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J Thorac Cardiovasc Surg 2005;129:1098-1103
© 2005 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Soluble {alpha}2-macroglobulin receptor is increased in endotracheal aspirates from infants and children after cardiopulmonary bypass

Eric A. Williams, MDa, Richard J. Ing, MB, BChb, Justin P. Hart, PhDc, James Jaggers, MDd, Frank H. Kern, MDa,b, Damian M. Craig, MSd, Salvatore V. Pizzo, MD, PhDc,*

a Departments of Pediatrics, Duke University Medical Center, Durham, NC
b Anesthesiology Duke University Medical Center, Durham, NC
c Pathology Duke University Medical Center, Durham, NC
d Surgery Duke University Medical Center, Durham, NC

Received for publication April 22, 2004; revisions received July 7, 2004; accepted for publication August 18, 2004.

* Address for reprints: Salvatore V. Pizzo, MD, PhD, Duke University Medical Center, Box 3712, Durham, NC 27710 (E-mail: willi055{at}mc.duke.edu).


   Abstract
Top
 Abstract
Methods and materials
 Results
 Discussion
 References
 
OBJECTIVE: Cytokine dysregulation contributes to the systemic inflammatory response after cardiopulmonary bypass. Clearance of cytokine binding proteins may be important in the resolution of inflammation. Our aim was to determine whether the cytokine binding protein {alpha}2-macroglobulin and its soluble receptor were upregulated in endotracheal aspirates from infants and children undergoing cardiopulmonary bypass.

METHODS: Seventy tracheal aspirates were collected before and after cardiopulmonary bypass from 35 infants and children undergoing surgical correction of congenital heart defects. {alpha}2-Macroglobulin and the soluble {alpha}2-macroglobulin receptor were identified by Western blot. With the use of multi-analyte cytokine profiling, pro-inflammatory and anti-inflammatory cytokines were quantified, normalized to total protein, and expressed as ratios. Paired t tests and Wilcoxon signed-rank tests were performed between prebypass and postbypass samples. Correlations were examined among {alpha}2-macroglobulin, soluble {alpha}2-macroglobulin receptor, cytokine ratios, and the clinical variables of cardiopulmonary bypass, aortic crossclamp, and circulatory arrest times.

RESULTS: {alpha}2-Macroglobulin increased by 50% (mean densitometry increase 82,683 ± 184,594, P = .012), and soluble {alpha}2-macroglobulin receptor increased by 17% (mean densitometry increase 506,148 ± 687,037, P = .0001) after cardiopulmonary bypass. The ratio of interleukin-8/interleukin-4 increased by 136% (P = .0001), and interleukin-8/interleukin-10 increased by 102% (P = .001). The increase in soluble {alpha}2-macroglobulin receptor was positively correlated with the ratios of interleukin-8/interleukin-4 and interleukin-8/interleukin-10. There were no statistically significant positive correlations between the increase in {alpha}2-macroglobulin or soluble {alpha}2-macroglobulin receptor and measured clinical variables.

CONCLUSIONS: We report for the first time the upregulation of {alpha}2-macroglobulin and soluble {alpha}2-macroglobulin receptor in tracheal aspirates after cardiopulmonary bypass in infants and children. Soluble {alpha}2-macroglobulin receptor correlates with increased {alpha}2-macroglobulin and a disproportionate increase in pro-inflammatory to anti-inflammatory cytokine ratios.

Cardiopulmonary bypass (CPB) contributes to a systemic inflammatory response by activation of cellular and humoral cascades. Inflammation after CPB is similar to sepsis. It involves activation of immunocompetent cells, complement and coagulation, endothelial cell dysfunction, proteinase/antiproteinase imbalance, and increased cytokine production, and may lead to multiorgan dysfunction.1–3 In particular, lung dysfunction after CPB can have detrimental effects on oxygen delivery and require ventilator management that may worsen cardiac output through unfavorable cardiorespiratory interactions. The progression to severe lung disease is believed to occur when regulatory mechanisms fail and inflammation becomes self-propagating.4 This auto-amplification may be the result of increased production or decreased clearance of cytokines. Ultimately, the balance of pro-inflammatory and anti-inflammatory factors influences subsequent lung injury.

