Protective effect of Xuebijing injection against acute lung injury induced by left ventricular ischemia/reperfusion in rabbits
- Authors:
- Published online on: April 20, 2016 https://doi.org/10.3892/etm.2016.3275
- Pages: 51-58
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Copyright: © Ji et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute myocardial infarction is a common medical emergency of the cardiovascular system. The clinical treatments for myocardial infarction mainly focus on interventional or thrombolytic therapy. Although interventional or thrombolytic therapy is able to clear the coronary artery and restore blood flow (1), it can also cause reperfusion injury (2). This means that blood reperfusion may occasionally further aggravate the damage (3), and can even cause respiratory dysfunction, with patients with severe cases succumbing to respiratory failure (4). Therefore, the development of drugs that effectively control or reduce ischemia/reperfusion (I/R)-induced lung injury is required. A previous study has found that an imbalance of inflammatory mediators is an important cause of myocardial I/R injury (5). Thus, redressing the balance of inflammatory mediators is an important target for reducing or preventing I/R injury.
Xuebijing (XBJ) is a traditional Chinese medicine preparation (6). In clinical settings, XBJ is combined with antibiotics to treat severe acute lung diseases, including acute lung injury (ALI) (7), sepsis (8) and multiple organ dysfunction syndrome (9). However, to the best of our knowledge, no previous studies have investigated the protective effects of XBJ injection against left ventricular I/R-induced ALI. Therefore, the present study established a rabbit model of left ventricular I/R-induced ALI in order to investigate the underlying pathogenic mechanisms and the protective role of XBJ on respiratory function. The following parameters were assessed: The partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2); the expression levels of tumor necrosis factor (TNF)-α in peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF); the lung wet/dry weight ratio (W/D); and the protein expression levels of intercellular adhesion molecule-1 (ICAM-1) and TNF-α in the rabbit lung tissue samples.
Materials and methods
Animals and grouping
A total of 120 healthy adult (6–7 months old) mixed-gender New Zealand rabbits weighing 200–250 g were obtained from the Experimental Animal Center of Zhengzhou University (Zhengzhou, China). Each rabbit was housed in an individual cage (at 20 ± 5°C) under a 12:12 h light and dark cycle for 1 week prior to experimentation. All rabbits had free access to water, and food was removed 8 h prior to the study. The rabbits were randomly divided into four groups (n=30/group), as follows: i) The normal control group (CG); ii) the ischemia group (IG); iii) the I/R group (I/RG); and iv) the I/R + XBJ treatment group (TG). In addition, each group was further divided into three subgroups (n=10/subgroup) as follows: i) 30 min pre-ischemia (T1); ii) 30 min post-ischemia (T2); and iii) 30 m in post-reperfusion (T3). For 12 h prior to the experiment, the rabbits were fasted but had ad libitum access to water. All experimental procedures were approved by the Ethics Committee of Xinxiang Medical University (Xinxiang, China). The present study was conducted in accordance with internationally recognized guidelines on animal welfare (10), as well as local and national regulations.
Reagents and instruments
The instruments included a Leica RM2235 microtome (Leica Microsystems GmbH, Wetzlar, Germany), a CR-21G High-Speed Refrigerated Centrifuge (Hitachi, Ltd., Tokyo, Japan), a DG5033A Enzyme-linked Immunosorbent Assay (ELISA) Analyzer (Shanghai Bogoo Biotechnology, Co., Ltd., Shanghai, China), a fully automated M248 Blood Gas Analyzer (Bayer China Ltd., Shanghai, China) and a BL-420 Biological Signal Collecting and Processing system (Chengdu TME Technology, Co., Ltd., Chengdu, China). The main reagents were as follows: XBJ (10 ml ampoules; Tianjin Chase Sun Pharmaceutical, Co., Ltd., Tianjin, China), 20% urethane (Shanghai Yunqiang Chemical, Co., Ltd., Shanghai, China), and ICAM-1 and TNF-α polyclonal antibodies (Beijing Biosynthesis Biotechnology Co., Ltd., Beijing, China). Surgical instruments and general laboratory supplies were provided by the Functional Laboratory of Xinxiang Medical University.
