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Ann Thorac Surg 2006;81:896-901
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Lung Perfusion With Clarithromycin Ameliorates Lung Function After Cardiopulmonary Bypass

Xiangming Fan, MD * , Yinglong Liu, MD, Qiang Wang, MD, Cuntao Yu, MD, Bo Wei, MD, Yingmao Ruan, MD

Department of Surgery, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Accepted for publication September 15, 2005.

* Address correspondence to Dr Fan, Department of Surgery, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China (Email: fanxiangming{at}126.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Macrolides antibiotics may affect neutrophil functions that correlate with the inflammation induced by cardiopulmonary bypass. Our study observed the protective effect of clarithromycin on inflammatory lung injury after cardiopulmonary bypass.

METHODS: Twelve adult sheep were randomly divided into two groups. After cardiopulmonary bypass was established, the lung was perfused through the pulmonary artery with either dextran solution (30 mL/kg) in the control group (n = 6) or dextran solution added to clarithromycin (10 mg/kg) in the experimental group (n = 6). Bypass was withdrawn after 90 minutes. Pulmonary function was determined and inflammatory factors were analyzed. Apoptotic neutrophils in the lung were assayed and lung biopsies were also performed.

RESULTS: Pulmonary vascular resistance (102.2 ± 14.0 dyne.s.cm-5) was lower in the experimental group compared with the control group (202.6 ± 47.3 dyne.s.cm-5, p < 0.01) whereas the oxygen index was higher in the experimental group (p < 0.05). Plasma myeloperoxidase in the experimental group (0.015 ± 0.006 U/L) was lower than that in the control group (0.029 ± 0.007 U/L, p < 0.01). Plasma interlukin-8 (0.18 ± 0.04 ug/L) and tumor necrosis factor (1.00 ± 0.13 ug/L) in the experimental group were lower than in the control group (0.39 ± 0.09 ug/L, 1.55 ± 0.35 ug/L, p < 0.01). Histologic analyses showed intra-alveolar hemorrhage and neutrophil accumulation in the control group, whereas there were no significant changes in the experimental group. The apoptosis rate of accumulated neutrophils was significantly lower in the control group (p < 0.01).

CONCLUSIONS: Lung perfusion with hypothermic protective solution containing clarithromycin distinctly inhibits inflammatory responses caused by cardiopulmonary bypass and ameliorates lung function.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
After cardiopulmonary bypass (CPB), the contact of blood components with the artificial circuit surface and ischemia-reperfusion injury trigger a systemic inflammatory response. Neutrophils may be activated by complements and other chemotactic factors, such as interleukin-6, interleukin-8, and tumor necrosis factor. Oxygen free radicals and enzymes produced by the adherent neutrophils damage the endothelial and epithelial cells of the alveoli [1–3]. The neutrophil-mediated inflammation may be the main cause of lung injury after CPB [4, 5].

Circulating neutrophils have a short life span of 6 to 8 hours owing to programmed cell death, "apoptosis," which normally ensures that the effete cells are recognized and cleared by phagocytes and other cells without spilling their potentially toxic components [6]. Apoptotic neutrophils detained in the lung can be phagocytized by alveolar macrophages, and the tissues may be free from the damage of inflammation [7]. Clarithromycin is a 14-membered ring macrolide that is thought to affect the neutrophil functions and accelerate its apoptosis [8, 9]. Our study was to observe the anti-inflammatory effect of clarithromycin on ameliorating lung function after CPB.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
All animals received humane care in compliance with "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 83-23, revised 1985).

Operation and Management
Twelve sheep, weighing 37 ± 5.5 kg, were randomized into control group (n = 6) and experimental group (n = 6). They were anesthetized with pentobarbital sodium (25 mg/kg) and ventilated with a volume-cycled ventilator (Siemens 900C, Germany). Inspired oxygen concentration was 100%. After left anterolateral thoracotomy and heparinization (300 IU/kg), CPB was established with ascending aorta and right atrium cannulation. After CPB was established, the pulmonary artery was clamped and perfused with protective solution containing clarithromycin in the experimental group and protective solution solely in the control group through a cannula inserted in the pulmonary artery. The protective solutions were 4°C, and the volume of perfusion was 30 mL/kg with a perfusion pressure of 40 cmH2O. Cardiopulmonary bypass was weaned after 90 minutes, and the sheep was cared for during the next 24 hours.

