[Alterations of metalloproteinases and their inhibitors concentrations in peripheral blood in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass]. / Zmiany stezen metaloproteinaz i ich inhibitorów w krwi obwodowej dzieci z wrodzona wada serca poddanych zabiegowi kardiochirurgicznemu z uzyciem krazenia pozaustrojowego.

Cardiac surgery with cardiopulmonary bypass (CPB) in children with congenital heart disease induces neutrophil activation, degranulation and systemic inflammatory response. Matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) are enzymes involved in degranulation and leukocyte extravasation. These are secreted as a pro-enzyme in response to several inflammatory mediators and are inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1) and tissue inhibitor of metalloproteinase-2 (TIMP-2). To explore metalloproteinase activation during cardiac surgery we investigated MMP-9, MMP-2, TIMP-1 and TIPM-2 levels in young children during and after surgery. We measured the dynamics of these enzyme concentrations in peripheral blood. Additionally we measured CD11b and CD66b molecule expression on neutrophils. These investigations were carried out in 39 children, aged 5-38 months who were undergoing cardiacsurgery with cardiopulmonary bypass (CPB). Serum concentrations of MMPs and their inhibitors, CD11b and CD66b expression on neutrophils were sequentially measured before induction of anesthesia, at the initiation of CPB, after 30 minutes of CPB, at the end of CPB, 4 and 48 hours after CPB. MMP-9 concentration increased at the end of CPB and remained elevated for a period of 48 hours. The concentration of MMP-9 detected at the end of CPB positively correlated with time of CPB (r=0.68, p=0.0045). TIMP-1 concentration decreased significantly after 30 minutes of CPB, remained lowered to the end of CPB, and returned to the start of CPB level after 48 hours. CD11b and CD66b expression on neutrophils increased at the initiation of CPB. Our data confirm that MMPs play an important role in inflammatory complications after cardiac surgery in children. These findings suggest that kinetics of MMPs concentrations in serum after cardiac surgery appear to depend on many factors. We demonstrated the link between CPB duration and the MMP-9 concentration. Future studies will determine whether inhibition of MMPs activity diminishes morbidity in children after cardiac surgery.

Proteolytic and cytokine balance abnormalities in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) in children with congenital heart disease induces a systemic inflammatory response. This inflammatory response is thought to be produced by exposing patients to proinflammatory factors. AIM: To explore the role of cytokines and proteolytic enzymes in inflammatory complications after cardiac surgery in children. METHODS: We investigated the dynamics of concentrations of IL-6, IL-8 and IL-10, and metalloproteinases (MMPs) MMP-2 and MMP-9, and their inhibitors - tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2. These investigations were carried out in 28 children, aged 4-34 months, who underwent a cardiac operation with CPB. Serum concentrations of proteins were sequentially measured before induction of anaesthesia, at the initiation of CPB, after 30 minutes of CPB, at the end of CPB, and 4 and 48 hours after CPB. RESULTS: The serum levels of IL-6 increased dramatically 4 hours after CPB compared with the level before anaesthesia (141.83+/-25.49 vs. 10.68+/-5.01 ng/ml, p=0.00004) and correlated with duration of CPB (r=0.74, p=0.00028). The serum levels of IL-8 increased 4 hours after CPB compared with the level before anaesthesia (267.1+/-41.3 vs. 8.5+/-6.3 ng/ml, p=0.00002). A significant increase of IL-10 concentration at the end of surgery and 4 hours after CPB was detected (95.12+/-23.57 vs. 10.34+/-6.45 ng/ml, p=0.000004 and 59.41+/-21.4 vs. 10.34+/-6.45 ng/ml, p=0.00004, respectively ). The MMP-9 concentration increased at the end of CPB and remained elevated for a period of 48 hours (44.40+/-13.95 vs. 19.53+/-7.58, p=0.000004 and 38.97+/-10.76 vs. 19.53+/-7.58, p=0.00004, respectively). The concentration of MMP-9 detected at the end of CPB positively correlated with duration of CPB (r=0.68, p=0.0045). The TIMP-1 concentration decreased significantly after 30 minutes of CPB, and remained lowered to the end of CPB (respectively 52.68+/-17.72 vs. 83.29+/-17.06 ng/ml, p=0.000006 and 34.94+/-10.58 vs. 83.29+/-17.06 ng/ml, p=0.00004,respectively). CONCLUSIONS: Cardiac surgery causes an increase of IL-6 and IL-8 concentrations in peripheral blood 4 hours after CPB termination. The concentration of anti-inflammatory IL-10 cytokine increases immediately after the end of CPB. We showed an increase of the MMP-2 and MMP-9 concentrations during and after CPB and simultaneous decrease of TIMP-1 inhibitor. We demonstrated a link between CPB duration and IL-6 and MMP-9 concentrations.

Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy.

BACKGROUND: The regulation of mesangial extracellular matrix (ECM) turnover engages a number of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). High glucose concentration affects ECM degradation and the activities of MMPs and TIMPs. ECM accumulation is involved in the pathogenesis of diabetic nephropathy. METHODS: Serum MMP-9, MMP-2, TIMP-2 and TIMP-1 were measured with ELISA in patients with either chronic renal failure (CRF, n=20), type 2 diabetes mellitus (DM2, n=16) or diabetic nephropathy (DM2+CRF, n=14), and healthy controls (n=20). RESULTS: Diabetic nephropathy was related with profound decrease of serum TIMP-2 (122.2 +/- 47.2 vs. 263.0 +/- 89.2 ng/mL), TIMP-1 (242.5 +/- 96.9 vs. 347.4 +/- 87.2 ng/mL) and MMP-2 (385.4 +/- 42.6 vs. 517.2 +/- 75.4 ng/mL) (p<0.001). Both TIMP-1 and TIMP-2 were reduced in diabetic nephropathy in comparison with either diabetes alone (p<0.01 and p<0.001; respectively) or CRF alone (p<0.001 for both). An approximately 2-fold increase of MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio was found in diabetic nephropathy when compared with diabetes with normal renal function (p<0.01). Further, in DM2 patients, TIMP-2 was decreased when compared with CRF alone (219.2 +/- 71.8 vs. 296.8 +/- 58.4 ng/mL). MMP-2 was lowered in both groups of DM2 and CRF patients (413.8 +/- 59.0 ng/mL and 409.7 +/- 93.1 ng/mL, vs. normal control value of 517.2 +/- 75.4 ng/mL; p<0.001). CONCLUSIONS: These data indicate that circulating TIMP-1, TIMP-2 and MMP-2 are decreased in patients with diabetic nephropathy when compared with either CRF or diabetes.

[The significance of neutrophil in inflammatory response after cardiac surgery with cardiopulmonary bypass]. / Rola neutrofila w reakcji zapalnej po zabiegu kardiochirurgicznym z uzyciem krazenia pozaustrojowego.

Cardiac surgery with cardiopulmonary bypass (CPB) can lead to postoperative complications like systemic inflammatory response syndrome (SIRS). These changes are associated with a risk of postoperative organ dysfunction and increased morbidity and mortality in the postoperative period. Its etiology is not yet clarified in details, but this thought to be of immunologic origin. The exact knowledge of these reactions is crucial for the selection of treatment strategies. Cardiac surgery induces neutrophil activation, degranulation and endothelial dysfunction. The nature of the participation of the neutrophil and its time course in the post CPB inflammatory response remains controversial. The aim of this work is to review state-of-the-art knowledge about neutrophil and the role of this cell as a regulator of immune response after cardiovascular surgery.

TNF-alpha priming effect on polymorphonuclear leukocyte reactive oxygen species generation and adhesion molecule expression in hemodialyzed patients.

INTRODUCTION: The study aimed to assess reactive oxygen species generation and the expressions of some surface antigens on polymorphonuclear leukocytes (PMNs) in patients on regular hemodialysis (HD) treatment. MATERIALS AND METHODS: The respiratory burst of PMNs was determined with luminol-dependent chemiluminescence (CL) in resting cells and following N-formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol 12-myristate 13-acetate (PMA), or opsonized zymosan (OZ) stimulation and expressed in arbitrary CL units times assay-time (aU x min). The expressions of CD11b/CD18, CD10, and CD13 receptors were determined with flow cytometry. RESULTS: Basal PMN CL was increased in HD patients to up to 1285 +/- 129 aU x min compared with 895 +/- 88 aU x min in healthy controls (p < 0.05). The CL of unprimed PMNs increased after fMLP stimulation from 3085 +/- 746 to 4529 +/- 808 aU x min, and after OZ stimulation from 12945 +/- 1296 to 14678 +/- 1355 aU x min. PMA-stimulated CL of PMNs was similar to control values. The oxidative burst in PMNs from HD patients and healthy controls was similar in response to TNF-alpha alone. The CL of TNF-alpha-primed PMNs in HD patients was significantly lower than CL measured in healthy controls (p < 0.05). The expressions of CD10 and CD13 metalloproteinase receptors were also increased (p < 0.05). Although CD11b expression was significantly increased at rest and after fMLP stimulation, the expression of another beta-integrin heterodimer compound, CD18, was not increased. CONCLUSIONS: These results provide evidence that TNF-alpha priming of PMNs is down-regulated in HD patients despite constitutive up-regulation of resting cytotoxicity and enhanced expression of adhesion and metalloproteinase receptors.