In addition to its role as a proteinase inhibitor, {alpha}2-macroglobulin ({alpha}2M) also functions as a cytokine binding protein.5,6 At sites of inflammation, {alpha}2M undergoes a conformational change to a receptor-recognized form, {alpha}2M*. We have shown that {alpha}2M* demonstrates increased binding to many cytokines and growth factors.5,7 In vivo, {alpha}2M* is increased in endotracheal aspirates (ETAs) from infants with lung disease,8,9 and {alpha}2M*-cytokine complexes have been identified in bronchoalveolar lavage (BAL) from adults with acute respiratory distress syndrome.10,11 The increased {alpha}2M may result from increased production/sequestration or decreased clearance. In general, cytokines and growth factors complexed with {alpha}2M* retain their biologic activity. However, {alpha}2M*-cytokine complexes are rapidly cleared when bound to the {alpha}2M cell surface receptor ({alpha}2MR).7

{alpha}2MR is a classic scavenger receptor found on many cell types including hepatocytes, monocytes, and macrophages. Recent studies have identified a soluble form of {alpha}2MR (S{alpha}2MR) with intact receptor binding that circulates in human plasma.12,13 An S{alpha}2MR that maintains its ligand-binding properties should act as a competitive inhibitor for the cellular form of the receptor. Soluble {alpha}2MR may inhibit the cellular internalization of {alpha}2M*-cytokine complexes (Figure 1).


Figure 1
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  		Figure 1. Transition of {alpha}2-macroglobulin ({alpha}2M) (blue molecule) to receptor-recognized form with exposure to proteinases (red circles) and binding of cytokines (green circles). {alpha}2M-cytokine complexes may bind to the {alpha}2M receptor ({alpha}2MR) at the cell surface with subsequent internalization and degradation or bind to the soluble form of the {alpha}2MR. The soluble {alpha}2MR (S{alpha}2MR) results from cleavage of the {alpha}2MR near the cell surface and may competitively inhibit clearance of {alpha}2M-cytokine complexes.

 
We evaluated the {alpha}2M*-cytokine regulatory axis, and our study for the first time demonstrates the relative increase of S{alpha}2MR in ETAs from infants and children after the inflammatory insult of CPB. The increase in S{alpha}2MR correlated with increased levels of the ratio of pro-inflammatory to anti-inflammatory cytokines. Increased levels of S{alpha}2MR may prolong the course of inflammation within the lung after CPB by increasing the half-life of {alpha}2M*-cytokine complexes.


   Methods and materials
Top
 Abstract
 Methods and materials
Results
 Discussion
 References
 
Monoclonal antibodies directed against the ß chain of human {alpha}2MR were purchased from Pharmingen (San Diego, Calif). Polyclonal antibodies directed against {alpha}2M were purchased from Sigma (St Louis, Mo). Reagents for sodium dodecyl sulfate-polyacrylamide gel electrophoresis, polyvinylidene difluoride membranes, and transfer reagents were purchased from Bio-Rad (Richmond, Calif). An enhanced chemifluorescent immunoblotting kit was purchased from Amersham (Buckinghamshire, United Kingdom). Complete protease inhibitors were purchased from Roche (Indianapolis, Ind).

Study subjects
After parental informed consent and Duke University Institutional Review Board approval were obtained, ETAs were collected from children (aged 2 days to 10 years) undergoing corrective congenital heart surgery requiring CPB. In each patient, ETAs were collected after intubation but before CPB. During CPB the lungs were not ventilated, but the patient’s endotracheal tube remained attached to the ventilator with humidified fresh gas flow. After inflation, a second sample was collected immediately before the separation from CPB, before the institution of modified ultrafiltration. Samples were obtained with a sterile endotracheal suction catheter. If necessary, patients received 0.5 to 1 mL of normal saline to assist aspiration of secretions.

Anesthesia and CPB were per institutional protocol. All patients aged less than 1 month received intravenous methylprednisolone 10 mg/kg (q6 x 2) preoperatively in addition to 30 mg/kg on pump prime. Children aged more than 1 month received methylprednisolone 10 mg/kg on pump prime.

Sample processing
After sample collection, 2.5 mL of Complete protease inhibitor (dilution 1:1) was added to prevent protein degradation, and the sample was placed on ice. Within 4 hours, samples were centrifuged at 1000 rpm for 8 minutes to remove cellular debris. Subsequently, samples were centrifuged at 100,000g for 30 minutes to isolate soluble components and stored at –80°C for further analysis.

Immunoblotting
Total protein analysis was performed with the BCA Protein Assay Kit (Pierce, Rockford, Ill). Polyacrylamide gel electrophoresis was performed at 150V for 3.5 hours per the manufacturer’s instructions. All gels were loaded with identical total protein for each pre-CPB and post-CPB pair. Western blotting was performed for {alpha}2M and S{alpha}2MR. After application of fluorescent dye, blots were dried and digitized on the Storm 860 gel and blot imaging system (Molecular Dynamics, Sunnyvale, Calif). Image densitometry was performed with ImageQuant v5.2 (Molecular Dynamics, Sunnyvale, Calif). Quantitative multi-analyte cytokine profiling was performed on all samples per standard protocol with 50-µL samples on the Luminex 100 (LuminexCorp, Austin, Tex).

