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Ann Thorac Surg 2002;74:363-370
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Proinflammatory and antiinflammatory cytokines after cardiac operation: different cellular sources at different times

Axel Franke, MD*a, Wolfgang Lante, MDb, Volker Fackeldey, MDa, Horst Peter Becker, MDa, Christian Thode, MDc, Wolf Dieter Kuhlmann, MDc, Andreas Markewitz, MDb

a Department of Surgery Koblenz, Germany
b Department of Cardiovascular Surgery, Central Military Hospital, Koblenz, Germany
c Department of Immunology, Central Institute of the Armed Medical Forces, Koblenz, Germany

Accepted for publication April 2, 2002.

* Address reprint requests to Dr Franke, Department of General Surgery, Central Military Hospital, Rübenacher Str 170, D 56072 Koblenz, Germany
e-mail: dr.axel.franke{at}t-online.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Cardiac operation produces substantial alterations within the immune system, which possibly predispose postoperative complications. However, the interplay between proinflammatory and antiinflammatory reactions and the cells involved in this process are not completely clear. Therefore, we investigated serum levels, as well as synthesis patterns, of proinflammatory and antiinflammatory cytokines.

Methods. Serum levels and production of interleukin (IL) IL-5, IL-6, IL-10, tumor necrosis factor-{alpha}, and interferon-{gamma}, using a mixed cell culture, (ie, monocytes, macrophages, and lymphocytes), as well as a purified lymphocyte culture were measured preoperatively (day 0), on postoperative day 1, on postoperative day 3, and on postoperative day 5 in 25 patients undergoing cardiac operations and were compared with 10 healthy volunteers.

Results. Serum level and mixed cell culture, production of IL-6, tumor necrosis factor-{alpha}, and IL-10 increased on postoperative day 1, but decreased in lymphocyte culture. Base line values were reached on postoperative day 5. Interferon-{gamma} serum levels remained unchanged, whereas IL-5 serum levels increased on postoperative days 3 and 5. Cell culture synthesis showed a significant suppression for both mediators in both cell cultures, which returned to baseline on postoperative day 3 in mixed cell culture. Interferon-{gamma} production by lymphocytes was suppressed until postoperative day 5, whereas IL-5 returned to preoperative values on postoperative day 5.

Conclusions. Cardiac operation induces a biphasic immune response. The first phase (postoperative day 1) appears to represent the proinflammatory and antiinflammatory reaction of the innate immune system returning to base line on postoperative day 3. The second phase (postoperative day 5) may represent the response of the adaptive immune system and is characterized by an antiinflammatory type of reaction. This may explain why the systemic inflammatory response occurs immediately after cardiac operation, whereas infections occur later.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Many studies have been published to elucidate the immune response after cardiac operations. They created some kind of understanding of what happens to and by the immune system in our patients. In vitro results indicate that cardiac operations with the combination of local surgical trauma, endotoxemia, reperfusion injury of the heart and lungs, and the contact of blood with the artificial surfaces of the cardiopulmonary bypass circuit have a primarily nonspecific proinflammatory response as well as an antiinflammatory response in which the cellular source has not been completely delineated.

Clinically, patients show two to three of the clinical symptoms indicating a whole body inflammation called systemic inflammatory response syndrome (SIRS) [1–5]. Besides the apparent and somewhat surprising lack of clinical consequences, we know only little about the interplay between the proinflammatory and antiinflammatory reactions and even less about the cells involved in this process. We know even less why some patients experience problems apparently associated with an overwhelming inflammation, whereas others have infections and sepsis develop.

Recent studies have focused on the kinetics and synthesis of so-called proinflammatory cytokines, such as interleukin (IL) IL-6, IL-8, tumor necrosis factor (TNF)-{alpha}, and IL-1ß, in the early postoperative period, which are considered to transmit the immune reaction from a local to a systemic level [1, 6–8]. This process is paralleled and is sometimes preceded by an increase in synthesis and expression of cytokines, known to have more antiinflammatory properties, such as TGFß, IL-10, IL-4, and IL-5 [9–13]. The elevation of these values may be the result of a physiologic reaction within the network of innate and adaptive immunity, but, as well, they could be the first step toward an immunoparalysis resulting in a hyper-susceptibility to infectious complications [14–17].

