytokines. The liver is also considered to be an organ in which HSP induction is difficult, and, thus, our glutamine administration technique seems to be of value.
NO is an inflammation-mediated vasoactive substance that plays both cytoprotective and cytotoxic roles in the development of inflammation.34 The ecNOS activity, despite being enhanced soon after the initiation of CPB, deteriorates as a result of the development of CPB-induced inflammation. Subsequent iNOS induction contributes to the attenuation of inflammatory response by compensating the reduced NO production from ecNOS.35 The efficacy of NO supplementation has been demonstrated,36,37 and we have demonstrated that selective iNOS inhibition aggregates CPB-induced inflammation.28 Therefore, enhanced NO production is considered an adaptive response and a key process for attenuating the development of this response. However, excessive NO from iNOS activation produces various kinds of cytotoxicity, including inhibition of cellular metabolism by direct reaction of heme and nonheme enzyme,38 nitration of tyrosine to form peroxynitrite,39 and induction of apoptosis.40
Endogenous NO regulation from ecNOS activation seems to minimize the adverse effects of iNOS-derived excessive NO production. Three hours after CPB termination, Western immunoblot analysis demonstrated that pretreatment with glutamine attenuated ecNOS deterioration and iNOS induction as well as enhanced HSP70 expression, whereas there were no significant differences in plasma NOx between the groups and %NO2-Tyr was significantly smaller in the glutamine-treated group. These results suggest that glutamine-mediated enhancement of HSP70 expression may increase NO production from ecNOS without providing adverse effects of iNOS activation. Although the detailed mechanism of HSP-mediated self-protection remains complex and should be investigated additionally, HSP70 may play a role in regulating NOS activity for the attenuation of CPB-induced inflammatory response.
Regarding clinical application of this glutamine-mediated HSP induction, the following 3 additional issues should be evaluated: the dose-dependent effect, the most simple and suitable method for administration, and the duration of HSP70 expression based on the above 2 factors. In particular, the duration of HSP70 expression should be of major concern in view of the pathophysiology of CPB-induced inflammatory response. The present study suggests that this glutamine administration method may be effective in enhancing HSP expression in the early phase of CPB-induced inflammatory response. However, CPB-induced inflammation has been shown to progress for several hours, even after CPB has been terminated. When this response is severe, it often causes multiple organ dysfunction at the late phase after open heart operations. Additional studies should be undertaken not only to induce larger amounts of HSP expression but also to prolong HSP expression longer after operations.
In conclusion, the regular glutamine administration for 1 week before CPB induces HSP70 expression before the onset of inflammation and enhances HSP70 expression after the termination of CPB. Pretreatment with glutamine attenuates CPB-induced inflammation by regulating NOS activity. These results suggest that preoperative glutamine administration may be a prospective management for conferring tolerance to CPB-induced inflammatory response before open heart operations and may be a novel therapeutic strategy to protect against this response by enhancing the body’s endogenous self-protective mechanism.
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Footnotes |
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Presented in part at the 74th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11–14, 2001, and published in abstract form (Circulation. 2001;104(suppl II):II-474).
Received June 26, 2002; revision received August 19, 2002; accepted August 19, 2002.
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