Inhibitory CD200R and proapoptotic CD95/CD95L molecules on innate immunity cells are modulated by cardiac surgery.

INTRODUCTION: Cardiac surgery directly initiates a systemic inflammatory response with the activation of both cellular and humoral parts of the immune system. Exaggerated immune system activation is associated with a risk of life-threatening multi-organ dysfunction (MOD) and increased morbidity and mortality in the postoperative period. The immune system response is regulated and terminated by inhibitory mechanisms, including the regulatory membrane molecules, such as CD200R, CD95, CD95L and soluble sCD200R. METHODS: We measured the expression of CD95, CD95L, CD200R and sCD200R molecules in granulocyte and monocyte populations in blood samples of 30 patients who underwent coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB). Samples collected before surgery, after surgery and in the postoperative period were analyzed by flow cytometry and ELISA. RESULTS: We found a significant increase in the percentage of granulocytes featuring the anti-inflammatory molecule CD200R (from 5% to 17.8%) after surgery. We presume that these cells were less susceptible to apoptosis because they rarely expressed CD95 as the CD200R(+)CD95(-) granulocyte sub-population prevailed. Only a small percentage of CD200R(+) granulocytes expressed simultaneously CD95 (from 0.5 to 2.06 %). This small population of CD200R(+)CD95(+) cells decreased expression of CD200R after surgery and, thus, was likely to be a source of increased sCD200R in serum (from 96 to 294 ng/mL). Also, the expression of CD95L on CD200R(+) granulocytes and CD95 on CD200R(+) monocytes was affected by surgery. The percentage of CD200R(+) monocytes was elevated on the 1(st) postoperative day (from 30.6 to 49.4 %) and dropped below the preoperative value on the 7(th) day after surgery (from 30.6 to 19.8 %). This population comprised mainly CD200R(+)CD95(+) monocytes in which the enhanced expression of CD95 was found. CONCLUSION: Our data show that the expression of CD200R, CD95 and CD95L was influenced by cardiac surgery and imply the role of these membrane molecules in cell regulation-inhibition and apoptosis following cardiac surgery.

Actual position of interleukin(IL)-33 in atherosclerosis and heart failure: Great Expectations or En attendant Godot?

Atherosclerosis has been recognized as an inflammatory/autoimmune disease. The long-standing low-grade inflammation which fuels its development is primarily focused on the components of the vessel wall. Originally, inflammation in atherogenesis was supposed to be driven by the pro-inflammatory Th1 cellular and cytokine immune response. On the basis of accumulating evidence, this view has been re-evaluated to include the Th17/Th1 axis which is shared by most diseases of sterile inflammation. The anti-inflammatory Th2 cellular and cytokine immune response is initiated concomitantly with the former two, the latter dampening their harmful reactions which culminate in full-blown atherosclerosis. Interleukin-33, a novel member of the IL-1 cytokine superfamily, was suggested to take part in the anti-atherogenic response by mediating the Th1-to-Th2 switch of the immune reactions. However, IL-33 is a multifaceted mediator with both pro- and anti-inflammatory activities, also called a "dual factor" or a "Janus face" interleukin. IL-33 occurs both in an extracellular (cytokine-like) and in a nuclear-bound (transcription factor-like) form, each of them performing distinct activities of their own. This review article presents the latest data relevant to IL-33's role in atherosclerosis and cardiac diseases as perceived by a cardiologist and a cardiac surgeon.

The long pentraxin PTX3: a candidate anti-inflammatory mediator in cardiac surgery.

Coronary artery bypass grafting (CABG) is performed with the use of cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) of the heart. The advantage of this technique, alternatively referred to as "on-pump" surgery, resides, for the surgeon, in relatively easy access to and manipulation with the non-beating, bloodless heart. However, the advantage that is, thereby, gained by the patient is paid off by an increased susceptibility to postoperative systemic inflammatory response syndrome (SIRS). Under unfavorable conditions, the inflammatory syndrome may develop into life-threatening forms of MODS (multiple organ dysfunction syndrome) or even MOFS (multiple organ failure syndrome). Deliberate avoidance of CPB, also known as "off-pump" surgery, attenuates early postoperative inflammation throughout its trajectory of SIRS→MODS→MOFS, but, in the long run, there appears to be no substantial difference in the overall mortality rates. In the last years, our knowledge of the pathophysiology of surgical inflammation has increased considerably. Recent findings, highlighting the as yet rather obscure role of pentraxin 3 (PTX3) in these processes, are discussed in this review article.