In fact, under stressful conditions (cardiac operations, surgical trauma, burn injury) a shift of T helper cell (TH) subpopulations toward an antiinflammatory (type 2 T helper cell [TH2]) mediated humoral response has been reported, whereas the proinflammatory (type 1 T helper cell [TH1]) mediated cellular immune response has been found to be depressed [17–20]. However, infectious complications rarely occur in the immediate postoperative period but rather at a later point in time, for which there is a lack of data regarding proinflammatory and antiinflammatory mediators in the literature.

Therefore, it was the aim of this study to investigate if there were differences in serum levels and cell culture synthesis of several proinflammatory and antiinflammtory cytokines to elucidate the cellular source of the mediators. In addition, we wanted to know if, and how, the type of cell culture influences synthesis patterns. For this purpose cytokine production of two different cell cultures (ie, a mixed cell culture consisting of monocytes, macrophages, and lymphocytes [PBMC], as well as a purified monocyte and macrophages depleted, lymphocyte cell culture) were assessed after unspecific, mitogenic in vitro stimulation up to postoperative day 5.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Patients
After approval by the Ethics Committee of the Medical Faculty of the University of Mainz, 25 male patients scheduled for elective CABG operation without known immune, renal or central nervous system dysfunction, as well as congestive heart failure, exogenous hormone therapy, malnutrition, diabetes, malignancy, infection, or inflammation were enrolled in this study. Clinical characteristics of the patients are given in Table 1.


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  		Table 1. Clinical Data of the Patients

 
Clinical management
Cardiopulmonary bypass technique and perioperative management were identical to those described previously [20]. Induction of anesthesia was achieved by administering etomidate (200 to 300 µg/kg) and fentanyl (20 to 30 µg/kg). After endotracheal intubation and relaxation using pancuronium (100 to 200 µg/kg), anesthesia was maintained with fentanyl, midazolam, and isoflurane (0.4% to 1.5%).

Cardiopulmonary bypass was performed with nonpulsatile roller pumps and membrane oxygenators (Affinity, Avecor, Bellshill, Scotland). The pump was primed with a standard electrolyte solution containing 5,000 IU heparin, 1,000 mL Ringer’s lactate, 500 mL NaCl 0.9%, 500 mL Biseko (Biotest, Dreieich, Germany) und 250 mL Osmofundin 15% (Braun Melsungen, Melsungen, Germany). Just before vascular cannulation, heparin (300 IU/kg) was administered. After institution of cardiopulmonary bypass (flow rate, 2.4 to 3 L/m2/min), the aorta was cross-clamped and cold crystalloid cardioplegic solution (St. Thomas’ [Pharmacy of Central Military Hospital, Koblenz, Germany] or Bretschneider’s [Custodial®, Dr Franz Köhler Chemie, Alsbach-Haehnlein, Germany] solution) was applied. After the end of the cardiopulmonary bypass protamine was infused, all patients received 2,000,000 IU of aprotinin before the onset and 1,000,000 IU at the end of cardiopulmonary bypass to protect thrombocyte function. Cefazolin (3x 1 g) Elzogram®, Lily, Bad Homburg, Germany) was given for perioperative antibiotic prophylaxis.

Measurements
Serum levels of IL-6, TNF-{alpha}, and interferon (IFN)-{gamma} were measured for assessment of the entire proinflammatory, nonspecific, and specific immune response. Serum levels of IL-5 and IL-10 were used as parameters of nonspecific and specific antiinflammation. Cytokine synthesis patterns of IL-6 and TNF-{alpha}, by the PBMC cell culture, were considered to indicate primarily the innate inflammatory response, whereas IFN-{gamma} and IL-5 production of the purified lymphocyte culture were considered to indicate T-cell derived proinflammatory and antiinflammtory immune response. The cellular source of the antiinflammatory mediator (IL-10) was to be delineated by this study.

Cell cultures
Blood samples were taken preoperatively (day 0) and on postoperative days 1, 3, and 5 at 8:00 AM. All patients included in this study underwent cardiac operation beginning at 8:30 AM to diminish a possible time-dependent variation of cytokine synthesis.