Statistical analysis was performed by Microsoft Excel 2002 (Redmond, Wash) and SAS (Cary, NC) and consisted of paired hypothesis tests between pre-CPB and post-CPB samples within each patient for image densitometry and cytokine ratios. Paired t tests were used for normally distributed data, and Wilcoxon signed-rank tests were used for non-normally distributed data. Spearman correlations were examined between S{alpha}2MR, {alpha}2M, and cytokine ratios as well as the clinical variables of CPB, aortic crossclamp, and circulatory arrest times.


   Results
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 Abstract
 Methods and materials
 Results
Discussion
 References
 
All measured variables except {alpha}2M were not normally distributed and required the Wilcoxon signed-rank test to determine statistical significance and are expressed as mean ± SD. Patient demographics are tabulated in Table 1. In our patients, 17 of 35 (49%) were aged more than 1 year and 18 of 35 (51%) were aged less than 1 year. Of the patients aged less than 1 year, 4 of 18 (22%) were aged less than 1 month. The longest CPB and aortic crossclamp times were required in this same subpopulation. In addition, they received hypothermic circulatory arrest. Aprotinin was administered to only 2 of 35 patients (6%).


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  		TABLE 1. Patient demographics
 
Representative Western blots for {alpha}2M and S{alpha}2MR are shown in Figure 2, A and B, respectively. The relative increases after CPB of the {alpha}2MR ß-chain image density and {alpha}2M image density for all patients was 17% (mean densitometry increase 506,148 ± 687,037, P = .0001) and 50% (mean densitometry increase 82,683 ± 184,594, P = .012), respectively.


Figure 2
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  		Figure 2. A, Western blot analysis probing {alpha}2M within 4 patients’ endotracheal aspirate (ETA) samples. The ~180 kDa band is the {alpha}2M subunit, 4 of which make up the native molecule. Pre-CPB (a) and post-CPB (b) time points. B, Western blot analysis probing S{alpha}2MR within 4 patients’ ETA samples. The ~55 kDa band represents the surface-cleaved extracellular portion of the ~85 kDa ß chain. Pre-CPB (a) and post-CPB (b) time points.

 
Total protein increased before CPB to after CPB from 346 ± 420 to 507 ± 563 µg/mL (P = .009). The results of the multi-analyte cytokine profiling are shown in Table 2. Interleukin (IL)-2, tumor necrosis factor-{alpha}, and granulocyte-macrophage colony-stimulating factor were below the limits of detection of the multi-analyte cytokine analysis. Cytokines normalized to total protein are shown in Table 3. The pro-inflammatory to anti-inflammatory ratios of IL-8/IL-10 and IL-8/IL-4 were increased after bypass. Specifically, mean IL-8/IL-10 increased from 13.1 to 26.5 (102%) (P = .001), and IL-8/IL-4 increased from 0.83 to 1.96 (136%) (P = .0001).


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  		TABLE 2. Cytokine analysis
 

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  		TABLE 3. Normalized cytokine analysis
 
The increase in S{alpha}2MR was positively correlated with the increase in {alpha}2M (Spearman coefficient R = 0.52, P < .01). The increase in S{alpha}2MR was also positively correlated with the ratios of IL-8/IL-4 (Spearman coefficient R = 0.50, P < .01) and IL-8/IL-10 (Spearman coefficient R = 0.39, P < .05). There were no statistically significant positive correlations between the increase in S{alpha}2MR or {alpha}2M and the clinical variables of CPB, aortic crossclamp, and circulatory arrest times.


   Discussion
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 Abstract
 Methods and materials
 Results
 Discussion
References
 
During CPB, serum {alpha}2M has been found to decrease, most likely because of dilutional effects.14,15 However, a critical component of the {alpha}2M-cytokine regulatory axis is the {alpha}2M receptor, a scavenger receptor located on many cell types.16 This study for the first time describes the increase of S{alpha}2MR in ETA from infants and children after the inflammatory insult of CPB. The increase in S{alpha}2MR had a positive correlation with {alpha}2M and the proinflammatory to anti-inflammatory ratios of IL-8/IL-4 and IL-8/IL-10. Previous in vivo research identified the presence of a soluble form of {alpha}2MR circulating in human plasma that maintained its ligand-binding properties and was increased in inflammatory states.12,13 Further in vitro modeling suggested that the release of S{alpha}2MR was through cleavage of {alpha}2MR at a membrane proximal region by a membrane-tethered metalloproteinase (Figure 1).13,17 In vitro treatment with a metalloproteinase inhibitor decreased the cleavage of {alpha}2MR, thereby decreasing the S{alpha}2MR available to compete with the cellular {alpha}2MR. Thus, mechanisms that affect the clearance of {alpha}2M*-cytokine complexes, such as receptor competition, could play a role in the modulation of inflammation after CPB.

