Eur J Cardiothorac Surg 2007;31:1037-1043. doi:10.1016/j.ejcts.2007.01.077
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
The preventative role of growth hormone on acute liver injury induced by cardiopulmonary bypass in a rat model
Yong An,
Ying-Bin Xiao*
Department of Cardiovascular Surgery, Cardiovascular Surgery Center of P.L.A, Xin-Qiao Hospital, Third Military Medical University, ChongQing, China
Received 17 November 2006;
received in revised form 22 January 2007;
accepted 31 January 2007.
* Corresponding author. Address: Department of Cardiovascular Surgery, Cardiovascular Surgery Center of P.L.A, Xin-Qiao Hospital, Third Military Medical University, ChongQing 400037, China. Tel.: +86 23 68755607; fax: +86 23 68755607. (Email: anyongsmcvs{at}163.com).
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Abstract
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Objective: Cardiopulmonary bypass (CPB)-induced acute liver injury is a life-threatening complication after cardiac surgery and is thought to be associated with inflammatory response and acute-phase response (APR). Recombinant human growth hormone (rhGH) can modulate the APR and inflammatory response. Here, we tested the protective effect of GH on CPB-induced liver injury in the rat. Methods: Adult male Sprague–Dawley rats (group G, received 2.5 mg/kg of rhGH intramuscularly at 8 a.m. every 24 h for 3 days and just before the initiation of CPB; group C served as control) underwent CPB (120 min, 120 ml/kg per minute, 34 °C) and were killed 3 h after the termination of CPB. Results: Administration of rhGH markedly increased serum insulin-like growth factor (IGF)-I and IGF-I-binding protein (IGFBP)-3 compared with group C. Group G showed significantly lower serum concentrations of alanine aminotransferase and total bilirubin after CPB termination. Those receiving rhGH demonstrated a significant increase in serum prealbumin and serum transferrin and a marked decrease in serum amyloid A and serum C-reactive protein compared with group C. rhGH significantly decreased serum tumor necrosis factor-
(TNF-) and interleukin-1ß (IL-1ß), whereas no changes were found for serum IL-6 and IL-10 compared with group C. rhGH significantly increased total liver protein content, hepatocyte proliferation, and decreased hepatocyte apoptosis versus group C. Conclusions: These results suggest that GH administration in rats seems to play a preventative role in acute liver injury associated with CPB via the decrease in acute-phase proteins, proinflammatory cytokines TNF- and IL-1ß, and hepatocyte apoptosis, which is associated with increase in constitutive hepatic proteins, total liver protein content, and hepatocyte proliferation.
Key Words: Growth hormone • Cardiopulmonary bypass • Liver injury • Acute-phase response • Cytokines • Inflammatory response • Rat • Disease model
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1. Introduction
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Cardiopulmonary bypass (CPB) is a severe stress, which can provoke a systemic inflammatory response syndrome [1]. The proinflammatory cytokines are potent inducers of the hepatic acute-phase protein (APP) synthesis. These excess inflammatory responses and prolonged acute-phase response (APR) injure various organs and contribute to morbidity and mortality after cardiac surgery with CPB. Liver is one of the vulnerable organs for the attack of proinflammatory cytokines. The incidence rate and mortality of acute liver dysfunction in patients undergoing CPB were reported to be 3% and 11.4%, respectively [2]. Furthermore, for patients with preoperative cirrhosis of liver, mortality of CPB surgery can attain 31% [3]. To protect vital organ from the harmful responses induced by CPB, various kinds of anti-inflammatory agents have been tried to attenuate CPB-induced inflammatory response and APR. However, additional improvement is still required, especially in compromised patients. Building tolerance to CPB-induced inflammatory response and APR during the unstressed condition may be a prospective strategy for organ protection.
The hepatic APR is an orchestrated cascade of events in response to tissue injury, infection, or inflammatory response. Growth hormone (GH) has been showed to enhance immune function and to diminish the hypermetabolic response after major surgery, trauma, sepsis, or thermal injury [4–7]. As animal and in vitro studies have shown, GH modulates the APR by increasing constitutive hepatic proteins, decreasing APPs, modulating cytokine expression, increasing insulin-like growth factor (IGF)-I concentrations, and playing a major role in liver regeneration after injury [8,9]. However, endotoxin and proinflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF-) induce a state of GH resistance and inhibit the anabolic GH-IGF-I axis [10]. Furthermore, the clinical benefits of GH therapy are controversial. However, the interaction between liver and recombinant human growth hormone (rhGH) after CPB has not been defined. In the current study, we tested the in vivo effect of GH using a rat CPB model.