For leukocyte studies, 30 mL of peripheral blood was obtained in sterile heparinized tubes containing a standard Ficoll-Hypaque density gradient (CPT-Tubes, Becton Dickinson, Heidelberg, Germany). Tubes were centrifuged (1,500 rpm, 20°C, 20 minutes) and cells were washed twice in Hanks’ balanced solution (Sigma, Deisenhofen, Germany). After re-suspending in Dulbecco’s modified Eagle’s medium (Sigma, Deisenhofen, Germany) (10% heat inactivated fetal calf serum and 2% penicillin-streptomycin) cell counts were performed with a hemocytometer using 0.1% trypan blue exclusion as a test of viability that always exceeded 95%. Untreated PBMCs were adjusted to a concentration of 4 x 106 PBMCs per mL in RPMI medium (10% heat inactivated fetal calf serum and 2% penicillin-streptomycin).

PBMCs were stimulated with lipopolysaccharide (25 µg/mL; an activator of macrophages and monocytes) and phytohemagglutinin (5 µg/mL; a nonspecific lymphocyte activator) to generate IL-6, TNF-{alpha}, IL-5, IL-10, and IFN-{gamma}. Cells were cultured at 37°C and 6% carbon dioxide. After 48 hours, supernatants were collected and stored at -80°C until assayed.

For lymphocyte culture, monocytes, and macrophages were depleted by adherence to cell culture flasks. Lymphocytes were cultured at a concentration of 4 x 106 cells/mL in RPMI medium (10% heat inactivated fetal calf serum and 2% penicillin-streptomycin). Then they were stimulated with phytohemagglutinin (2.5 µg/mL) to generate IL-5, IL-6, IL-10, TNF-{alpha}, and IFN-{gamma}. Cells were cultured at 37°C and 6% carbon dioxide. After 48 hours, supernatants were collected and stored at -80°C until assayed. All reagents were derived from SIGMA, Deisenhofen, Germany.

Cytokine assays
IL-6, TNF-{alpha}, and IL-10 in serum samples were measured using the commercially available Immulite-system (DPC-Biermann, Bad Nauheim, Germany) which basically uses a luminometric assay with a sensitivity of 5 pg/mL for each measurement.

Cell culture derived cytokines IL-10 and IL-5 were assayed using the flow cytometric cytokine bead array kit (Beckton Dickinson, Heidelberg, Germany) (sensitivity 5 pg/mL) and a Facscalibur cytometer (provided by Becton-Dickinson, Heidelberg, Germany). IFN-{gamma} in cell culture supernatant was analyzed using a commercially available enzyme-linked immunoadsorbent assay (DPC Biermann and Millenia Biotec, Bad Nauheim, Germany).

For assessment of IL-5 and IFN-{gamma} in ethylenediaminete-traacetic acid containing plasma probes, a modified cytokine bead array kit was used. Thereby the volume of standards (as well as samples) was increased fivefold to reach a lower detection limit (for IFN-{gamma}: 2 pg/mL; IL-5: 0.5 pg/mL).

Serum levels of cytokines were corrected for hemodilution because of the surgical procedure comparing preoperative and postoperative hemoglobin levels at each sampling time. Unless otherwise indicated, only corrected serum levels are shown.

Statistical analysis
Statistical analysis was done from raw data using the analysis of variance test and the intergroup analysis. Fisher’s PLSD or the Student’s t test was used for intragroup comparison. A p value less than 0.05 was considered significant. The results are expressed as mean ± standard error of the mean unless otherwise indicated.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Clinical results
Operative and postoperative data are given in Table 2. There were no operative deaths and no patients experienced serious postoperative complications.


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  		Table 2. Operative Data of the Patients

 
Proinflammatory cytokines IL-6 and TNF-{alpha}
Serum levels, as well as PBMC production of proinflammatory mediators, increased significantly on postoperative day 1. IL-6 remained elevated until postoperative day 5, whereas TNF-{alpha} reached preoperative levels on postoperative day 3. Preoperative values of the patients did not differ from the results in healthy controls (Fig 1A, B).



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  		Fig 1. Levels of (A) the proinflammatory cytokines IL-6 and TNF-{alpha} in serum samples and (B) cell culture supernatant of patient derived PBMC or isolated lymphocytes during the first 5 postoperative days (preoperative day [d0]; postoperative day 1 [d1], postoperative day 3 [d3], and postoperative day 5 [d5]) after coronary artery bypass grafting. Data are compared with cytokine levels of PBMC derived from 10 healthy volunteers (controls). (# indicates p < 0.05 vs d0; ## indicates p < 0.001 vs d0; n.s. = not significant). (IL = interleukin; PBMC = monocytes, macrophages, and lymphocytes; TNF-{alpha} = tumor necrosis factor {alpha}).