The CPB circuit was composed of Sarns 7000 roller pumps, bubble oxygenator (XiJing Corp, XiAn, China) and standard arterial filter (XiJing Corp).

The pulmonary protective solution consisted of low molecular weight dextran in the control group and low molecular weight dextran with clarithromycin (10 mg/kg) in the experimental group.

Physiologic Measurements and Analysis of Blood Samples
A flow-directed thermodilution catheter (Biosensors International PTE, Singapore) that was connected to a multichannel physiologic recorder (Nihon Kohden, Shinjuku-ku, Tokyo, Japan) was inserted into the femoral vein and advanced into the main pulmonary artery. Hemodynamic measurements including mean arterial pressure, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), and thermodilution cardiac output (CO) were obtained before and 0, 3, 6, 12, 24 hours after CPB. Pulmonary function indices included oxygen index and pulmonary vascular resistance (PVR) according to the following formulas: oxygen index = PaO2 / FiO2; and PVR = 79.92 x (PAP – PCWP) / CO.

Intraoperative blood samples were obtained from the femoral artery for determination of myeloperoxidase and the cytokines interleukin-6, interleukin-8, tumor necrosis factor at 0, 3, 6, 12, 24 hours after CPB. Plasma myeloperoxidase was determined kinetically. Briefly, 150 uL plasma was incubated with 3 mL of assay reagent containing O-dianisidine dihydrochloride (0.167 g/L), hydrogen peroxide (0.0005%), and potassium phosphate buffer (50 mmol/L, pH 6.0). Product formation was linear for 2.5 minutes and measured spectrophotometrically at 460 nm. Myeloperoxidase activity was expressed as absorbance change per milliliter. Interleukin-6, interleukin-8, and tumor necrosis factor were measured in duplicate by using a commercial radioimmunoassay kit (Radio-immunity Institution of PLA General Hospital, Bingjing, China). These inflammation factors were corrected by hemodilution according to the formula: corrected concentration = measured concentration x packed red cell volume before CPB / packed red cell volume during CPB.

Twenty-four hours after CPB bronchoalveolar lavage was performed. Two aliquots of 25 mL normal saline were introduced into the right superior bronchus through an 18F suction catheter and aspirated back. The bronchoalveolar lavage fluid was centrifuged at 160g for 10 minutes at 4°C to sediment the cells. The supernatant were divided into aliquots, frozen and stored at -70°C with dipotassium ethylene diamine tetra acetic acid (1.8 mg/mL). The cytokines in the supernatant were detected. The cells in the bronchoalveolar lavage fluid were stained with hematoxylin and eosin. The in-situ end-labeling technique was used to detect neutrophils apoptosis in the bronchoalveolar lavage fluid. Lung biopsies were obtained 24 hours after CPB.

Statistical Analysis
Values were expressed as mean ± SE. Data at different time points were analyzed with variance analysis of repeated measures. All analyses were performed using SPSS software for Windows (SPSS, Chicago, Illinois), and differences were considered statistically significant at a probability level of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
There was no statistically significant difference between the two groups in peak airway pressure, oxygen index, PVR, myeloperoxidase, and cytokines before CPB.

Assessments of Lung Function
Oxygen index decreased significantly in the control group compared with in the experimental group; the differences were significant at 0 and 24 hours after CPB (70 ± 15 mm Hg and 123 ± 48 mm Hg versus 164 ± 46 and 188 ± 46 mm Hg, respectively, p < 0.05; Fig 1). Pulmonary vascular resistance increased dramatically and maintained a higher level after CPB in the control group compared with the experimental group. The differences between the two groups were significant at 0, 12, and 24 hours after CPB (Table 1).


Figure 1
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  		Fig 1. Oxygen index before and after cardiopulmonary bypass (post-CPB). *p < 0.05, **p < 0.01, control group (diamonds) versus experimental group (squares).

 

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  		Table 1. Pulmonary Vascular Resistance (dyne · s · cm–5) Before and After Cardiopulmonary Bypass (Post-CPB)
 
Analysis of Blood Samples and Bronchoalveolar Lavage Fluid
Plasma myeloperoxidase increased in both groups after CPB. It was higher in the control group, and the differences were significant at 12 and 24 hours after CPB (Table 2).


