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ABSTRACT |
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Although recent studies have shown that adhesion molecules on alveolar macrophages are important
in a variety of pulmonary diseases, there have been few studies on the phenotypic and functional changes of alveolar macrophages during cardiopulmonary bypass. To investigate the possible role of
alveolar macrophages in activating pulmonary immunity during cardiopulmonary bypass, we measured the expression of adhesion molecules on alveolar macrophages and peripheral blood monocytes in patients undergoing cardiopulmonary bypass. Antigens were stained with monoclonal antibodies against adhesion molecules, and the expression of antigens was quantified by flow cytometry
as the ratio of specific to nonspecific linear fluorescence. On alveolar macrophages obtained after the
release of aortic cross-clamp, macrophages as compared with alveolar macrophages obtained before
cardiopulmonary bypass, there was a significant enhancement of CD11a, CD11b, CD11c, and CD18.
In addition, alveolar macrophages, but not peripheral monocytes, produced higher levels of TNF-
and IL-8 when they were cultured in vitro. A higher expression of CD11 and CD18 on alveolar macrophages and enhanced production of cytokines after release of the aortic cross-clamp may contribute to immune activation in lung by macrophage-lymphocyte interaction.
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INTRODUCTION |
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Cardiopulmonary bypass (CPB) exposes blood to a wide
range of synthetic materials and triggers a whole body inflammatory reaction, which includes postoperative bleeding, infection, and systemic organ dysfunction, including acute respiratory distress syndrome (ARDS) (1, 2). It has been reported
that CPB activates neutrophils by activating complement and
that these activated neutrophils accumulate in the lung (3)
and increase vascular permeability and interstitial edema (5).
Therefore, neutrophils are thought to be the main cause of
lung injury during CPB. Although there have been many studies on cytokine release such as TNF (6, 7), IL-1
(8), IL-6
(9), IL-8 (10), and surface markers (11, 12) in peripheral blood
during and after CPB, little is known about changes of alveolar macrophages (AMs). The lung is a special organ that contains many AMs and is continuously exposed to organisms
and particles in inhaled air. Resting AMs have been reported
to have a poor capacity for antigen presentation and cytokine
release, and they have a suppressive effect on lymphocytes, so
that they protect the normal lung against lymphocyte activation and inflammation (13). However, under pathologic conditions such as ARDS (14) and idiopathic pulmonary fibrosis
(15), AMs have been reported to release numerous secretary
products and express several surface receptors (16). Melis and
coworkers (17) reported the increased expression of CD11a
and CD54 on AMs of patients with pulmonary sarcoidosis.
Hoogsteden and coworkers (18) reported an increased number of AMs expressing CD11/CD18 in smokers. Therefore we
hypothesized that AMs may play an important role in immune
cell activation and subsequent lung injury during CPB.
Because recent studies have shown that pathogenetically relevant changes in the expression and function of adhesion molecules of AMs are involved in a variety of pulmonary diseases, we focused on adhesion molecule expression by AMs and cytokine release in bronchoalveolar lavage fluid (BALF) to investigate the possible role of AMs in immune activation of lung associated with CPB. Here we report the evidence of activation on AMs recovered from patients who underwent open heart surgery with CPB.
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INTRODUCTION
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Patients
Six patients who underwent open heart surgery with CPB were studied. The study group consisted of three children and three adults with a mean age of 31.3 ± 28.7 yr. None of the patients in this study had a history of pulmonary hypertension, recent pneumonia, or asthma. One patient was a smoker and five were nonsmokers. The clinical features of the patients are given in Table 1. The study and lavage protocol were approved by the local review committee, and all of the patients gave their informed consent. As controls, five patients who underwent general thoracic surgery without CPB were also studied.
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Cardiopulmonary Bypass
Identical anesthesia and monitoring were used in each patient. All of the patients received methylprednisolone (20 mg/kg) before CPB. The extracorporeal circuit consisted of a roller pump, a right atrial two-stage cannula for venous drainage, membrane oxygenation, and 40-mm arterial line filter with arterial return to the ascending aorta. The circuit was primed as needed with Ringer's lactate. Heparin was infused to maintain an activated clotting time of more than 400 s during bypass. A flow rate of 2.4 L/m2/min was used to maintain a systemic perfusion pressure. All of the patients were cooled to 28 to 25° C. Myocardial protection was achieved by cold cardioplegia supplemented by ice-slush topical hypothermia. Upon discontinuation of the bypass, anticoagulation was reversed by protamine sulfate. CPB time ranged from 53 to 215 min, with a mean of 133 ± 56 min.