 
In contrast, lymphocyte production of these mediators was reduced on postoperative day 1 and returned to preoperative levels on postoperative day 3. (Fig 1B)

Antiinflammatory cytokine IL-10
Serum levels, as well as PBMC production of the antiinflammatory mediator IL-10, increased significantly on postoperative day 1 and returned to baseline on postoperative day 3. (Fig 2A)



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  		Fig 2. Cytokine levels of (A) IL-10 in serum samples and (B) cell culture supernatant of patient derived PBMC versus isolated lymphocytes. Data are compared with cytokine levels of serum, isolated lymphocytes, and PBMC derived from 10 healthy volunteers (controls). (# indicates p < 0.05 vs d0; ## indicates p < 0.001 vs d0). (d0 = preoperative day 0; d1 = postoperative day 1; d3 = postoperative day 3; d5 = postoperative day 5; IL = interleukin; PBMC = monocytes, macrophages, and lymphocytes).

 
In contrast, isolated lymphocytes showed a persistent suppression of IL-10 synthesis capacity on postoperative day 1, which remained suppressed until the end of the observation period (Fig 2B).

T-lymphocyte derived proinflammatory and antiinflammatory cytokines
Serum levels
IFN-{gamma} levels did not change during the observation period (Fig 3A). IL-5 levels remained unchanged on postoperative day 1 and increased significantly on postoperative days 3 and 5 (Fig 4A).



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  		Fig 3. Cytokine levels of (A) TH1 lymphocyte derived IFN-{gamma} in plasma and (B) cell culture supernatant of patient derived PBMC and isolated lymphocytes during the first 5 postoperative days (preoperative day [d0]; postoperative day 1 [d1], postoperative day 3 [d3], and postoperative day 5 [d5]) after coronary artery bypass grafting. Data are compared with cytokine levels of plasma samples, PBMC, and lymphocytes derived from 10 healthy volunteers (controls). (# indicates p < 0.05 vs d0; ## indicates p < 0.001 vs d0). (IFN-{gamma} = interferon-{gamma}; PBMC = monocytes, macrophages, and lymphocytes; TH1 = type 1 T helper cell).

 


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  		Fig 4. (A)TH2 lymphocyte derived IL-5 in plasma samples and (B) patient derived PBMC and isolated lymphocytes during the first 5 postoperative days (preoperative day [d0]; postoperative day 1 [d1], postoperative day 3 [d3], and postoperative day 5 [d5]) after coronary artery bypass grafting. Data are compared with cytokine levels of plasma samples, PBMC, and lymphocytes derived from 10 healthy volunteers (controls). (# indicates p < 0.05 vs d0). (IL = interleukin; PBMC = monocytes, macrophages, and lymphocytes; TH2 = type 2 T helper cell).

 
Pbmc
Synthesis of the proinflammatory mediator IFN-{gamma} was significantly suppressed on postoperative day 1 and reached preoperative levels on postoperative days 3 and 5 (Fig 3B).

Similarly, production of the antiinflammatory mediator IL-5 decreased significantly on postoperative day 1 returning to baseline on postoperative day 3. On postoperative day 5, synthesis of IL-5 was significantly elevated (Fig 4B).

Lymphocytes
Cell culture supernatants of purified lymphocytes showed a persistent significant depression of IFN-{gamma} synthesis capacity until the end of the observation period with no trend toward normalization (Fig 3B).

Similarly, IL-5 levels were depressed on postoperative days 1 and 3, but reached preoperative values on postoperative day 5 (Fig 4B).


   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
The results of this study corroborate the data of previous studies, which found an increase in serum levels of the proinflammatory cytokines IL-6 and TNF-{alpha}, as well as the antiinflammtory mediator IL-10, immediately after cardiac operations [6, 8, 13, 21–23].

