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Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

ABSTRACT: Leukocyte (LE) activation during cardiopulmonary bypass (CPB) promotes a systemic inflammatory response that contributes to organ injury and postoperative organ dysfunction. A leukocyte modulatory device (L-MOD) for use during (and after) CPB to limit leukocyte-mediated organ injury was tested in a preclinical model. Twenty-two pigs underwent 180 minutes of CPB and 5 hours postoperative observation. Pigs received no intervention (group 1, n = 9), 3 hours of therapy by incorporation of L-MOD into the CPB circuit (group 2, n = 6), or 8 hours of therapy using a femoral venovenous L-MOD circuit during and after CPB (group 3, n = 7). Leukocyte activation was increased at the end of CPB and leukocyte counts, namely neutrophils, increased postoperatively in most animals. These indices trended much lower in group 3. Systemic vascular resistance was not as reduced post-CPB for the L-MOD-treated pigs, and urine output was significantly greater for group 3 (p < 0.01). At 5 hours post-CPB, group 3 had a lower troponin-I (1.59?±?0.68?ng/ml) than group 1 or group 2 (3.97?±?2.63 and 3.55?±?2.04?ng/ml, respectively, p < 0.05) and a lower urine neutrophil gelatinase-associated lipocalin (7.57?±?3.59?ng/ml) than the average of the other groups (50.71?±?49.17, p < 0.05). These results demonstrate the therapeutic potential of L-MOD therapy to mitigate the inflammatory response to CPB. Eight hours of venovenous L-MOD resulted in less organ injury and post-op organ dysfunction in this model.

SUBMITTER: Johnston KA

PROVIDER: S-EPMC6251777 | biostudies-literature | 2019 May/Jun

REPOSITORIES: biostudies-literature

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Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

Johnston Kimberly A KA Westover Angela J AJ Rojas-Pena Alvaro A Haft Jonathan W JW Toomasian John M JM Johnson Thomas T Buffington Deborah A DA Humes H David HD

ASAIO journal (American Society for Artificial Internal Organs : 1992) 20190501 4

Leukocyte (LE) activation during cardiopulmonary bypass (CPB) promotes a systemic inflammatory response that contributes to organ injury and postoperative organ dysfunction. A leukocyte modulatory device (L-MOD) for use during (and after) CPB to limit leukocyte-mediated organ injury was tested in a preclinical model. Twenty-two pigs underwent 180 minutes of CPB and 5 hours postoperative observation. Pigs received no intervention (group 1, n = 9), 3 hours of therapy by incorporation of L-MOD into ...[more]

PMID: 29863627

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Project description:Many children with a congenital heart defect undergo surgical correction requiring cardiopulmonary bypass. One-sixth of these patients take an angiotensin-converting enzyme inhibitor for heart failure treatment. The effect of angiotensin-converting enzyme inhibition on the fibrinolytic and inflammatory response in children undergoing cardiopulmonary bypass is unknown. In adults, angiotensin-converting enzyme inhibition attenuates the increase in plasminogen activator inhibitor-1 after cardiopulmonary bypass, whereas the effect on the interleukin-6 response is uncertain. This study tests the hypothesis that preoperative angiotensin-converting enzyme inhibition attenuates postoperative plasminogen activator inhibitor-1 and interleukin-6 expression after cardiopulmonary bypass in children.Single-center prospective, randomized, nonblinded study.University-affiliated pediatric hospital.Children undergoing elective surgical correction of a congenital heart defect requiring cardiopulmonary bypass and taking an angiotensin-converting enzyme inhibitor.Children were randomized to continue angiotensin-converting enzyme inhibitor until the morning of surgery (angiotensin-converting enzyme inhibitor group, n = 11) or to discontinue therapy 72 hrs before surgery (no angiotensin-converting enzyme inhibitor group, n = 9).Blood samples were collected at baseline before cardiopulmonary bypass, at 30 mins of cardiopulmonary bypass, on arrival to the intensive care unit, and on postoperative day 1. Baseline bradykinin concentrations were significantly higher and angiotensin-converting enzyme activity significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin-converting enzyme inhibitor group (p = .04 and .001, respectively). Plasminogen activator inhibitor-1 antigen increased 15-fold after cardiopulmonary bypass and peaked on postoperative day 1 (from 4.6 ± 1.2 to 67.7 ± 9.5 ng/mL; p < .001). Postoperative day 1 plasminogen activator inhibitor-1 antigen correlated significantly with cardiopulmonary bypass time (r2 = 0.40, p = .03) and was significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin-converting enzyme inhibitor group (p = .03). The proinflammatory markers interleukin-6 and interleukin-8 as well as the anti-inflammatory marker interleukin-10 increased significantly after cardiopulmonary bypass (all p < .001). Interleukin-6 concentrations were significantly higher in the angiotensin-converting enzyme inhibitor group after cardiopulmonary bypass (p = .02) even after controlling for potential confounding factors such as age, cardiopulmonary bypass time, and transfusion volume.Angiotensin-converting enzyme inhibition attenuates the increase in postoperative plasminogen activator inhibitor-1 but enhances the interleukin-6 response in children undergoing cardiopulmonary bypass.