Surgical procedure
The rabbits underwent general anesthesia with 20% urethane (5 ml/kg) via the ear vein, followed by isolation and intubation of the trachea, right jugularis externa and left carotis communis. Following a thoracotomy, the left anterior descending coronary artery was separated and ligated, with the ST segment elevation arched upward, and with regional myocardial darkening serving as an effective indicator of ischemia. In the CG, the left anterior descending coronary artery was separated but not ligated, and the rabbits were observed for 4 h. In the IG, myocardial ischemia was established by making a slipknot using a 6–0 silk suture around the left anterior descending coronary artery for 1.5 h. In the I/RG, following ligation of the left anterior descending coronary artery for 30 min, the ligature was loosened and the blood supply was restored. The TG underwent the same procedures as the I/RG, and were also given XBJ (10 ml/kg) at two time points: 10 min prior to ischemia and immediately following reperfusion. Prior to the thoracotomy, needle electrodes were inserted into the limbs and chest, and connected to the BL-420 Biological Signal Collecting and Processing system. The electrocardiogram (ECG; paper speed, 50 mm/sec; gain, l mV=20 ram) and diaphragm discharge curve were monitored continuously. One end of a lead was connected to a hook positioned on the skin at the point of strongest respiratory movement, and the other end of the lead was connected to a pressure transducer chip connected to the BL-420 system for the recording of respiratory curves.
Samples
At the T1, T2 and T3 time points, 5-ml peripheral blood samples were collected from the left common carotid artery, and the PaO2 and PaCO2 were measured using the M248 Blood Gas Analyzer. Also, 2-ml venous blood samples were collected from the right external jugular vein for measurement of the level of TNF-α. Subsequently, all rabbits were sacrificed by aeroembolism and the lungs were harvested. BALF samples (5 ml) were collected using Y-type tracheal intubation with one inlet connected to a 50-ml syringe of air, and another connected a 10-ml syringe containing 10 ml 0.9% NaCl. Air and 0.9% NaCl were concurrently introduced into the lungs, and then the 10-ml syringe was pumped back and forth several times to collect the BALF. The lower lobe of the right lung was removed, fixed with paraformaldehyde solution (1 ml/100 g; Qingzhou Hengxing Chemical Co., Ltd., Qingzhou, China), embedded in paraffin (Dekang Medical Instrument Co., Ltd., Xinxiang, China) and cut into 5-µm sections using the Leica RM2235 microtome, prior to being fixed to glass slides coated with (3-aminopropyl)triethoxysilane (Dekang Medical Instrument Co., Ltd.).
ELISA
The level of TNF-α in the venous blood and BALF was measured by a double-antigen sandwich ELISA (EIA-1126; Beijing Zhongshan Golden Bridge Biological Technology, Co., Ltd.), according to the manufacturer's protocol. Briefly, each sample (sera; diluted with coating buffer) was applied in triplicate to 96-well plates pre-coated with anti-TNF-α antibody and incubated overnight at 4°C. Following this, the plates were washed three times with phosphate-buffered saline (PBS) and then incubated with biotinylated goat anti-rabbit IgG (1:20,000) for 2 h at 37°C. The plates were then incubated with 0.01% 3,3′,5,5′-tetramethylbenzidine (Beijing CellChip Biotechnology Co., Ltd., Beijing, China), after which 2 M H2SO4 (Nanjing Taiye Chemical Industry Co., Ltd., Nanjing, China) was added to terminate the reaction. The optical density was recorded at 450 nm using a DG5033A ELISA Analyzer. The experiments were performed in triplicate. The sensitivity and specificity of the ELISA were 99 and 92%, respectively.
Lung weight and water content
Lungs were weighed, and then dried in a vacuum drying oven (cat. no. DHG-9420; Shanghai Haixiang Equipment Factory, Shanghai, China) at 80°C for 48 h to obtain the dry weight. The lung wet weight/dry weight (W/D) ratios of left lung tissue samples were determined, and the water content of the lung tissue was calculated using the following formula: Water content (%) = (wet weight - dry weight)/wet weight × 100.
