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CARDIOVASCULAR ANESTHESIA

Cardiopulmonary Bypass Produces Greater Pulmonary than Systemic Proinflammatory Cytokines

Naoki Kotani, MD^*, Hiroshi Hashimoto, MD^*, Daniel I. Sessler, MD, Masatoshi Muraoka, MD^*, Jian-Sheng Wang, MD, Michael F. O’Connor, MD, and Akitomo Matsuki, MD^*

*Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan; Department of Anesthesia and Perioperative Care, University of California–San Francisco, San Francisco, California; and Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois

Address correspondence and reprint requests to Naoki Kotani, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8562, Japan. Address e-mail to nao{at}cc.hirosaki-u.ac.jp

	Abstract

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Cardiopulmonary bypass (CPB) impairs pulmonary endothelial injury in part by increasing expression of adhesion molecules that results in neutrophil influx. Although numerous proinflammatory cytokines up-regulate these responses, the extent to which systemic and pulmonary proinflammatory cytokines increase remains unknown. We therefore examined systemic and pulmonary gene expression and production of proinflammatory cytokines during CPB. Bronchoalveolar lavage and peripheral blood sampling were performed just after the induction of anesthesia and at the end of surgery in 80 patients undergoing CPB. RNA was extracted from harvested cells and cDNA was synthesized by reverse transcription. The expression of interleukin (IL)-6, IL-8, and tumor necrosis factor- (TNF-) was measured by semiquantitative polymerase chain reaction using ß-actin as an internal standard. We also measured these cytokines in cultured alveolar macrophages and plasma monocytes in standard medium alone, or in the presence of lipopolysaccharide. We found 2- to 20-fold increases in gene expression for these cytokines in both plasma and alveolar leukocytes at the end of surgery. However, the increases were 4–8 times greater in alveolar than plasma leukocytes. Alveolar macrophages obtained at the end of surgery produced 1.5–3 times more IL-6, IL-8, and TNF- than those obtained at the beginning (P < 0.0001). Although plasma monocytes produced more IL-8 at the end of surgery (P < 0.001), TNF- and IL-6 did not increase. The production of all cytokines was 1.5–3 times greater in alveolar macrophages obtained at the end of surgery than in plasma monocytes obtained simultaneously (P < 0.005). Our data thus suggest that CPB provokes a greater pulmonary than systemic inflammatory response.

Implications: Both gene expression and production of proinflammatory cytokines were greater in alveolar than plasma leukocytes after cardiopulmonary bypass. These results suggest that cardiopulmonary bypass provokes more serious pulmonary than systemic inflammatory responses.

	Introduction

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Cardiopulmonary bypass (CPB) induces systemic release of proinflammatory cytokines. These proinflammatory cytokines up-regulate neutrophil and endothelial surface adhesive molecule expression, promoting enhanced neutrophil-endothelial adherence (1). Increased neutrophil-endothelial adherence and subsequent neutrophil influx are thought to cause organ injury during clinical inflammatory con-ditions (2,3). Proinflammatory cytokines also increase cellular expression of inducible nitric oxide synthase, thus increasing cellular production of nitric oxide, a known inflammatory mediator (2,3). CPB further changes the integrity of the bronchoalveolar architecture by inducing atelectasis (4). Atelectasis lasting only 1 h facilitates production of proinflammatory cytokines by alveolar macrophages, resulting in serious distal airway inflammation (5).

Alveolar leukocytes, more than 90% of which are macrophages, are a normal cellular element in the distal airway and are critical defenses against pulmonary insults. Even general surgery under general anesthesia activates alveolar leukocytes and provokes inflammation in the distal airway (6–9). Because of endothelial and epithelial injury, CPB may provoke greater pulmonary than systemic inflammatory responses. However, little is known about changes of alveolar leukocytes after CPB (10,11) and the extent to which bypass increases proinflammatory cytokines in distal airways.