Bronchoalveolar Lavage
Bronchoalveolar lavage was performed at two points: (A) after heparin administration, before CPB, and (B) 5 min after the release of
aortic cross-clamp. BAL was performed in the middle lobe through an
endotracheal tube via a flexible bronchoscope using 200 ml of sterile
0.9% saline at 30° C in 50-ml aliquots for adults, and 100 ml in 25-ml
aliquots for children. The aspirate of the first aliquot was not used in
this study. The aspirates of all remaining aliquots were pooled before
use. The cells were separated from the fluid by centrifugation. Aliquots of BAL supernatant were recovered and stored 
80° C until cytokine measurement. In the control patients, BAL was performed just
after thoracotomy and before closure of thorax.
Preparation of Alveolar Cells
The lavage fluid was passed through gauze and centrifuged at 400 × g for 8 min at 4° C. After washing twice with phosphate-buffered saline (PBS), cells were suspended in RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum (FCS). Aliquots were then adjusted to 2 × 106 cells/ml and cultured for 2 h. Aliquots of cell suspension were placed on 60-mm plastic tissue culture dishes and incubated for 2 h at 37° C in 5% CO2. The adherent cells were > 98% macrophages and were used for further study.
Blood Samples
Blood samples for determination of cytokines and macrophages were
collected under sterile conditions. They were obtained at the same
time as BAL. Peripheral blood mononuclear cells were isolated by
centrifugation on Ficoll-Hypaque. The cells were washed twice with
PBS and then suspended at a concentration of 2 × 106 cells/ml in
RPMI 1640 supplemented with 10% FCS. Aliquots of the cell suspensions were placed on 60-mm plastic tissue culture dishes and incubated for 2 h at 37° C in 5% CO2. The adherent cells were > 98%
macrophages and were used for further study. The serum was stored
at 80° C for analysis of cytokines.
Monoclonal Antibodies
Fluorescein isothiocyanate (FITC)-conjugated anti-leukocyte-function-associated antigen-1 (anti-LFA-1) (CD11a), FITC-anti-P150,95 (CD11c), FITC-anti-LFA-1 (CD18), FITC-anti-ICAM-1 (CD54), and FITC-antitransferin receptor (CD71) were purchased from Serotec. Phycoerythrin (PE)-conjugated anti-C3bi receptor (CD11b) and
FITC-anti-HLe-1 (CD45) were purchased from Becton-Dickinson
(Mountain View, CA). Cells were adjusted to 1 × 106 cells/ml. Cells
were incubated with 10% normal human serum for 10 min to block
nonspecific Fc binding sites and then stained with 10 µl of each monoclonal antibody. After being washed with 0.01% sodium azide PBS,
the cells were passed through a nylon-mesh filter and analyzed with a
FACScan (Becton Dickinson). Log fluorescence intensity of 10,000 cells was displayed on a histogram in arbitrary units. From the median
channel number, the data were transformed to calculate the linear
median intensity of the entire AM population. To determine the specific fluorescence of the surface markers, the linear median intensity
emitted by bound primary monoclonal antibody was divided by linear
median intensity of the corresponding isotype control according to the
methods described by Wasserman and coworkers (19).
Preparation of Culture Supernatant Derived from Alveolar Macrophages and Peripheral Monocytes
PBMCs or AMs were isolated as described above. The cells were suspended at a concentration of 2 × 106 cells/ml in RPMI 1640 supplemented with 10% FCS and then incubated for 24 h at 37° C in 5%
CO2. After 24 h, cell-free supernatants were harvested and frozen at
80° C.
Cytokine Measurement
The levels of TNF, IL-6, and IL-8 were measured in the same AM
and PBMC supernatants with commercially available enzyme-linked immunosorbent assay (ELISA) kits (Endogen, Boston, MA). Results are expressed as the means of duplicate assays. All of these analyses were similar in method. The ELISA method used a murine monoclonal antibody specific for the particular cytokine to be analyzed on the microliter plate to create the solid phase.