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2. Materials and methods
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2.1 Animal care
Adult male Sprague–Dawley rats, weighing 480 ± 20 g (Animal Supplier Center of Third Military Medical University (TMMU), Chongqing, China), were housed in wire-bottomed cages in a temperature-controlled room with a 12-h light/dark cycle. Rats were acclimatized to the environment for 7 days. All animals received human care in compliance with European Convention on Animal Care. The study was reviewed and approved by the Animal Care and Use Committee of TMMU, Chongqing, China, and followed the National Research Council's guidelines.
2.2 Group classification
Thirty rats were randomly divided into two groups according to the administration of GH before the initiation of CPB. Group G (n
= 15) intramuscularly received 2.5 mg/kg body weight of recombinant human GH (Serono, Inc., Switzerland) at 8 a.m. every 24 h for 3 days and just before the initiation of CPB. Group C (n
= 15) served as control and only saline was added in the same way.
All rats underwent 120 min of CPB and were killed 3 h after the termination of CPB. Ten rats from each group were used for blood analysis. The remaining 10 (5 from each group) were used for histological examinations.
2.3 Surgical procedure for rat CPB
Rats were anesthetized by intraperitoneal administration of urethane (1 mg/kg) and placed in the supine position. During surgery, the rat was ventilated with a 14-gauge cannula (FiO2 1.0, frequency 65, tidal volume 10 ml/kg body weight) by the use of a rodent ventilator (Rodent respirator, DH-150, China). Ventilation was finely adjusted to keep an arterial carbon dioxide tension (PaCO2) of 35–40 mmHg. During CPB, additional urethane was inflated into the oxygenator in order to maintain anesthesia. The left femoral artery was cannulated by a 22-gauge heparinized catheter (BD Intima-2 integrated catheter, China) for continuous pressure measurement and to collect arterial blood gas analysis (Blood gas analyzer, GEM Premier 3000,USA). The homolateral femoral vein was cannulated with a 20-gauge catheter for liquid replacement. An 18-gauge catheter was inserted into the right jugular vein and advanced to the right atrium. This position resulted in well drainage. Subsequently, the left carotid artery was exposed and cannulated with a 22-gauge catheter placed into the aortic arch that served as the arterial perfusion line for the extracorporeal circuit. For anticoagulation, heparin (300 IU/kg) was applied: half of the dose was given directly via the left femoral catheter and the other half was given into the extracorporeal circuit.
The CPB circuit composed of a roller pump (Polystan A/S, Denmark), a hollow fiber oxgenator (surface area 0.075 m2, specially made by Xijing Medical Instrument, Inc., China), a poikilothermy water tank (Michigan, Sarns, USA), a venous reservoir (BD, 20 ml injection syringes, China), and sterile tubing with an inner diameter of 4 mm for the venous line and 1.6 mm for the arterial line. The high siphon level was 30 cm. The blood was drained from the right atrium via right jugular by gravity and siphon and further transferred by the roller pump to the hollow fiber oxgenator and back to the rat via the left carotid artery. Priming consisted of 8 ml plasma expander, 2 ml 7% sodium bicarbonate, 2 ml mannitol, 4 ml LR solution, and 1.5 mg tobramycin. Furthermore, the GH group rats received 10 mg/kg of rhGH intramuscularly 30 min before the establishment of CPB. CPB was stably performed at 120 ml/kg per min for 120 min and perfusate temperature was set at 34 °C. At the initiation of CPB, the flow rate was gradually adjusted to a level that could sustain the mean arterial pressure (MAP) near 80 mmHg; at this point, ventilation was terminated. During CPB, MAP was regulated at 60–80 mmHg. The hematocrit was about 25–30%. With an inspired oxygen fraction of 100%, 50-ml/min gas flows were sufficient to achieve adequate oxygenation and to maintain PaCO2 within 35–40 mmHg. After weaning from the circuit, the cardiac function was retained with heart beating and pulsation. Routinely, termination of CPB was aided by continuous administration of dobutamine (3 µg/kg per minute). The remaining priming solution was infused gradually after the termination of CPB.