Immunohistochemistry
Lung tissue sections, fixed in formalin (Shanghai Fengshou Biotechnology Co., Ltd., Shanghai, China) and embedded in paraffin, were deparaffinized, routinely rehydrated using graded ethanol, peroxidase-quenched with 3% H2O2, blocked with 5% normal goat serum (Amyjet Scientific, Inc., Wuhan, China) and probed with rabbit anti-rabbit ICAM-1 antibody (final concentration:0.1%; bs-0608R) or rabbit anti-rabbit TNF-α antibody (final concentration:0.1%; bs-2081R) overnight at 4°C. The sections were then thoroughly washed with PBS for 5 min, repeated three times. Subsequently, the tissue sections were incubated with goat anti-rabbit IgG secondary antibody (bs-0295Gs; Beijing Biosynthesis Biotechnology Co., Ltd.) at room temperature for 1 h. The sections were thoroughly washed with PBS for 5 min, repeated three times. Following this, sections were incubated with horseradish peroxidase (HRP)-conjugated rabbit anti-goat antibody (bs-0294R-HRP; Beijing Biosynthesis Biotechnology Co., Ltd.) at 4°C for 30 min. Eventually, reaction products were visualized following diaminobenzidine (DAB) and hematoxylin (Shanghai Yantuo Biotechnology Co., Ltd., Shanghai, China) counterstaining.
The protein expression levels of ICAM-1 and TNF-α in the lung tissue samples of the rabbits at each of the T1, T2 and T3 time points were measured. These experiments were performed in triplicate. According to the results of a semi-quantitative method (11), 10 random fields were selected under a Nikon microscope (80i; Nikon Instruments Co., Ltd, Shanghai China), in which 100 cells were counted. The tissue sections were scored as follows: No staining, ‘-’; <25% positive cells, ‘+’; 25–75% positive cells, ‘++’; and >75% positive cells, ‘+++’.
Statistical analysis
Statistical analyses were conducted using SPSS software, version 11.0 (SPSS, Inc., Chicago, IL, USA). Data are presented as the mean ± standard deviation. The data were analyzed using an Independent Samples t-test and categorical data were analyzed using a χ2 test. P<0.05 was considered to indicate a statistically significant difference.
Results
Comparison of respiratory curves
Respiratory curves (Fig. 1) were collected and recorded using the BL-420 Biological Signal Collecting and Processing system. At the T1, T2 and T3 time points, the breathing of the rabbits in the CG was steady and the respiratory amplitude and duration did not significantly fluctuate. Conversely, the respiratory amplitude for the rabbits in the IG was shallow and the respiratory duration was short. In addition, respiratory fluctuations were observed between the three time points. In comparison with the IG, the respiratory amplitude for the rabbits in the I/RG was more shallow and the respiratory duration was shorter. The respiratory curves for the rabbits in the TG resembled those of the rabbits in the CG (Fig. 1).
Comparison of PaO2 and PaCO2
The PaO2 and PaCO2 were measured using the fully automated M248 Blood Gas Analyzer. The PaO2 and PaCO2 of rabbits in the TG were not significantly different from those in the CG at the T1, T2 and T3 time points (P>0.05). The PaO2 values of the rabbits in the IG and I/RG were significantly decreased compared with those in the CG, at the T2 and T3 time points (P<0.001), and particularly decreased at T3 in the I/RG. Furthermore, the PaCO2 values of the rabbits in the IG and I/RG were significantly increased compared with those in the CG, at the T2 and T3 time points (P<0.001; Fig. 2).
Comparison of W/D value and water content in the left lung tissue samples of the rabbits
At the T1, T2 and T3 time points, the W/D weight ratio and water content of the left lung tissue from the CG did not significantly differ (P>0.05). Conversely, those of the tissue from the IG and I/RG were significantly increased (P<0.001) compared with those in the CG, with the greatest increases being observed for the I/RG. The W/D weight ratio and water content of the left lung tissue from the TG were not significantly different from those in the CG at any of the three time points (P>0.05; Fig. 3).
General observation of the rabbit lungs at T3
At the T3 time point, the lungs of rabbits in the CG were light pink and small in size. In the IG, the lungs appeared dark red and small, with an uneven surface and visible hemorrhages. Similarly, congestion and pulmonary edema were apparent in the lungs of the I/RG, and the volume was larger, the margins of the lungs were blunt, the color was uneven and clear spot bleeding and bruising was observed in the lower lobe of the lungs. In addition, white foamy/bloody liquid was overflowing from the lung section. Conversely, the TG lungs exhibited only mild edema, appeared red in color and had a smooth surface.