Statistical Analyses
All values are expressed as means ± standard errors. The data comparing before with after CPB values were analyzed using the Mann-Whitney U test for nonparametric data. A p value of < 0.05 was considered significant. All analyses were carried out using StatView 4.11 software (Abacus Concepts Inc., Berkeley, CA) on an Apple Macintosh computer.
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Changes in Surface Antigen
To determine the different cell counts, we first prepared air-dried smears from BALF and stained these with May-Grunwald-Giemsa stain. The data on BAL fluid recovery, as well as the total number and the number of each different type of recovered BAL cells in patients who underwent CPB are shown in Table 2. There was no significant differences in these parameters between before and after release of the aortic cross-clamp. However, it is notable that neutrophils did not increase at this early point. To obtain macrophages for further experiments, we next cultured cells from BALF and peripheral blood with RPMI 1640 supplemented with 10% FCS. Cells were recovered (98% macrophage) and stained with monoclonal antibodies against adhesion molecules. A representative flow cytometric analysis of AMs (Patient 1) is shown in Figure 1. The scatterplot shows the complete AM population and reveals that lymphocyte contamination was less than 1%. All of the cells were CD45-positive, and there was no contamination of nonleukocyte cells, i.e., broncheal epithelial cells (data not shown). The results of individual cases as well as mean values of AM phenotyping are summarized in Figure 2. The expression of CD11a, CD11b, CD11c, and CD18 was increased in every case on AMs after aortic cross-clamp release, whereas there was no significant change in the expression of CD54 or CD71. However, this upregulation of adhesion molecules in AMs did not correlate with operative parameters such as CPB time and aortic cross-clamp time. All patients were extubated on the day of operation or the day after surgery, and no postoperative pulmonary complications were observed.
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Cytokine Levels in Serum and BAL Fluid
The analysis of cytokines produced by macrophages is important since they may play a major role in the immune response.
Some characteristics of these cytokines in serum from patients
undergoing CPB have been reported elsewhere (10). The
cytokines TNF, IL-6, and IL-8 were measured at two points.
These cytokines were chosen since it has been suggested that
these proinflamatory cytokines play an important role in various pathologic lung diseases and that AMs are a major source
of these cytokines. As shown in Figure 3, the levels of TNF,
IL-6 and IL-8 from BALF and serum before CPB and after release of the aortic cross-clamp were essentially the same (BALF:
TNF, 10.2 ± 3 versus 12.0 ± 3 pg/ml; IL-6, 40 ± 8 versus
44 ± 6 pg/ml; IL-8, 62 ± 7 versus 70 ± 5 pg/ml; serum: TNF,
12.5 ± 2 versus 14.2 ± 2 pg/ml; IL-6, 32.0 ± 5 versus 38.0 ± 4 pg/ml; IL-8, 58.0 ± 6 versus 60.0 ± 7 pg/ml). Because cytokine levels in BALF may be influenced by the dilution factor
because of altered alveolar permeability, these data need to be
standardized base on albumin or urea levels (20). However, in
our case, the level of albumin and urea did not change before
and after CPB.
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Cytokine Secretion by Blood Monocytes and Alveolar Macrophages in vitro
AMs and PBMCs were cultured at a concentration of 2 × 106/
ml without stimulation for 24 h, and cell-free supernatant was
collected. Cytokine secretion by blood monocytes is shown in
Figure 4. Even in the absence of stimulation, PBMCs from patients who underwent CPB produced TNF, IL-6, and IL-8.
However, there were no significant differences between before CPB and after release of the aortic cross-clamp (TNF;
210 ± 20 versus 240 ± 18 pg/ml; IL-6; 178 ± 20 versus 192 ± 15 pg/ml; IL-8; 310 ± 50 versus 276 ± 19 pg/ml).
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In sharp contrast, AMs produced significantly more TNF
(720 ± 40 versus 220 ± 30 pg/ml; p < 0.01) and IL-8 (712 ± 30 versus 392 ± 14 pg/ml; p < 0.01) after release of the aortic
cross-clamp than before CPB. There was no difference in IL-6
production by AMs at these two points (400 ± 24 versus 482 ± 45 pg/ml).