This study adds that the increase of these cytokines represents primarily a nonspecific response of the innate immune system, because PBMC production of these mediators paralleled serum levels, whereas their synthesis by purified lymphocyte culture was significantly reduced. In addition, the cellular source of IL-10 was clarified; this may provide more insight into the role of IL-10 after cardiac operations. It appears likely that the increase of IL-10 represents a part of the compensatory antiinflammatory response syndrome (CARS) counteracting systemic inflammatory response syndrome (SIRS) after cardiac operation [24, 25]. In contrast, the hypothesis that IL-10 as a TH2 cytokine may suppress TH1 activity as well appears to be unlikely when looking at the results of IL-10 production by the lymphocyte culture in this study.

Nevertheless, the results of this study confirm previous work by this and other groups [20, 26–29] to indicate that the adaptive immune system is temporarily impaired and particularly affects the TH1-mediated cellular part of the specific immune response more than the TH2-mediated humoral part. Production of IFN-{gamma}, a pivotal TH1-mediator, by both a purified (ie, primarily lymphocytes) and a nonpurified cell culture (PBMC, ie, monocytes and macrophages in addition and excess to lymphocytes) was significantly depressed on postoperative day 1 and remained depressed until postoperative day 5 in the lymphocyte culture, whereas PBMC production recovered on postoperative day 3.

In contrast, lymphocyte production of the TH2-cytokine IL-5, which was depressed on postoperative day 1 as well, returned to baseline values on postoperative day 5 and was even significantly elevated in the PBMC culture at that time. Taken together, the ratio of serum levels and synthesis patterns of IFN-{gamma} and IL-5 indicate that the adaptive immune system reacts in a predominantly antiinflammatory way to cardiac operations.

The initial synthesis depression of both mediators can be explained by the significant reduction of T lymhocytes and T helper cells, which has been consistently observed by this and other groups [19, 20, 30, 31]. The faster and earlier recovery of the TH2-mediated part of adaptive immunity resulting in a polarization toward a humoral, antiinflammatory response, as hypothesized previously, is confirmed by an increase in B cells as well as by an increase in serum levels of immunoglobulin-E observed in the literature [30, 32, 33].

The results of this study in addition show that at least the antiinflammatory response after cardiac operation is biphasic with each phase being mediated by another cell type. In the period immediately after cardiac operation, antiinflammation is primarily the result of a nonspecific IL-10 release as indicated by the elevation of IL-10 synthesis in PBMC in contrast with the depressed synthesis in lymphocytes on postoperative day 1. On postoperative day 5, with IL-10 levels already back to baseline in both cell cultures, IL-5 significantly increased in the PBMC culture. This second peak appears to represent the specific antiinflammatory response.

The question remains, why does this second peak occur? The data of this study cannot answer this question. However, having in mind that the human body produces and stores inhibitors in excess to activators, it may be attractive to speculate that the second antiinflammatory response is aimed at balancing the restored synthesis of proinflammatory mediators within the network of specific immunity in the late postoperative period. This hypothesis is supported by the observation that serum levels of the antiinflammatory mediator IL-10 increase before proinflammatory cytokines [5]. The IL-5 increase could parallel this nonspecific immune response for the specific part of immunity, because they increase before the proinflammatory mediator IFN-{gamma} returns to baseline. Figure 5 summarizes this hypothesis.



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  		Fig 5. Synopsis of our data. Onset and kinetics of proinflammatory and antiinflammatory cytokine synthesis in vitro after cardiac operation are shown to focus on the time dependent changes during the postoperative period. (0h = zero hours, or postoperatively; IFN-{gamma} = interferon-{gamma}; IL = interleukin; OP = operation; TH1 = type 1 T helper cell; TH2 = type 2 T helper cell).

 
It remains to be investigated whether an imbalance within the 2 phases of immune response may be part of the underlying mechanism resulting in the overwhelming whole body inflammation with subsequent multiple organ dysfunction or immunoparalysis with subsequent sepsis, or both. At least the time points at which both events occur during the postoperative period makes this hypothesis attractive to study.

Another striking find of this study was the difference in cytokine synthesis pattern between the two cell cultures. For IL-6, TNF-{alpha}, and IL-10, synthesis depression in lymphocyte cultures versus synthesis augmentation in PBMC cultures can be explained by the hypothesis that these mediators are predominantly produced by cells of the innate immune system. However, this hypothesis does not explain why the synthesis of T helper cell-derived cytokines, (ie, IFN-{gamma} and IL-5 recovered earlier and to a larger extent in PBMC culture). For this finding, there are at least 2 possible explanation: (1) cytokine synthesis capacity of a purified lymphocyte cell culture overestimates the depression in T helper cell cytokines, and (2) monocytes and macrophages or their mediators are needed as co-stimulatory factors for TH1 and TH2 cytokine synthesis.