Light microscopy observations of the rabbit lungs at T3
At the T3 time point, the alveolar structure of the lungs in the CG group was clear, the walls of the alveolae were thin and no inflammatory cells had infiltrated into the alveolar space and lung interstitium. In the IG, pulmonary vascular congestion, focal alveolar hemorrhages and small focal alveolar collapse/atelectasis were observed in some areas of the lung. In the I/RG, dilatation and congestion was observed in the pulmonary capillaries, the alveolar septum was thickened, a large number of leukocytes had infiltrated and aggregated and hemorrhage and exudation were detected in the alveolar cavity. In addition, atelectasis was observed in some alveolae. Conversely, in the TG, the alveolar structure was relatively complete and hemorrhage and exudation of the alveolar was markedly reduced, as compared with the I/RG lungs, although alveolar atrophy and infiltrated inflammatory cells were infrequently observed (Fig. 4).
Expression levels of TNF-α in the BALF and the peripheral blood
The expression levels of TNF-α in the BALF and peripheral blood from the four groups were detected by performing an ELISA. At the T1, T2 and T3 time points, there was no significant difference in the expression levels of TNF-α in the peripheral blood and BALF between the CG and TG (P>0.05). In the IG, the expression levels of TNF-α in the peripheral blood and BALF were increased at T2, and reached a maximum at T3 (P<0.001), these changes were more pronounced in the I/RG (P<0.001). At T2 and T3, the expression levels of TNF-α in the peripheral blood and BALF in the TG were significantly lower compared with those in the IG and I/RG (P<0.001; Fig. 5).
Protein expression of ICAM-1 and TNF-α in the rabbit lung tissue samples at T3
The immunoreactive product of ICAM-1 was brown and was observed in the membrane and cytoplasm. TNF-α formed dark brown-to-yellow granules that were observed in the cytoplasm. As shown Figs. 6 and 7, there was an evident increasing trend in the expression of ICAM-1 and TNF-α from CG and IG to I/RG at T3, and the levels of ICAM-1 and TNF-α in the TG were comparable to those in the CG and markedly lower than those in the IG and I/RG.
Comparison of the association between the protein expression levels of ICAM-1 and TNF-α in the rabbit lung tissue samples at T3
The association between the protein expression levels of ICAM-1 and TNF-α in the rabbit lung tissues samples at T3 was investigated. A positive correlation between the protein expression levels of ICAM-1 and TNF-α was observed (Table I).
 | Table I.Comparison of the association between the protein expression levels of ICAM-1 and TNF-α in the lung tissue samples of rabbits in the 4 groups at the T3 time point. |
Discussion
Due to the structural characteristics of the left anterior descending coronary artery, the blood supply of the heart is prone to ischemia (12–14), and the recovery of blood perfusion to the ischemic myocardium is an important therapeutic strategy that reduces the occurrence of ischemic injury. However, in some cases reperfusion may further aggravate damage or induce irreversible damage; this phenomenon is called reperfusion injury. As an important organ with roles in immunity and metabolism, the lung has a high probability of being affected by reperfusion injury and is prone to inflammation (15).
Previous studies have demonstrated that the activation of a large number of neutrophils occurs in the early stages of ischemia (16), and that these neutrophils enhance the process of reperfusion (17). In addition, activated neutrophils promote the release of large amounts of inflammatory cytokines, including TNF-α (18,19), interleukin (IL)-6 (20,21), IL-10 (22–24) and ICAM-1 (25), in order to expand the inflammatory response. ICAM-1 has a key role in neutrophil aggregation, activation and the release of inflammatory mediators (26–28). Under normal circumstances, the protein expression levels of ICAM-1 are negligible, and this prevents pathological damage to the body (29). However, during I/R and other pathological conditions, the expression of proinflammatory mediators is stimulated and the expression levels of ICAM-1 are increased significantly (30). This in turn promotes the adherence of neutrophils to endothelial cells and their migration across the endothelial barrier, resulting in inflammation and various pathological changes that characterize reperfusion injury (7).