We therefore tested the hypotheses: 1) that CPB induces expression of genes for proinflammatory cytokines and enhances production of inflammatory cytokines in alveolar macrophages; and 2) that expression and production of proinflammatory cytokines was greater in alveolar macrophages than plasma monocytes.

	Methods

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The protocol for this study was approved by our institutional review board, and written, informed consent was obtained from all the participants. We studied 80 patients scheduled to undergo elective coronary arterial bypass grafting using CPB. Medical treatments such as nitroglycerin, calcium antagonists, and diuretics were continued and nonsteroidal antiinflammatory drugs and anticoagulants were discontinued at least 1 wk before surgery. Patients were excluded if they were current smokers (nonsmoking period less than 8 wk) or if they had chronic obstructive or restrictive lung disease (diagnosed by respiratory physician), pulmonary infections or neoplasm, cardiac failure (New York Heart Association, Class III), or arrhythmia. Patients were also excluded if they took steroid medication at the time of the study, had an ASA physical status IV or V, an abnormal chest radiograph, or a forced vital capacity or forced expiratory volume in 1 s less than 70% of the expected values. A single physician conducted preoperative screening to ensure consistent application of these criteria.

All patients were premedicated with oral diazepam (0.2 mg/kg) and famotidine (20 mg) 90 min before the induction of anesthesia. Radial arterial pressure, electrocardiogram, and SPO₂ were monitored in all patients. We induced and maintained anesthesia with 30 µg/kg fentanyl and 0.5%–1% isoflurane supplemented with vecuronium. Before CPB, 5–7 mL · kg^-1 · h^-1 lactated Ringer’s solution was given. Nitroglycerin (0.5–1.5 µg · kg^-1 · min^-1) was administered continuously. We did not administer steroids, antiprotease, and nonsteroidal antiinflammatory drugs at any time during anesthesia. A pulmonary-artery catheter was inserted via the right internal jugular vein. Patients’ lungs were mechanically ventilated throughout anesthesia, except during total CPB; tidal volume was maintained at 10 mL/kg with 100% oxygen. Ventilation was controlled to maintain PaCO₂ between 35 and 45 mm Hg.

The bypass apparatus was primed with 1700 mL of crystalloid solution containing 0.8 g/kg mannitol, bicarbonate, and heparin. No blood or blood products were added to the prime. After median sternotomy, heparin (300 units/kg, IV) was administered before performing standard cannulations of the ascending aorta and inferior and superior vena cavas for initiation of bypass. The perfusion rate was maintained between 2.0 and 2.4 L · m^-2 · min^-1 during moderate hypothermia (30°–32°C esophageal temperature) with a membrane oxygenator and nonpulsatile roller pump. The mean arterial blood pressure was maintained between 40 and 60 mm Hg during bypass. Additional heparin was administered as necessary to maintain activated clotting time >450 s. During total bypass, the endotracheal tube was connected to the breathing circuit without positive pressure.

Immediately after termination of total bypass, the lungs were inflated manually for 10 s to 40 cm H₂O five times to reduce the severity of atelectasis based on a technique by Rothen et al. (12). The mean volume for this hyperinflation maneuver was 4–5 times the intraoperative tidal volume. All patients were weaned from CPB by using dobutamine starting at 3 µg · kg^-1 · min^-1 up to 10 µg · kg^-1 · min^-1. Epinephrine was added when dobutamine was insufficient. Residual heparin was neutralized with 3–4 mg/kg protamine. Mechanical ventilation was continued postoperatively (e.g., during the post-bypass period).

Immediately after the induction of anesthesia (Beginning) and on completion of surgery (End), bronchoalveolar lavage was performed as previously described (6,7,9). A flexible fiberoptic bronchoscope was introduced through the endotracheal tube. The tip of the bronchoscope was wedged into a subsegment of the left or right lower lobe of the lungs. This subsegment was then lavaged via the suction port after instilling 20 mL of sterile buffered saline solution (pH 7.4). The lavage fluid was gently aspirated. This procedure was repeated five times so the total instillation of solution was 100 mL. A different randomly chosen subsegment was lavaged each time.