In addition, it is attractive to speculate that IFN-{gamma} and IL-5 synthesis may again differ from the results of this study when assessed in whole blood. In fact, this was already demonstrated for IL-6, IL-8, and IL-10 after cardiac operation [34]. While plasma levels of these mediators increased significantly during the first 6 postoperative hours, their production after lipopolysaccharide stimulation of a whole blood culture of the same 17 patients was significantly depressed. The discussion of the numerous possible explanations is beyond the scope of this article. At least, it appears important to note, that the type of measurement (eg, serum levels, lymphocyte cell cultures with or without monocytes and macrophages, whole blood culture, type of stimulation) may influence results of immunologic investigations after cardiac operation more than the operation itself. Consequently the same applies to the hypotheses regarding the possible clinical impact derived from the results.

Limitations of the study
The number of patients investigated is too small to permit general conclusions, and only one kind of major surgical trauma with an uneventful clinical course was studied. However, the results of this study are either in line with or an explanation of the findings of many other groups [1, 3, 12, 18, 20, 29]. This may indicate that the picture of a temporary alteration within the immune system of patients having undergone cardiac operations affecting the innate and the adaptive part at different time points appears to be close to reality. Because all the patients received aprotinin and a small number received blood products perioperatively, an immunomodulating effect of this treatment in the early postoperative period cannot be excluded. We know from the literature that administration of aprotinin enhances IL-10 levels during the first 24 hours [35, 36]. However, this does not invalidate our data presented for the later postoperative period and it may influence the early data only to a limited extent without changing the basic message.

We did not include the results of cellular phenotyping in this study, because it has been extensively and consistently published in the literature [19, 20, 30]. In addition, we investigated only a limited number of cytokines, whereas other important mediators, (eg, IL-2 and IL-4 were not studied). However, IL-2 and IL-4 are rarely detectable in serum by the methods available today. Because cell culture investigations require too many resources to become a clinical routine, we wanted to show only the results of cytokines for which more readily available serum tests exist. By clarifying the cellular source for these cytokines, the results of this study may facilitate the selection of parameters to be measured and the interpretation of their serum levels for immunomonitoring after cardiac operation.

The most important limitation is the limited clinical impact. This calls for studies of patients at risk for complications, or for patients who have had complications already develop; although our data provided some information to the puzzle of immune response after cardiac operation, which were previously less understood.

In conclusion, this study could add the following to the current understanding of how the immune system reacts to cardiac operation under physiologic conditions (ie, in patients with no signs of adverse clinical events).

  1. According to the nature and design of the innate, nonspecific, and the adaptive, specific immune system, a biphasic immune response emerges after cardiac operation. The first phase, represented by the increase of IL-6, TNF-{alpha}, and IL-10 serum levels, paralleled by an increase in the synthesis capacity for these cytokines in PBMC culture, appears to result from the reaction of the nonspecific immune system. The second phase, represented by the restored serum levels of the T-cell derived proinflammatory cytokine IFN-{gamma} and an increase of T-cell derived anitinflammatory IL-5 serum levels, paralleled by similar changes in cell culture appears to indicate the response of the specific immune system.
  2. The time pattern of both antiinflammatory responses occurring in parallel or before proinflammatory reactions indicates that under normal conditions the immune response during and after cardiac operations is aimed at preventing and localizing the proinflammatory actions rather than reacting to it.
  3. Purified cell cultures may give detailed insight into the functional capabilities of a particular cell line. However, with growing evidence that the actions of the immune system, like all other systems of the human body, cannot simply be understood as the sum of its parts but as the result of a dynamic interactive process of all parts, the clinical relevance of the results obtained from isolated cell cultures may be limited.
However, with the picture of physiologic immune response becoming clearer, data of the immune response in patients with a high preoperative risk or serious postoperative complications, or both, are now needed to find out if there are differences to the normal response, which of these differences might be beneficial and which not, if the alterations considered to be harmful can be counteracted, and finally, if counteraction results in a benefit for the patient. The results of these studies could clarify, in addition, if, when, which, and how different parts of immunity are involved in the process of complications that patients have developed.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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