XBJ is a traditional Chinese medicine preparation with anti-bacterial, anti-endotoxin and anti-inflammatory properties (31). XBJ is a herbal preparation consisting mainly of red peony root, chuanxiong, Salvia divinorum and Angelica sinensis. XBJ has a critical role in inhibiting the generation of free oxygen radicals and endotoxins, as well as the uncontrolled release of inflammatory mediators (32).
The present study established a rabbit model of left ventricular I/R-induced ALI, in order to investigate the protective effects of XBJ against lung reperfusion injury. The results of the present study demonstrated that, as compared with the CG and IG, the respiratory amplitude of rabbits in the I/RG was shallow, the respiratory frequency was increased, the PaO2 and PaCO2 were decreased and the lung volume was enlarged at the T3 time point, thus suggesting that ALI occurred in the rabbits of the I/RG. Conversely, for the rabbits in the TG, the PaO2 and PaCO2 increased, edema and hyperemia of the lung tissue was reduced and the W/D weight ratio was decreased, suggesting that XBJ was able to improve respiratory function. A quantitative analysis revealed that, as compared with that in the CG, the levels of TNF-α in the peripheral blood and BALF were significantly increased in the IG at T2, and reached a peak at T3. Similarly, the TNF-α levels were significantly increased in the I/RG at T2 and T3, as compared with the CG, and at T3, as compared with IG. Conversely, there was no significant difference between CG and TG at the T1, T2 and T3 time points.
A gross observation of the lung tissue indicated that lung tissue injury occurred in the IG, and was aggravated in the I/RG at T3. Conversely, lung tissue damage in the TG was markedly attenuated, as compared with that in the I/RG. Immunohistochemical analyses demonstrated that the expression levels of ICAM-1 and TNF-α exhibited an increasing trend from CG and IG to I/RG at T3, whereas the expression levels of ICAM-1 and TNF-α in the TG were markedly lower, as compared with the IG and I/RG. A correlation analysis demonstrated that the expression levels of ICAM-1 were positively correlated with the expression levels of TNF-α in the IG, I/RG and TG at T3. These results suggested that, during the pathogenesis of left ventricular I/R-induced ALI, a large number of neutrophils were activated, promoting the release of proinflammatory mediators, including TNF-α. The excessive release of TNF-α in turn induced the overexpression of ICAM-1, which led to the adhesion of neutrophils to endothelial cells, eventually leading to lung inflammatory injury. XBJ exhibited a protective effect in the rabbit lung tissue samples, inhibited the excessive release of early inflammatory cytokines, including TNF-α, and decreased the expression levels of ICAM-1.
In conclusion, the present study investigated the effect of XBJ on left ventricular I/R-induced ALI by performing a blood gas analysis and measuring the expression levels of ICAM-1 and TNF-α. The results demonstrated that, following treatment with XBJ, the release of the inflammatory mediators ICAM-1 and TNF-α was effectively inhibited, and the PaO2 was improved. Understanding the molecular mechanism underlying the anti-inflammatory effect of XBJ will provide a theoretical basis and experimental evidence for its clinical application.
Acknowledgements
The present study was supported by grants from the Foundation of Henan Educational Commission (grant no. 2011GGJS-127) and the Henan Science and Technology Bureau (grant no. 132300410160). The authors would like to thank Professor Zhibin Qian for providing the facilities to carry out the study.
Glossary
Abbreviations
Abbreviations:
|
ICAM-1 |
intercellular adhesion molecule-1 |
|
TNF-α |
tumor necrosis factor-α |
|
XBJ |
Xuebijing injection |
|
CG |
control group |
|
IG |
ischemia group |
|
I/RG |
ischemia/reperfusion group |
|
TG |
treatment group |
|
T1 |
30 min pre-ischemia |
|
T2 |
30 min post-ischemia |
|
T3 |
30 min post-reperfusion |
|
PaO2 |
partial pressure of oxygen |
|
PaCO2 |
partial pressure of carbon dioxide |
|
BALF |
bronchoalveolar lavage fluid |
|
ELISA |
enzyme-linked immunosorbent assay |
|
ECG |
electrocardiogram |
|
ALI |
acute lung injury |
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