After filtration through a single layer of loose cotton gauze, viability and types of the alveolar immune cells were evaluated by previously reported methods (6–9). The lavage fluid was immediately centrifuged, and the cell-free supernatant was decanted. The alveolar leukocytes were washed and resuspended in RPMI 1640 solution^TM (Gibco BRL, Life Technologies, Inc., Rockville, MD) at 1 x 106 cells/cm³. Resuspended cells were divided into two equal volumes for cell culture and determination of expression of genes for proinflammatory cytokines.

One milliliter of suspended medium was plated in 24-well dishes and incubated for 30 min. Neutrophil contamination in the cultures of alveolar macrophages can have a considerable effect on cytokine production (13). Consequently, we removed all nonadherent cells with three washings of warm RPMI with (2 U/mL) penicillin. The resulting adherent population consisted of more than 99% macrophages as assessed by Wright-Giemsa staining. Cell viability exceeded 98%. After removal of nonadherent cells, alveolar macrophages were incubated in 5% CO₂ in air with RPMI 1640 containing 100 U/mL penicillin, 100 µg/mL streptomycin, and 2% fetal calf albumin for 24 h at 37°C, with or without 10 µg/mL lipopolysaccharide (Escherichia coli 0–125: B8^TM; Difco Lab., Detroit, MI). After 24 h, cell-free supernatants were harvested and frozen at -80°C pending analysis of cytokines.

Immediately before each bronchoalveolar lavage, blood was sampled from the radial-arterial catheter and was anticoagulated with 10 mg EDTA. One milliliter of blood was used for determination of the number and distribution of leukocytes by cell type. Plasma mononuclear cells were isolated by centrifugation on Ficoll-Hypaque. Harvested mononuclear cells were used for cell culture and determination of gene expression of proinflammatory cytokines. The monocytes for cell culture were isolated and incubated by using the same method as for the alveolar macrophages. The adherent cells were more than 98% monocytes. After culturing, the cell-free supernatants were frozen at -80°C pending analysis of cytokines.

The following molecular analysis was based on our previously described method (8). At first, harvested plasma and alveolar immune cells were dissolved in 0.5 mL of guanidinium buffer solution. RNA was isolated from the guanidinium buffer by the well-established acid guanidinium-phenol-chloroform method. We obtained 1.6–2.4 µg RNA from each sample. By incubation at 40°C for 60 min, cDNA was synthesized from 1.5 µg RNA with 20 µL total reaction mixture, including Tris-HCl buffer (pH 8.3), 1 mM dNTPs, 0.125 µM oligo dT primers, 20 units RNase inhibitor, and 0.25 units avian myeloblastosis virus reverse transcriptase. After 60-min incubation, reverse transcriptase was inactivated at 95°C for 2 min.

The reversed transcription-polymerase chain reaction mixture (50 µL) contained cDNA synthesized from 0.5 µg RNA, Tris-HCl (pH 8.3), KCl, 2.5 mM MgCl₂, dNTP, 0.2 µM 5' and 3' oligonucleotide primers, and 2.5 units Taq polymerase^TM (Takara Co., Tokyo, Japan). The reaction mixture was then amplified in a DNA thermocycler^TM (Perkin-Elmer Co., Irvine, CA). Each cycle consisted of denaturation at 94°C for 1 min, annealing at 56°C (interleukin [IL]-6) or 59°C (for IL-8 and tumor necrosis factor- [TNF-]) for 1 min, and extension at 72°C for 1 min. The optimal number of polymerase chain reaction (PCR) cycles for each primer set was determined in preliminary experiments so that the amplification process was performed during the exponential phase of amplification. The numbers of PCR cycles are as follows: 26 for ß-actin, 35 for IL-6, and 27 for IL-8 and TNF-. The sequence of cytokine specific primer pairs, 5' and 3', was shown in our previous study (9). Coamplification of the cDNA for each cytokine and ß-actin was then performed in single tubes. The ß-actin primers were added after several cycles with only cytokine primer so that the final number of PCR cycles was optimal for both the cytokine and ß-actin.