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DISCUSSION |
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We have demonstrated that the expression of CD11a, CD11b, CD11c, and CD18 on AMs is upregulated after release of the aortic cross-clamp in patients who underwent CPB. Although surface marker analysis has been performed on PBMs obtained from patients undergoing CPB (11, 12), flow cytometry studies of AMs are quite limited because macrophages have high background levels of autofluorescence (21). To overcome the problem of autofluorescence, we used two techniques. First, reduction of nonspecific background staining by blocking FcIgG receptors with human immunoglobulin (22). Second, data were expressed as a ratio of specific to nonspecific linear fluorescence (as described in METHODS). Even after blocking FcIgG receptors, there is a symmetric shift in the fluorescence of the entire cell population in most cases. The flow data, expressed as the ratio of specific to nonspecific linear fluorescence, estimate the average antigen density. To our knowledge, this is the first study to analyze the expression of surface antigen on AMs in patients undergoing CPB by flow cytometry. Because adhesion molecules on AMs seem to reflect the status of activation of these cells and to serve as a trigger of inflammatory events, we focused on these adhesion molecules in this study. Our observations are consistent with previous studies that have shown changes in the expression and function of adhesion molecules in various pulmonary diseases (17, 18, 23). Marked increased in the expression of CD11/CD18 and ICAM-1 have also been reported in both allergic reactions in the respiratory tract (24) and acute and chronic lung injury (25). Upregulation of these molecules may stimulate the trapping of other cells in the lung and tighten cell adhesion, which triggers cell activation. These molecules also mediate signals for differentiation and activation of lymphocytes and neutrophils, which in turn release cytokines and trigger the cytokine network. Therefore, AMs may contribute to the immunologic activation in the lung caused by CPB.
There may be several mechanisms regarding upregulation of adhesion molecules in alveolar macrophages. First, cardiopulmonary bypass directly activates macrophages by activating complement as well as neutrophils. Second, reperfusion caused after release of the aortic cross-clamp may affect alveolar macrophages. Horgan and coworkers (26, 27) reported that adhesion molecules on AMs were upregulated after lung reperfusion in a rabbit model and that antibodies against CD18 and ICAM-1 could prevent reperfusion injury. Therefore, reestablishing blood flow to ischemic lung may enhance adhesion molecules on AMs locally as well as those of vascular endothelium. Third, secondary effects of CPB such as hemodilution and rewarming from hypothermia may be involved. It is likely that a combination of the above factors leads to upregulations of AMs during CPB. Because AMs obtained from patients who underwent general thoracic surgery without CPB did not show any changes in adhesion molecules, we concluded that upregulation of adhesion molecules were specific to CPB.
Inflammatory cytokines are thought to be important modulators of lung injury. Among several cytokines, TNF, IL-6,
and IL-8 have been reported to increase in plasma and BALF
supernatants of patients with various lung diseases, including
ARDS. TNF is a potent cytokine released early in inflammation and trigger recruitment of inflammatory cells by inducing
expression of adhesion molecules (28). IL-8 belongs to a superfamily of neutrophil-attracting and activating peptides, and
it is related to neutrophil sequestration in the lungs (29). Donnelly (30) reported that among several cytokines, IL-8 concentrations in BALF are highest in patients destined to develop
ARDS. In the cytokine study, we found no changes in cytokine
levels between before CPB and after release of the aortic
cross-clamp in either serum or BALF. However, AMs produced greater amounts of TNF and IL-8 when macrophages
were cultured without stimulation in vitro. This selective enhancement of cytokines has been observed by several investigators. Hallsworth and coworkers (31) reported the enhanced
production of GM-CSF, TNF, IL-1, and IL-8 by AMs in
asthmatic patients. Magnan and coworkers (32) reported the
enhanced production of IL-6 in lung transplant recipients. The
reason for the discrepancy in TNF and IL-6 in our culture study is not clear. TNF and IL-6 could be differently regulated depending on the trigger of lung inflammation. Our data
suggest that macrophages recovered during CPB may already
have been primed in vivo and have the potential for enhanced
cytokine production.
Although upregulation of adhesion molecules on AMs did not accompany lung dysfunction clinically, alveolar macrophages may contribute, at least in part, to lung damage in patients in critical condition. Further studies are necessary to confirm this preliminary report. In conclusion, we reported some evidence of AMs activation during CPB.
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Footnotes |
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Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.
Correspondence and requests for reprints should be addressed to Masanori Tsuchida, M.D., Department of Thoracic and Cardiovascular Surgery, Niigata University School of Medicine, 1-757 Asahimachi Niigata, 951 Japan.
(Received in original form November 14, 1996 and in revised form May 23, 1997).
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References |
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