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  		Table 2. Plasma Myeloperoxidase (U/L), Interleukin-8 (ug/L), and Tumor Necrosis Factor (ug/L) Before and After Cardiopulmonary Bypass (Post-CPB)
 
Plasma interleukin-8 and tumor necrosis factor increased after CPB, and the concentrations in the control group were higher than in the experimental group. The differences of interleukin-8 between the two groups were significant at 0 and 24 hours (0.62 ± 0.16 and 0.39 ± 0.09 ug/L versus 0.34 ± 0.11 and 0.18 ± 0.04 ug/L, respectively, p < 0.01) and 3 hours after CPB (0.44 ± 0.16 ug/L versus 0.23 ± 0.04 ug/L, p < 0.05; Table 2) whereas the difference of tumor necrosis factor was significant at 12 and 24 hours after CPB (Table 2). Interleukin-6 also increased after CPB, and the concentration in the control group was higher than that in the experimental group; however, there was no significance (p < 0.05). Interleukin-6, interleukin-8, and tumor necrosis factor levels in bronchoalveolar lavage fluid were lower in the experimental group than in the control group, and the differences of interleukin-8 (0.49 ± 0.12 ug/L versus 0.29 ± 0.09 ug/L) and tumor necrosis factor (1.35 ± 0.25 ug/L versus 0.79 ± 0.25 ug/L) were significant (Fig 2).


Figure 2
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  		Fig 2. Interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF) levels in bronchoalveolar lavage fluid before and after cardiopulmonary bypass (post-CPB). *p < 0.01, control group (solid bars) versus experimental group (hatched bars).

 
Bronchoalveolar lavage inflammatory cells consist of neutrophils and macrophages in both groups. But most of the cells in the control group were neutrophils whereas in the experimental group, most the cells were macrophages (Fig 3A and B).


Figure 3
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  		Fig 3. Histologic appearance of the cells in bronchoalveolar lavage fluid in the control group (A) and experimental group (B). Most cells in the control group were neutrophils, whereas in the experimental group, most cells were macrophages. (Hematoxylin and eosin, original magnification x200.)

 
Apoptotic neutrophils were confirmed with yellow staining by in-situ end-labeling technique, and most of the nertrophils in the experimental group were apoptotic (73% ± 11% versus 29% ± 8%, p < 0.01; Fig 4A and B).


Figure 4
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  		Fig 4. The apoptosis of neutrophils in the control group (A) and experimental group (B). Most neutrophils in the experimental group were apoptotic compared with the control group. (Yellow staining by in-situ end-labeling technique, original magnification x200.)

 
Analysis of Tissue
The light microscopic analyses showed hyperemia and hemorrhages in the capillaries in the control group. Alveolar exudate was obvious, and neutrophils were seen in the capillary of the alveolar wall and the alveolar space (Fig 5A, B, and C).


Figure 5
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  		Fig 5. Histologic appearance of the control group showing capillary hyperemia and hemorrhage (A) with leukocytes accumulated (B), whereas in the experimental group lung parenchyma was normal (C). (Hematoxylin and eosin, original magnification x200.)

 
Transmission electron microscopy showed accumulation of erythrocyte and neutrophil in alveolus. Various degrees of swelling and vacuolation were seen in mitochondria and endoplasmic reticulum of alveolar epithelial cells. However, the lung biopsy of experimental group showed well-preserved alveolar structure with slightly alveolar exudate and few neutrophil accumulation in alveolus (Fig 6A, B, and C).


Figure 6
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  		Fig 6. Mitochondria and endoplasmic reticulum of alveolar epithelial cells showed various degrees of swelling and vacuolation in the control group (A), whereas in the experimental group the alveolar structure was well preserved with slight exudation (B), and apoptotic neutrophil could be seen in alveolus (C). (Electron microscope, original magnification x8,000.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Pulmonary dysfunction after CPB was described 40 years ago and continues to be the subject of a considerable amount of experimental and clinical research. Neutrophil-mediated inflammatory lung injury is thought to be closely correlated with pulmonary dysfunction after CPB [4, 5]. Neutrophils may be activated by complements and other chemotactic factors, such as interleukin-6, interleukin-8, and tumor necrosis factor. Neutrophils migrated to the distal airway become activated and further damage bronchoalveolar architecture by secreting oxygen free radicals and lysozomal enzymes [1–3].