2.4 Blood analysis
Arterial blood was sampled at the following three times: (1) before the initiation of CPB, (2) at the termination of CPB, and (3) 3 h after the termination of CPB.
2.4.1 Measurements
2.4.1.1 Liver function
Blood samples were analyzed for serum concentration of albumin, alanine aminotransferase (ALT), and total bilirubin (TB) by an automated biochemical analyzer (Beckman array 3000, USA).
2.4.1.2 Serum GH, GHBP, IGF-I, and IGFBP-3
To determine whether the rhGH was biologically active and caused a response, serum human and endogenous rat GH concentrations were determined using a human GH radioimmunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA) or a rat GH radioimmunoassay (Biosource Int., Camarillo, CA). Serum growth hormone-binding protein (GHBP), IGF-I, and insulin-like growth factor-binding protein (IGFBP)-3 were determined by radioimmunoassay (Biosource Int., Camarillo, CA).
2.4.1.3 Serum constitutive hepatic proteins and APPs
We measured serum constitutive hepatic proteins such as prealbumin and transferrin, type I serum APPs such as C-reactive protein (CRP) and 1-acid glycoprotein, and type II APPs such as heptoglobin and 1-antitrypsin by using a Behring nephelometer (Behring, Dearfield, IL). We determined type I serum APP amyloid A (SAA) by enzyme-linked immunosorbent assay (ELISA; Genzyme, Cambridge, MA).
2.4.1.4 Serum cytokines
We determined serum concentrations of TNF-, IL-1ß, IL-6, and IL-10 by using a rat-specific ELISA (Genzyme, Cambridge, MA).
2.5 Liver changes
All rats were killed 3 h after the termination of CPB. The entire liver was harvested, weighted, and sectioned. One section (500 mg) was fixed in 4% formalin for histological examinations, one section (500 mg) was used for wet/dry weight ratios, and one (5 g) was snap-frozen in liquid nitrogen for storage. Hepatic water content was determined by measuring wet/dry weight ratios (hepatic water content and wet/dry weight ratio were measured by drying a portion of the liver, at 55–60 °C, to a constant weight.). Liver protein concentration was determined by protein assay (Bio-Rad, Hercules, CA).
2.5.1 Proliferation
Liver cell proliferation was determined by immunohistochemical staining for proliferative cell nuclear antigen (PCNA). PCNA stains proliferate cells during the G1-M cycle. To determine proliferating cells, sections were deparaffinized, rehydrated, and treated with proteases and HCl to decrease background contamination. Nonspecific antigen-binding sites were bound by incubating sections with goat serum, after which the sections were incubated with PCNA–horseradish peroxidase conjugate (SC-56) at a 1:50 dilution overnight at 4 °C, and then washed with phosphate-buffered saline. Finally, the sections were treated with diaminobenzidine–hydrogen peroxidase for 3–6 min under microscopic control and counterstained with Mayer's hematoxylin.
PCNA-positive cells (stained dark brown) were counted on two sections from each animal. In each section, two masked observers selected four different sections for counting PCNA-positive cells. Proliferating cells were identified as those with a brown staining of the nucleus or cytoplasm. All hepatocytes within the field were counted, and proliferation was expressed as a percentage of proliferating cells per 100 hepatocytes. Values for all sections were averaged to calculate proliferation for the river of each animal.
2.5.2 Apoptosis
We used the terminal deoxyuridine nick end labeling (TUNEL) immunohistochemical method (ApopTag, Chemicon, Temecula, CA) for histological identification of apoptotic cells in the liver. Formalin-fixed tissues were processed and embedded in paraffin. Sections of 4 µm, obtained at 40- to 50-µm intervals, were deparaffinized, rehydrated in graded alcohol, and washed in deionized water. Protein was digested using proteinase K (20 µl/ml in phosphate-buffered saline) to decrease background contamination. The sections were then intubated with freshly prepared terminal deoxyribonucleotidyl transferase (TdT) enzyme at 37 °C for 2 h. After the enzyme incubation, the sliders were incubated with antidigoxigenin peroxidase at room temperature for 30 min. The sections were thoroughly washed and diaminobenzidine–hydrogen peroxidase was applied for color development for 3–6 min under microscopic control. Lastly, the sections were counterstained with Mayer's hematoxylin and mounted.