[Vitamin C and its physiological role with respect to the components of the immune system]. / Fyziologická úloha vitaminu C ve vztahu ke slozkám imunitního systému.

Vitamin C is a water soluble micronutrient commonly found in our diet which orchestrates the function of both innate and adaptive immune system, influencing both cellular and humoral immune responses. Vitamin C inhibits excessive activation of the immune system to prevent tissue damage, but also supports antibacterial activity, stimulates NK cells and differentiation of Th0 subset into Th1 characterized by interferon γ production. In addition, vitamin C interferes with the synthesis of proinflammatory cytokines, or with the expression of adhesive molecules. Moreover, vitamin C as an antioxidat protects the immune cells against intracellular ROS (reactive oxygen species) formed in the inflammatory response. Vitamin C as an enzymatic cofactor is extremely important in maintaining tissue integrity, and plays a crucial role in formation of skin, epithelial and endothelial barriers.

Pentraxin 3(PTX 3): an endogenous modulator of the inflammatory response.

Inflammatory or anti-inflammatory? That is the question as far as the acute-phase response and its mediators, the pentraxins, are concerned. Only some ten years ago, the classical or short pentraxin C-reactive protein and the newly discovered long pentraxin PTX3 were considered to exert most of the detrimental effects of acute inflammation, whether microbial or sterile in origin. However, accumulating evidence suggests an at least dichotomous, context-dependent outcome attributable to the pentraxins, if not a straightforward anti-inflammatory nature of the acute-phase response. This paper is focused on the inherent effects of pentraxin 3 in inflammatory responses, mainly in coronary artery disease and in Aspergillus fumigatus infection. Both are examples of inflammatory reactions in which PTX3 is substantially involved; the former sterile, the latter infectious in origin. Apart from different inducing noxae, similarities in the pathogenesis of the two are striking. All the same, the introductory question still persists: is the ultimate impact of PTX3 in these conditions inflammatory or anti-inflammatory, paradoxical as the latter might appear? We try to provide an answer such as it emerges in the light of recent findings.

Impact of methylprednisolone in priming solution of cardiopulmonary bypass on anti-inflammatory CD163 receptor during cardiac surgery.

We evaluated the influence of methylprednisolone in cardiopulmonary bypass fluid on scavenger receptor for hemoglobin CD163 molecule expression on monocytes of patients who underwent elective coronary artery bypass grafting with cardiopulmonary bypass with either exposure to methylprednisolone present in the cardiopulmonary bypass fluid (20 patients), or without methylprednisolone in the cardiopulmonary bypass fluid (22 patients) and operated on without cardiopulmonary bypass (42 patients). The dynamics of CD163 expression was also followed in patients operated on without cardiopulmonary bypass. This study was a retrospective analysis of a comparison of two studies. The expression of CD163 was determined quantitatively by standardized flow cytometry technique. The similarities in the dynamics of CD163 monocyte expression, comparing the patients operated on with or without cardiopulmonary bypass, were found. Compared to the preoperative level, CD163 monocyte expression was significantly elevated on the 1(st) postoperative day. Monocyte CD163 expression on the 1(st) postoperative day was evidently similar in both groups of patients operated without cardiopulmonary bypass (median value of mean fluorescence intensity (MFI) 18,896; interquartile range from 27,538 to 57,711; median value of MFI 18,863; interquartile range from 16,514 to 26,559; n.s.), suggesting high reproducibility of our flow cytometric method; the monocyte CD163 expression was significantly higher (median value of MFI 37,902; interquartile range from 27,538 to 57,711) on the 1(st) postoperative day in patients exposed to methylprednisolone compared to patients without this exposure (median value of MFI 20,995; interquartile range from 16,321 to 29,623) (p<0.001). We concluded that the expression of hemoglobin scavenger receptor CD163 on monocytes of cardiac surgical patients is induced by methylprednisolone present in cardiopulmonary bypass fluid.