Project description:Background Cardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll-like receptor 4) and TNF-α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB-induced inflammation and cardiac dysfunction. Methods and Results Rats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart-lung machine. Compared with vehicle, AdipoRon application attenuated the CPB-induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle-treated animals. The AdipoRon-mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K+. In myocardial tissue, AdipoRon activated AMP-activated protein kinase (AMPK) while attenuating CPB-induced degradation of nuclear factor κB inhibitor α (IκBα), upregulation of TNF-α, IL-1β, CCL2 (C-C chemokine ligand 2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inducible nitric oxide synthase. Correspondingly, in cultured cardiac myocytes, cardiac fibroblasts, and vascular endothelial cells, AdipoRon activated AMPK, upregulated IL-10, and attenuated activation of nuclear factor κB, as well as upregulation of TNF-α, IL-1β, CCL2, NADPH oxidase, and inducible nitric oxide synthase induced by lipopolysaccharide or TNF-α. In addition, the treatment of cardiac myocytes with the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside resulted in a similar inhibition of lipopolysaccharide- and TNF-α-induced inflammatory cell phenotypes as for AdipoRon. Conclusions Our observations indicate that AdipoRon attenuates CPB-induced inflammation and impairment of cardiac function through AMPK-mediated inhibition of proinflammatory TLR4 and TNF-α signaling in cardiac cells and upregulation of immunosuppressive IL-10.

Project description:IntroductionInduction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB.MethodsWe performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled.ResultsEight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.ConclusionsAlthough the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.

Project description:ObjectivesChildren undergoing cardiopulmonary bypass develop clinically impactful capillary leak of unclear etiology. A widely held hypothesis that exposure of circulating cells to the cardiopulmonary bypass circuit induces the release of inflammatory mediators that act to disrupt intercellular junctions of capillary endothelial cells inducing paracellular capillary leak either directly or through new gene expression.DesignCohort study.SettingTertiary pediatric hospital.PatientsTwenty children undergoing surgery with cardiopulmonary bypass for congenital heart disease. Serum was collected before cardiopulmonary bypass, 2 hours after cardiopulmonary bypass, and 18 hours after cardiopulmonary bypass.InterventionsNone.Measurements and main resultsWe analyzed the effects of 10% patient sera on the "function, structure, and gene expression" of cultured human dermal and pulmonary microvascular endothelial cells. Changes in barrier "function" were measured using transendothelial electrical resistance. Associations between changes in transendothelial electrical resistance and subject characteristics were analyzed using linear mixed effects model with area under the resistance curve as outcome. Changes in junctional "structure" were assessed by analyzing the organization of the endothelial cell junctional proteins claudin-5 and VE-cadherin using immunofluorescence microscopy. Changes in inflammatory "gene expression" were measured using real-time quantitative reverse transcription-polymerase chain reaction. All serum samples induced a transient, 120-minute increase in transendothelial electrical resistance followed by persistent loss of barrier function. Unexpectedly, sera collected postcardiopulmonary bypass-induced significantly less loss of barrier function in both dermal and pulmonary capillary endothelial cell compared with precardiopulmonary bypass sera. Consistent with the transendothelial electrical resistance results, claudin-5 and vascular endothelial-cadherin junctional staining showed less disruption in cultures treated with postcardiopulmonary bypass sera. Expression of genes commonly associated with inflammation was largely unaffected by patient sera.ConclusionsContrary to the hypothesis, sera taken from children after cardiopulmonary bypass induces less capillary barrier disruption relative to sera taken from children before cardiopulmonary bypass, and none of the sera induced significant changes in expression of inflammatory genes.

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Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

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Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

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