Our goal has been to evaluate the inflammatory response within the lung in hopes of understanding the more clinically severe forms of acute lung injury and acute respiratory distress syndrome.18 We chose CPB as a model of inflammation because of its predictable onset. This is in contrast with the poor predictability of lung disease secondary to sepsis, in which clinical samples before the onset of inflammation may be impossible to obtain. We confirmed inflammatory upregulation after CPB by measuring the ratios of inflammatory mediators IL-8/IL-4 and IL-8/IL-10 from the lung and found them increased.

Systemic inflammation is upregulated by CPB with activation of plasma protein systems: contact, intrinsic and extrinsic coagulation, fibrinolysis, and complement, as well as cellular systems: platelets, endothelial cells, neutrophils, monocytes, and lymphocytes.3 Despite a complex inflammatory response, the majority of patients are extubated early after CPB with minimal ventilatory requirements. However, in patients requiring prolonged mechanical ventilation, positive pressure can exacerbate the inflammatory response because of overdistension of lung tissue.19 Thus, both the inflammatory insult and supportive therapy may potentiate lung injury. To date, studies have implemented novel therapies directed at reducing inflammatory cytokines and the associated potential for prolonged inflammation (eg, steroids, modified ultrafiltration, complement inhibitors, and proteinase inhibitors).20–23 Despite these efforts, the physiologic response to CPB in infants and children can be exaggerated and lead to organ dysfunction in the postoperative period, clinically evidenced in the lung.24

Clinically, lung disease may become exaggerated with dysfunction of cytokine-binding proteins.25 Found in abundance at sites of inflammation, {alpha}2M* binds a host of pro-inflammatory cytokines and growth factors, and we previously showed that in vitro binding to {alpha}2M* is specific.5 {alpha}2M* is increased in ETA from intubated infants with lung disease.8,9 Studies have measured {alpha}2M* levels from BAL fluid in infants and adults and found increases in those patients with inflammatory lung diseases.26,27 The increase in {alpha}2M* in BAL fluid has been presumed secondary to leakage from plasma after lung injury and localized production by alveolar macrophages and fibroblasts.25 We found {alpha}2M increased in the inflammatory state associated with CPB. Decreased clearance of {alpha}2M*-cytokine complexes may contribute to the increase in {alpha}2M*.

ETA samples were obtained as representative of the milieu of the alveolar compartment. To date, ETA samples have been used to measure components within the alveolar compartment of intubated neonates and infants.8,9,28 Dilutional effects on S{alpha}2MR measurements have been taken into account by loading identical protein concentrations on the gels for pre-CPB and post-CPB samples. By examination of the ratio of pro-inflammatory to anti-inflammatory cytokines at any time point, the dilutional variability can also be removed. Here, the data indicate a disproportionate increase in pro-inflammatory to anti-inflammatory mediators before to after CPB. Despite these attempts, it is unclear how well tracheal aspirates can represent the acellular components of the lower respiratory tract and how well we can use these measurements to distinguish temporal changes resulting from pathology or therapy.

Interpretation of our results requires careful consideration. Although we understand that steroids may alter the inflammatory response to CPB, our study was not designed to determine this effect. Because of the inherent variability of patient demographics and the influence of varying amounts of immunomodulators, our current sample size does not provide the statistical power required to delineate the contributions of these effectors. For example, in addition to having the lowest temperatures, all of the neonates (n = 4) received 2 additional doses of methylprednisolone before their surgery on CPB. The lack of a statistically significant increase in S{alpha}2MR in the neonatal subgroup may not be solely attributable to the small sample size of 4. Recent clinical data indicate that combined preoperative and intraoperative steroids can reduce inflammatory mediator expression greater than intraoperative steroids alone.29 Thus, we cannot rule out the potential contribution from the extra doses of steroids in this subgroup.

We report for the first time the presence of S{alpha}2MR in ETAs from infants and children and the increase of S{alpha}2MR after the inflammatory insult of CPB. On the basis of our findings, we hypothesize that therapy directed at decreasing cleavage of {alpha}2MR, by inhibiting metalloproteinases, will lead to increased {alpha}2MR-dependent cellular internalization and degradation of {alpha}2M*-cytokine complexes. This hypothesis supports therapy directed at reducing or inhibiting metalloproteinases within the lung to reduce inflammation.30 Future studies will be directed toward understanding the mechanisms of {alpha}2MR release and the effect of S{alpha}2MR on the clearance of {alpha}2M*-cytokine complexes in vitro.


   Footnotes
 
Eric A. Williams, MD, is a National Institute of Child Health and Human Development Fellow of the Pediatric Scientist Development Program (National Institute of Child Health and Human Development Grant Award K12-HD00850). Salvatore V. Pizzo, MD, PhD, is funded by National Heart, Lung, and Blood Institute HL 24066.


   References
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 Abstract
 Methods and materials
 Results
 Discussion
 References
 

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