Two sections of each block of tissue were obtained at 40- to 50-µm intervals. In each section, one masked observer selected five fields in four different sections (
5500 cells) for counting TUNEL-positive cells. Apoptotic cells were identified as those with a brown staining of the nucleus, or as apoptotic bodies, which are fragments of apoptotic cells engulfed by neighboring epithelial cells.
All hepatocytes within the field were counted, and apoptosis was expressed as a percentage of apoptotic cells per 1000 hepatocytes. Values for all sections were averaged to calculate apoptosis for the liver of each animal.
2.6 Statistical analysis
Comparisons between groups were tested by unpaired t-test, followed by post hoc analysis with the Bonferroni correction. Comparison among groups was performed using ANOVA. Statistical analyses were performed with computerized statistical packages (SPSS 10.0 software, SPSS, Chicago, IL, USA).
A P-value of 0.05 was considered significant. All data are presented as mean ± SD.
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3. Results
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As for mean body weight, body temperature, hemoglobin value, and PO2, there were no significant differences among the groups before CPB. There were no technical failures or operative deaths in the animals used in this study. 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 two groups.
3.1 Liver function
There was significant liver injury at CPB termination and 3 h after CPB termination in both groups. Administration of rhGH decreased serum levels of ALT at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05). rhGH also decreased serum levels of TB 3 h after CPB termination compared with group C (P
< 0.05; Fig. 1
). No difference between groups could be shown for serum albumin levels.
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Fig. 1. Changes in serum levels of ALT (A) and TB (B) before and after CPB. Data are expressed as mean ± SD. Pre-CPB, before the initiation of CPB; CPB-off, at the termination of CPB; after 3 h, 3 h after CPB termination.
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3.2 Serum GH, GHBP, IGF-I, and IGFBP-3
Serum human GHBP levels were increased at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05). Endogenous rat GH levels were higher in group C than in group G (P
< 0.05). Administration of rhGH also increased serum levels of both IGF-I and IGFBP-3 at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05).
3.3 Serum constitutive hepatic proteins
All serum constitutive hepatic proteins dropped time-dependently below normal levels after CPB. rhGH significantly increased prealbumin and transferrin at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05; Fig. 2
).
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Fig. 2. Changes in serum levels of prealbumin (A) and transferring (B) before and after CPB. Data are expressed as mean ± SD. Pre-CPB, before the initiation of CPB; CPB-off, at the termination of CPB; after 3 h, 3 h after CPB termination. (*) P
< 0.05 vs group C.
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3.4 Serum APPs
All APPs determined in this study increased time-dependently above normal levels after CPB. Administration of rhGH decreased serum level of type I APP SAA and CRP significantly at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05; Fig. 3
). No difference between groups could be found in serum levels of type II APPs.
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Fig. 3. Changes in serum levels of CRP (A) and SAA (B) before and after CPB. Data are expressed as mean ± SD. Pre-CPB, before the initiation of CPB; CPB-off, at the termination of CPB; after 3 h, 3 h after CPB termination.
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3.5 Serum cytokines
All cytokines increased time-dependently after CPB. Administration of rhGH decreased serum level of TNF- and IL-1ß significantly at CPB termination and 3 h after CPB termination compared with group C (P
< 0.05; Fig. 4
). No difference between groups could be found in serum levels of IL-6 and IL-10.
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Fig. 4. Changes in serum levels of TNF- (A) and IL-1ß (B) before and after CPB. Data are expressed as mean ± SD. Pre-CPB, before the initiation of CPB; CPB-off, at the termination of CPB; after 3 h, 3 h after CPB termination.
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3.6 Liver changes
rhGH treatment significantly decreased the hepatic water assimilation at 3 h after CPB termination compared with group C (group G vs C: 0.66 ± 0.01 vs 0.71 ± 0.01, P
< 0.05). rhGH significantly increased hepatic protein concentration at 3 h after CPB termination compared with group C (group G vs C: 0.98 ± 0.05 vs 0.89 ± 0.02 mg/ml, P
< 0.05).
3.7 Proliferation
Hepatocyte proliferation increased in both groups at 3 h after CPB termination when compared with physiologic hepatocyte proliferation. Administration of rhGH increased mitogenic activity of hepatocytes 3 h after CPB termination compared with group C (group G vs C: 0.45 ± 0.06 vs 0.21 ± 0.08, P
< 0.05; Figs. 5 and 6
).