[Role of interleukin 10 in inflammatory response after cardiovascular surgery with cardiopulmonary bypass]. / Rola interleukiny 10 w odpowiedzi zapalnej po zabiegu kardiochirurgicznym z zastosowaniem krazenia pozaustrojowego.

Cardiac surgery (CS) induces a systemic inflammatory response that may be implicated in postoperative organ dysfunction. The exposure of blood cells and plasma to artificial membranes and the activation of several cell types in the setting of ischemia and reperfusion are believed to play an important role in the development of this reaction. Various mediators have been reported to be involved in the CS-induced reaction, which can lead to postoperative organ dysfunction. Understanding the role of these mediators in systemic inflammatory response may lead to better prognostic assessment and therapeutic modalities. Interleukin 10 (IL-10) is a pleiotropic cytokine produced by both T cells and macrophages and possesses anti-inflammatory properties. IL-10 circulates in the blood of patients undergoing CS with cardiopulmonary bypass (CPB), and increased concentrations of IL-10 have been associated with an adverse clinical outcome. The aim of this work is to review current know-ledge about the role of IL-10 as a regulator of immune response after CS.

[Alterations of procalcitonin and interleukin 6 after cardiopulmonary bypass in children with congenital heart disease]. / Zmiany stezen prokalcytoniny i interleukiny 6 u dzieci z wrodzonq wadq serca podczas zabiegu kardiochirurgicznego i po jego zakonczeniu.

UNLABELLED: Cardiac surgery induces systemic inflammatory response that may have been implicated the postoperative organ dysfunction. This inflammatory response is thought to be produced by exposing patients to proinflammatory factors. The aim of our study was to investigate alterations in procalcitonin (PCT) concentration in peripheral blood in children as the potential early indicator of complications occurring during and after surgery in extracorporeal circulation. Additionally, we evaluated the perioperative time course of IL-6. MATERIAL AND METHODS: The investigations were carried out in 21 children undergoing cardiac operation with cardiopulmonary bypass (CPB). Serum concentrations of PCT and IL-6 were sequentially measured before induction of anesthesia, at the initiation of CPB, at the end of CPB, and 24 hours, and 72 hours after CPB. RESULTS: There was no significant PCT-elevation at all 5 times of measurement. Levels of IL-6 increased significantly after surgery, and remained elevated for up to 1 day. Peak values correlated with the duration of CPB (r=0.68, p=0.0006). CONCLUSIONS: We conclude, that cardiac surgery with CPB did not have any influence on the secretion of PCT in children. These results suggest that IL-6 was more effective than PCT to monitor patients with a favorable outcome.

Effect of cardiopulmonary bypass on neutrophil activity in pediatric open-heart surgery.

INTRODUCTION: The nature of the participation of neutrophils in the post-cardiopulmonary bypass (CPB) inflammatory response is not very clear. The aim of our study was to investigate alterations in neutrophil phagocytic activity and adhesion molecule expression on these cells in children during and after CPB. MATERIAL/METHODS: Twenty-one children aged 6-33 months with congenital heart disease, scheduled for pri mary corrective surgery, were enrolled. The expressions of CD11b adhesion molecules and Fc? receptor on neutrophils and their phagocytic activity were evaluated. The studied markers were sequentially measured before, at the initiation of, and after CPB. RESULTS: During the course of the operation, CD11b molecule expression on neutrophils showed a slight elevation at the start of CPB (876.5+/-104.8 mean fluorescence intensity, MFI, vs. 768.1+/-178.2; p = 0.0047), followed by a significant decrease to 689.01+/-166.7 MFI after completion of the procedure. The expression of CD11b molecule on neutrophils measured at the end of CPB inversely correlated with the duration of CPB (r = -0.68, p = 0.00059). The expression of CD16 antigen dropped significantly at the start of CPB (1164.6+/-307.3 MFI vs. 1327.4+/-345.3 MFI; p = 0.0007) and remained decreased until the end of CPB (814.0+/-198.1 MFI). CONCLUSIONS: These findings suggest that the characteristics of the neutrophil response to cardiac surgery appear to depend on many factors. We demonstrated a link between the duration of CPB and adhesion molecule expression on neutrophils.