The PCR products were separated by electrophoresis on a 1.8% agarose gel containing 0.5 µg/mL ethidium bromide. PCR products were visualized on a transilluminator (Model FBTIV-816^TM; Fisher Scientific, Pittsburgh, PA) at a 312-nm wavelength and photographed with Polaroid 667 film. The PCR products were quantified by densitometry measurements as shown in previous methods (8). To evaluate the relative amount of cytokine mRNA in each sample, the cytokine/ß-actin ratio of the intensity of ethidium bromide luminescence for each PCR product was calculated.

Data between "beginning" and "end" time points were analyzed by using two-tailed paired t-tests. We analyzed data between plasma and alveolar cells using two-tailed unpaired t-tests. Differences were considered significant when P < 0.05. Data were expressed as means ± SD.

	Results

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Morphometric and demographic characteristics, preoperative cardiopulmonary functions, preoperative medical treatment, and the duration of surgery are shown in Table 1. None of the patients had difficulty during weaning from CPB without epinephrine. Emergence from anesthesia occurred within 2 h after completion of surgery in all patients. No blood or blood product was given before final bronchoalveolar lavage. Once extubated, none of the patients experienced subsequent serious respiratory complications or required reintubation. PaO₂ decreased, and the lung injury score increased significantly. Although pH and PaO₂ decreased at the end of surgery, the other hemodynamic and respiratory measurements did not differ significantly over time (Table 2).

View larger version (15K): [in this window] [in a new window]   Figure 1. Expression of the genes for IL-6, IL-8, and TNF- by alveolar macrophages (circles; n = 80) and plasma monocytes (squares; n = 80). Beginning is immediately after induction of anesthesia; End is completion of surgery. Asterisks indicate statistically significant differences (P < 0.001) from induction; pound signs identify significant difference (P < 0.05) from the plasma monocytes. Ratios of cytokine mRNA to ß-actin mRNA are presented as means ± SDs. IL = interleukin, TNF = tumor necrosis factor .

View larger version (24K): [in this window] [in a new window]   Figure 2. In vivo secretion (ng/mL) of IL-6, IL-8, and TNF- by alveolar macrophages (circles; n = 80) and plasma monocytes (squares; n = 80) without lipopolysaccharide (LPS-) and with 10 µg/mL lipopolysaccharide (LPS+). Beginning is immediately after induction of anesthesia; End is completion of surgery. Asterisks indicate statistically significant differences (P < 0.001) from induction; pound signs identify significant difference (P < 0.05) from secretion by plasma monocytes. Data are expressed as means ± SDs. IL = interleukin, TNF = tumor necrosis factor .

	Discussion

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A notable finding is increased gene expression for IL-6 at the end of surgery in alveolar leukocytes. The increase was much greater in alveolar than plasma leukocytes. We have previously reported that there was little or no expression of the gene for IL-6 in alveolar leukocytes after anesthesia and general surgery (9). The in vitro production of IL-6 was also much greater in alveolar macrophages than in plasma monocytes. This result was comparable with that reported by Hauser et al. (14), who also observed that average IL-6 concentrations, corrected for the estimated volume of epithelial lining fluid, are up to 25 times greater than those in plasma after CPB.

IL-8 is a powerful chemotactic factor for polymorphonuclear neutrophils and stimulates adherence of polymorphonuclear neutrophils to pulmonary epithelial and endothelial cells. In our study, the increases in gene expression and production of IL-8 were much greater in the lung than in the plasma. IL-8 is especially important for evaluating pulmonary inflammation. Pulmonary inflammatory responses induce gene expression and production of IL-8 in alveolar macrophages (16). Boutten et al. (17) reported that IL-8 in the lavage fluid correlates with the degree of pulmonary dysfunction.