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Fig. 5. Proliferation rates of hepatocytes (proliferative cell nuclear antigen (PCNA) index) in a representative section in rats receiving rhGH 3 h after CPB. Hepatocytes that stained dark brown were identified as hepatocytes that underwent mitosis and were considered to be positive. Magnification x200. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
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Fig. 6. Proliferation rates of hepatocytes (PCNA index) in a representative section in rats receiving saline 3 h after CPB. Compared with Fig. 5, only a few hepatocytes were identified to undergo mitosis. Magnification x200.
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3.8 Apoptosis
Hepatocyte apoptosis increased time-dependently after CPB in both groups. rhGH decreased hepatocyte apoptosis 3 h after CPB termination compared with group C (group G vs C: 0.025 ± 0.001 vs 0.056 ± 0.002, P
< 0.05; Figs. 7 and 8
).
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Fig. 7. Apoptotic rates of hepatocytes (TUNEL index) in a representative section in rats receiving rhGH 3 h after CPB. Only a few hepatocytes were identified that underwent apoptosis (stained dark brown) and were considered to be positive. Magnification x200. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
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Fig. 8. Apoptotic rates of hepatocytes (TUNEL index) in a representative section in rats receiving saline 3 h after CPB. Compared with Fig. 7, more hepatocytes were identified to undergo apoptosis. Magnification x200.
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4. Discussion
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CPB-induced acute liver injury is a life-threatening complication after cardiac surgery and is thought to be associated with inflammatory response and APR. The present study uses a rat model to ascertain whether GH attenuates CPB-induced hepatic APR aroused by proinflammatory cytokines and thereby protects the liver.
The liver plays a critical role in the APR. The hepatic APR is initiated by the organism in response to injury, with the aim of restoring homeostasis [11]. However, because a prolonged and uncontrolled elevation of this response might be detrimental, a decrease would improve survival and clinical outcomes [12,13]. Mediators of the APR are cytokines, including the IL-1family (IL-1/ß and TNF-/ß) and the IL-6 family (IL-6, IL-11, ciliary neurotropic factor, and cardiotrophin-1) [11]. Synthesis and expression of these cytokines subsequently regulate the synthesis of APP [11]. The IL-1 family regulates the synthesis of type I APPs such as SAA, CRP, and 1-acid glycoprotein. The IL-6 family regulates the synthesis of type II APPs such as heptoglobin, fibrinogen, and 1-antitrypsin. In our experiment, although CPB-induced response increased proinflammatory responses as indicated by increases in both TNF- and IL-1ß, GH administration could attenuate the rise of them significantly. Decreases in serum TNF- and IL-1ß were associated with decreased type I APP SAA, CRP, and 1-acid glycoprotein. These findings are in agreement with published data from a rat study [9]. GH had no effect on IL-6-like cytokines and type II APPs.
The mechanism by which GH modulates the APR is not entirely defined; however, it has been demonstrated that GH binds to GH receptor (GHR) and leads to tyrosine phosphorylation of the CCAAT box/enhancer-binding proteins (C/EBP-), the AP-1 family of transcription factors, intracellular tyrosine kinases (JAKs), octamer-binding proteins, and signal transducers and activators of transcription (STATs) [7,9,14]. These signal transcription factors translocate to the nuclei where they can interact with specific DNA sequences to modulate the gene expression of c-fos/c-jun and nuclear factor (NF)-
B, which regulate the expression of the constitutive hepatic and APP [9,14]. Interestingly, cytokines regulate constitutive hepatic and APP expression through a similar cascade [11]. IL-1-like cytokines bind to their receptors, leading to an activation/phosphorylation, which activates cellular signals AP-1, NF-B, and C/EBP-ß [14,15]. The stimulation of these signals activates the transcription and translation of type I APP genes. Further, many type I APPs contain NF-B response elements in their promoter region but not the type II APPs [11]. NF-B controls the transcriptional regulation of many proinflammatory cytokines, including IL-1ß and TNF- [11,14]. Modulating NF-B activation may cause a decrease in IL-1-like cytokines and type I APPs. Given that GH decreases IL-1-like cytokines, it is unknown whether GH decreases type I APPs through a direct down-regulation or through modulation of IL-1-like cytokine expression that decreases these cellular signals and consecutively decreases type I APPs [9,11,16].