Apoptotic neutrophils are recognized and phagocytosed by macrophages, and this process may limit the release of neutrophil contents from disintegrating cells that could cause tissue injury and amplify inflammation. Neutrophil apoptosis and phagocytosis by macrophages play an important role in the resolution of inflammation [7, 10, 11]. However, CPB inhibits the neutrophils apoptosis and prolongs neutrophil-mediated inflammation [12, 13]. So it is an ideal method to accelerate the resolution of inflammation by inducing the apoptosis of neutrophil [14]. Theoretically, it is difficult to suppress the impairment effect of the neutrophils without influencing its phagocytotic and bactericidal function. Macrolide is an ideal choice because of its unique effect [8, 9]. The 14-membered ring macrolide antibiotic clarithromycin may accelerate neutrophil apoptosis and enhance neutrophil phagocytosis and bactericidal function [8, 15, 16]. The macrolides exhibit favorite distribution properties and can penetrate and accumulate in a variety of tissues, especially the higher respiratory tissue, and reach high intracellular level in phagocytes such as neutrophils [8]. Clarithromycin is a macrolide that achieves a high tissue penetration; it has been employed in the treatment of upper respiratory tract and dermatologic infections.

There was no effective method to cope with lung injury directly, although many techniques have been tried to ameliorate CPB-induced injury. As enlightened by cardioplegia and lung storage in vitro, we designed the method of lung perfusion with hypothermic protective solution to relieve lung injury during CPB [17, 18]. Lung perfusion decreased pulmonary temperature, improved pulmonary ischemia, and avoided reperfusion injury. In the present study, we observed the effect of hypothermic protective solution containing clarithromycin on lung function after CPB.

The myeloperoxidase is an important lytic agent secreted by neutrophils, and it is the index of neutrophil activity. The plasma myeloperoxidase increased obviously after CPB [19], and myeloperoxidase level was lower in the experimental group than in the control group. This difference implied that clarithromycin inhibited the release of myeloperoxidase by affecting the function of neutrophils. Interleukin-6, interleukin-8, and tumor necrosis factor are potent proinflammatory chemoattractant cytokines. They can induce blood neutrophils migration through vascular endothelium and bronchial epithelium, and the increases of the cytokines are greater in alveolar than in plasma after CPB [20, 21]. In our study, concentrations of interleukin-6, interleukin-8, and tumor necrosis factor were lower in the experimental group than in the control group. Interleukin-6, interleukin-8, and tumor necrosis factor in the bronchoalveolar lavage were also detected, and the concentrations were also lower in the experimental group than in the control group. These results suggested that both systemic and pulmonary inflammatory response in the experimental group were significantly milder compared with the control group. Our experiment also found lower pulmonary vascular resistance, higher oxygen index, and milder pathologic changes in the experimental group. These results suggested that lung perfusion with hypothermic protective solution containing clarithromycin relieved lung injury and improved lung function after CPB.

Apoptosis is a form of cell death. Neutrophil apoptosis is an important mechanism to confine tissue impairment and accelerate the resolution of inflammation [8, 9]. In a previous study, we found that clarithromycin accelerates neutrophil apoptosis, and it might be relevant to the high expression of Fas. Large numbers of inflammatory mediators increase obviously after CPB, including interleukin-6, interleukin-8, and tumor necrosis factor, which are inhibitors of neutrophil apoptosis [22, 23]. Cytotoxic substances may be released, and lung injury may be the result because of the delay of neutrophil apoptosis. The apoptotic rate of accumulated neutrophils in the lung was lower in the control group, confirmed by the in-situ end-labeling technique. We presumed that the protective effect of hypothermic protective solution containing clarithromycin in CPB may be relevant to its apoptosis-inducing effect on accumulated neutrophils in the lung.

In conclusion, lung perfusion with hypothermic protective solution containing clarithromycin distinctly inhibits CPB-induced inflammatory responses and ameliorates lung function.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This project was supported by the National Natural Science Foundation of China. Doctor Liu is in charge of this project.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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