The increases in gene expression and production of IL-8 after CPB were similar to those observed previously in plasma monocytes (18). A study showed increased IL-8 concentrations after blood was circulated through an isolated bypass circuit (19). This result suggests that blood contact to bypass apparatus per se stimulates IL-8 secretion by plasma leukocytes. Additionally, IL-8 may be released from various organs during CPB. For example, Burns et al. (20) reported that both heart and muscle produce considerable amounts of IL-8 during CPB. Finally, increased production of IL-8 in alveolar macrophages suggests that the lungs also contribute to increases in circulating IL-8 after CPB. However, the influence of other sources cannot be determined from our study.

TNF- is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with critical inflammatory conditions (16). Our results demonstrated that gene expression of TNF- in plasma leukocytes increased after CPB. This result was comparable with that in a previous study by Hattler et al. (21), who also showed that gene expression of TNF- increased as a function of CPB duration. It is well known that the synthesis of TNF- by plasma leukocytes increases during hemodialysis and does not correlate with the presence and absence of endotoxin in dialysate (21). These findings suggest direct contact to synthetic bypass apparatus as a causative factor for expression of TNF- in our patients.

Alveolar macrophages produced more TNF- than plasma monocytes both before and after CPB. Furthermore, gene expression of TNF- was markedly greater in alveolar than plasma leukocytes both before and after CPB. Rich et al. (22) reported that alveolar macrophages produce less IL-1ß, but more TNF-, than plasma monocytes. This may be a reason that plasma TNF- is frequently undetectable in the plasma after CPB.

Our data demonstrate that CPB produces a greater pulmonary than systemic proinflammatory cytokine response. In contrast, our results differ from a preliminary study by Tsuchida et al. (1), who reported similar production of IL-6, IL-8, and TNF- before and after CPB in both alveolar macrophages and plasma monocytes. The difference may be explained by their intraoperative use of methylprednisolone. Both systemic and pulmonary production of IL-8 are considerably suppressed by intraoperative use of steroids after CPB (10,11).

One possible reason for systemic inflammation after CPB is endotoxemia. However, endotoxin reduces capacity of plasma leukocytes to produce in vitro proinflammatory cytokines (23). Marie et al. (24) reported reduced in vitro production of IL-8 by neutrophils undergoing cardiopulmonary bypass. Endotoxemia induced by CPB might have decreased production of proinflammatory cytokines by peripheral monocytes in our study.

In addition to CPB, all our patients were anesthetized and undergoing surgery, and their lungs mechanically were ventilated. Duration of anesthesia, as well as the use of volatile anesthetics, augments gene expression of proinflammatory cytokines in alveolar leukocytes (8,9). Consequently, we cannot determine the independent contributions of each factor to the observed alterations.

We performed cell culture in alveolar macrophages and plasma monocytes. However, even adherence to plastic test tubes for separation of alveolar macrophage and plasma monocytes activates gene expression of proinflammatory cytokines (13). We therefore did not separate the macrophages or monocytes from other cells to avoid any artificial influence of the sorting process on gene expression of proinflammatory cytokines. Because activated neutrophils can produce proinflammatory cytokines—including IL-6, IL-8, and TNF-—we cannot draw a definite conclusion regarding cell source for the observed increase in gene expression. Moreover, migrated leukocytes to the distal airway were already activated, and this may be in part another mechanism for more augmented gene expression in alveolar leukocytes.

In summary, CPB induced expression of genes for proinflammatory cytokines and enhanced production of inflammatory cytokines. Gene expression and production of proinflammatory cytokines were much greater in the distal airway than in the plasma. Our results thus suggest that CPB produces greater pulmonary than systemic proinflammatory responses.

	Acknowledgments

 
This study was supported by Grant-in-aid for Scientific Research No. 08457399 (Department of Education, Japan), National Institutes of Health Grant GM58273 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, CA), and the Fonds zur Förderung der wissenschaftlichen Forschung (Vienna, Austria).

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999