Effects of cardiopulmonary bypass on the expression of adhesive molecules in children undergoing cardiac surgery due to congenital heart disorders.

BACKGROUND: Infants and small children who undergo cardiac surgery due to congenital heart disorders, are at risk of developing inflammatory complications and multi-organ failure. AIM: To assess the changes in the expression of adhesive molecules on neutrophils and in peripheral blood plasma in children undergoing cardiac surgery with or without the use of cardiopulmonary bypass (CPB). METHODS: In 18 children who underwent surgery with the use of CPB and in 7 children who underwent surgery without CPB, the expression of CD11b, CD11c and CD62L molecules on neutrophils and soluble adhesive molecules - L-selectin and ICAM-1, was assessed before, during and after cardiac surgery. RESULTS: A significant increase in the expression of CD11b on neutrophils at the time of the initiation of CPB was observed. The most pronounced decrease in the expression of CD11c was detected at the end of surgical procedure. There was also a negative correlation between L-selectin concentration measured at the end of CPB and CPB duration as well as between ICAM-1 concentration and duration of hypothermia. CONCLUSIONS: Cardiac surgery influences the expression of adhesive molecules on neutrophils and in blood plasma. These changes are more pronounced in children who undergo CPB, and depend on CPB duration as well as the use of hypothermia.

[Effect of cardiopulmonary bypass on selected neutrophil functions in children with cyanotic congenital heart disease]. / Wplyw krazenia pozaustrojowego na wybrane funkcje neutrofili u dzieci z wrodzona sinicza wada serca.

BACKGROUND: Cardiopulmonary bypass (CPB) is known to induce several pathogenic responses in cardiovascular surgery. Children suffering from cyanotic congenital heart disease (CCHD) have been assumed to have a deficiency in their defence mechanisms. The preoperative clinical condition (hypoxemia and circulation disorders) could initiate post CPB inflammatory response. The nature of the participation of neutrophils and its time course in the post CPB inflammatory response, however, is less clear. THE AIM of our study was to investigate alterations in expression of adhesion molecules and L-selectin on neutrophils, and soluble adhesion molecules levels in CCHD children. MATERIALS AND METHODS: 23 infants and children with congenital heart disease, scheduled for primary corrective surgical repair; were enrolled. Expression of CD11b. CD18, and CD62L on neutrophils was determined by cytometry. Additionally, serum concentrations of soluble ELAM-1, L-selectin were measured using enzyme-linked immunoassay. Blood samples of children with CCHD were collected at the following times: before anaesthesia, at the initiation of CPB, after 30 minutes of CPB, at the end of CPB, and 24 hours and 72 hours after surgery. RESULTS: The expression of CD11b molecule on neutrophils was increased significantly at the start of CPB and returned to the baseline after 24 hrs. In all patients, preoperative CD11b expression on neutrophils correlated with hypoxemia. Reduced CD62L expression on neutrophils and soluble L-selectin concentration were observed at the end of CPB. CONCLUSION: We conclude, that cardiac surgery with CPB has a suppressive effect on adhesion molecules expression in children with CCHD, These findings also suggest that the type of neutrophil response to cardiac surgery appears to depend on preoperative clinical condition.

[Participation of procalcitonin in inflammatory response after cardiovascular surgery]. / Udzial prokalcytoniny w reakcji zapalnej po zabiegu kardiochirurgicznym.

Cardiovascular surgery is associated with systemic inflammatory response syndrome (SIRS), and these patients are recognized to be at increased risk for delayed infectious complications. There is a need for effective and accurate biological and biochemical tests to support, or exclude, the diagnosis of infection. Inflammatory response involves the release of a wide array of mediators, which has led to the suggestion that some of these mediators could be used as markers of infection or sepsis severity. Recently, plasma procalcitonin (PCT) concentration has been proposed as an indicator of the presence of infection. The aim of this work is to review state-of-the-art knowledge about PCT and the role of this peptide as a regulator of immune response after cardiovascular surgery.