Interferon gamma receptor expression on granulocytes of cardiac surgical patients is modulated differently by the type of cardiopulmonary bypass used.

AIMS: To follow the IFNγ receptor expression on monocytes and granulocytes of cardiac surgical patients with respect to the type of cardiopulmonary bypass (CPB). METHODS: Expression of IFNγ receptor on monocytes and granulocytes of 26 cardiac surgical patients operated with the use of either "standard" or "miniaturised" CPB was determined by flow cytometry. RESULTS: The significant increase in IFNγ receptor expression on monocytes on the 1(st) and on the 3(rd) postoperative days was revealed in both groups of patients (p<0.001) irrespective of the type of CPB used, being non-significantly different between groups. In contrast, the expression of IFNγ on granulocytes displayed significant differences in terms of the CPB used. Whereas, in "standard" CPB patients, granulocyte INFγ receptor expression reached its maximum immediately after surgery (p<0.01), in "miniivasive" CPB patients, the peak in INFγ receptor expression was postponed to the 1(st) postoperative day (p<0.05). Statistically significantly higher IFNγ receptor expression on granulocytes was found in "standard" CPB patients (p<0.05). CONCLUSION: Compared to "miniaturised" CPB patients, the significantly higher IFNγ receptor expression on granulocytes was found in "standard" CPB patients (p<0.05) on the 1(st) postoperative day.

Interleukin-33, a novel member of the IL-1/IL-18 cytokine family, in cardiology and cardiac surgery.

Interleukin-33 is a newly recognized cytokine of the IL-1 family. Unlike its other members IL-1α, IL-1ß and IL-18, interleukin-33 induces predominantly Th2-skewed immune responses. In this context, the effects of IL-33 are mostly anti-inflammatory. However, depending on the actual cytokine and cellular milieu, IL-33 can promote both Th1 and Th2 immune reactions. Most importantly for cardiology and cardiac surgery, IL-33 has emerged to represent the as yet unknown ligand of the orphan receptor ST2. Before the advent of IL-33, the ST2 receptor, currently recognized as the soluble one of its two isoforms, was considered to be an unfavorable prognostic marker in myocardial infarction, congestive heart failure and trauma/sepsis shock patients. Now we know that IL-33, when bound to the cellular membrane-anchored ST2L isoform of the receptor, can have certain beneficial effects on the aforementioned conditions. Various forms of IL-33 interaction with the respective isoforms of its cognate receptor are discussed here. The focus is on physiological and prognostic values in cardiac patients.

Neutrophil apoptosis by Fas/FasL: harmful or advantageous in cardiac surgery?

Polymorphonuclear leukocytes or neutrophils are the main executors of cellular death, both in septic inflammation during bacterial infection and in sterile inflammation during trauma or surgery. Whereas in septic inflammation neutrophils perform a useful function to fortify the host's defense against infection, in sterile inflammation, by contrast, they contribute to unwelcome tissue damage. Regardless of the situation, activated neutrophils exhibit a prolonged lifespan and delayed apoptotic death which, under normal conditions, is a prerequisite for their natural renewal. Traditionally, delayed neutrophil apoptosis was considered to promote trauma or surgical injury. According to the results of recent studies, however surprising they may appear, the reverse might be in keeping with what happens IN VIVO. Apoptotic signaling in neutrophils could, by contrast, contribute to intrinsic protection of the host's tissues. This review article, aimed preferentially but not exclusively at the cardiac surgeon, presents some new information in support of this viewpoint, which fits in with our own observations.

[Mucosal immunity with emphasis on urinary tract immunity and diabetes]. / Imunita na sliznicích se zretelem na sliznici urogenitálního traktu a diabetes.

Protective immune response in urinary tract is frequently impaired in patients with diabetes. Immunity in this mucosal compartment displays unique characteristics; e.g. absence of physiological microflora and lack of mucus. Pathogens are identified by the PRR receptors expressed on both epithelial and immune cells. Inflammatory response characterised by the acumulation ofgranulocytes is followed. Both protective and harm characteristics of inflammatory response are inseparable linked and delineated by gene polymorphisms in PRR receptors.