In contrast to APP, constitutive hepatic proteins are decreased during the APR, because of a reprioritization of the liver during the APR [11]. However, constitutive hepatic proteins fulfil important physiologic functions [17]. Their down-regulation has been described as potentially harmful, and syntheses of these proteins have been used as predictors for mortality, clinical markers for nutritional status and severity of stress, and indicators of improved recovery [6,17]. In the present study, we demonstrated that CPB decreased constitutive hepatic proteins. GH administration increased endogenous prealbumin, transferrin, and total protein concentrations. Similar to the APP, the mechanism by which GH increases the concentrations of endogenous constitutive hepatic proteins are unknown; however, GH might exert this effect through activation of C/EBP- [18]. C/EBP- is a transactivator of liver-specific genes such as albumin and transferrin, and its messenger RNA concentration decreases during trauma and stress and can be considered as a negative regulated acute-phase gene [11]. C/EBP- messenger RNA levels, which are decreased after trauma, were shown to increase with GH, indicating that a stimulation of -isoform may lead consecutively to a stimulation of constitutive hepatic proteins such as prealbumin and retinol-binding protein [19]. We suggest that this increase in constitutive hepatic proteins may be due to a decrease in production of APPs, which allows the liver at least in part to redirect its liver protein synthesis.
GH exerts its effect by means of IGF-I stimulation. The importance of such a regulatory mediator during the APR had been described. IGF-I activates JAK/STAT transcription factors during the APR, as well as C/EBP- receptors, and C/EBP- stimulates IGF-I expression [20]. IGF-I may activate the same transcription factors as GH, indicating that the IGF-I, JAK/STAT, and C/EBP- cascade may be a major axis in modulating the APR that can be activated through GH, IGF-I, or both substances [21]. We demonstrated in this study that serum IGF-I and IGFBP-3 were increased with exogenous GH administration, indicating that GH-IGF-I axis may play an important role during the APR in CPB.
Preservation of organ homeostasis depends on a balance between cell proliferation and cell death [22]. Cell death can occur by two distinctly different mechanisms: apoptosis and necrosis. Apoptosis, or programmed cell death, is a genetically determined energy-dependent process by which senescent or dysfunctional cells are removed without extrusion of the intracellular contents or subsequent inflammation [22]. This is in direct contrast to necrosis, another mode of cell death, which is a passive process initiated by direct injury to the cell. CPB has been shown to induce epithelial cell apoptosis with a concomitant loss in cellular mass and absorptive surface of the small bowel, and to induce apoptosis in myocardial cells with impairment in cardiac function [23]. In the present study, we have shown that CPB induces hepatocyte apoptosis. Alterations in the balance between apoptosis and proliferation may lead to changes in organ function, integrity, and homeostasis [22,23]. Thus, it may be beneficial after CPB for the organ function either to increase proliferation or decrease apoptosis. In the present study, we demonstrated that GH increased hepatocyte proliferation and liver protein synthesis, indicating that GH assuages the hypermetabolic response and diminishes the negative nitrogen balance. We further demonstrated that GH decreased hepatocyte apoptosis, which was found to be increased after CPB.
The mechanisms by which CPB induces programmed cell death in hepatocyte are not defined. Studies have suggested that, in general, hypoperfusion, ischemia–reperfusion, and increased proinflammatory cytokines such as IL-1/ß, TNF-, and IL-6 are associated to promote apoptosis [24]. In the present study, we did not examine the effect of GH on blood flow; however, we showed that GH decreased the proinflammatory cytokines IL-1ß and TNF-. This attenuation may be the reason why GH decreases hepatocyte apoptosis.
In conclusion, GH administration in rats seems to prevent acute liver injury associated with CPB via modulation of APR by affecting IGF-I and proinflammatory IL-1-like cytokine expression, which leads to decreased type I APPs, proinflammatory cytokine synthesis, and hepatocyte apoptosis and increased constitutive hepatic proteins, total liver protein content, and hepatocyte proliferation. This strategy should be prospectively examined in a randomized controlled study in patients undergoing a major cardiac surgery.
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Acknowledgments
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The authors thank Ping Zheng and Hong Chen for their technical support, and the reviewers for critically reading the manuscripts.
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Abstract
1. Introduction