[Cardiac surgery operations and their influence on serum level of antiinflammatory cytokine interleukin-10]. / Kardiochirurgické operace a jejich vliv na sérovou hladinu protizánetového cytokinu interleukinu-10.

BACKGROUND: Cardiac surgical operation is followed by the development of inflammatory reaction. This reaction is regulated in many ways including the production of antiinflammatory cytokines such as IL-10 to avoid potentially harmful effects of inflammation. METHODS AND RESULTS: We compared serum levels of cytokines IL-10, IL-6, and IL-13 in the group of patients undergoing cardiac surgical operation using either cardiopulmonary bypass (CPB, n=17) or surged on the beating heart (n=17). We found significant elevation in the serum level of IL-10 during surgery with the peak immediately after finishing surgery in CPB patients and at the first postoperative day in non-CPB patients, respectively. There is statistically significantly higher level of IL-10 in CPB patients in comparison with non-CPB patients at the end of surgery. Serum level of IL-6 is elevated in both groups during surgery reaching maximum immediately after surgery in CPB patients and at the first postoperative day in patients without CPB, respectively. The serum levels of IL-13 are only nonsignificantly changed during operation and in postoperative period in both groups. CONCLUSIONS: The intensity of inflammatory response in CPB patients which is enhanced by massive contact activation of blood and extensive ischemia-reperfusion injury is regulated by the production of antiiflammatory IL- 10 cytokine.

[Transcription factor KLF2 (Krüppel-like factor 2) and natural defence of vascular endothelium]. / Transkripcní faktor KLF2 (Krüppel-like factor 2) a prirozená ochrana cévního endotelu.

Vascular endothelium, monocytes and T-lymphocytes belong to the key cellular populations, which take an active part in the host's defence reactions. A successful course of these reactions is determined by a meticulous control of all phases since the very first steps until final healing of all incurred wounds. Any failure of the control mechanisms may lead to the development of chronic inflammatory diseases with an autoimmune component, such as the rheumatoid arthritis or atherosclerosis. An inflammatory reaction which is already under way is regulated by anti-inflammatory cytokines. However, of equal importance is the maintenance of cellular participants of inflammatory reactions in a quiescent state while no pro-inflammatory stimuli are present. One of the most important endogenous mediators, which prevent a self-initiated activation of endothelial cells, monocytes and T-lymphocytes, is represented by the transcription factor Krüppel-like factor 2. Its impact on the mentioned cells is almost identical with the so-called pleiotropic effects of inhibitors of the enzyme HMG CoA reductase or statins. This review article offers an insight into basic preventive mechanisms exerted by KLF2, notably those related to atherosclerosis.

[Innate immunity, receptors for exogenous and endogenous danger patterns in immunopathogenesis of atherosclerosis--part II: TLR receptors, significance of genetic polymorphism of danger signals receptors]. / Pirrozená imunita, receptory pro exogenní a endogenní nebezpecné vzory v imunopatogenezi aterosklerózy II. cast. Receptory TLR, význam polymorfizmu receptoru pro nebezpecné vzory.

The most important set of receptors for danger patterns are TLR receptors. Together ten different TLR receptors were identified so far. Majority of TLR receptors is expressed on the cell surface to identify extracellulary localized danger signals. Some TLR receptors are also expressed in the intracellular compartment to identify intracellular danger signals. Receptors for danger signals display individual differences delineated by genetic polymorphism. The individual immune reactivity is developed in the context of genetic predisposition and the exposition to variable environmental factors. The differences in an individual immune reactivity are probably responsible for individual susceptibility or resistance to the development of immunopathological reactivity, which is involved in the immunopathogenesis of atherosclerosis.

[Innate immunity, receptors for exogenous and endogenous danger patterns in immunopathogenesis of atherosclerosis--part 1: identification of danger signals by innate immunity]. / Prirozená imunita, receptory pro exogenní a endogenní nebezpecné vzory v imunopatogenezi aterosklerózy I. cást: Prirozená imunita, rozlisení signálu nebezpecí.

Cellular and humoral components of innate immunity are able to identify danger signals both of the exogenous and endogenous origin. Exogenous danger signals are evolutionary conserved mosaics of danger patterns which are frequent in pathogenic microbes. Endogenous danger signals are raised during damage of self structures, by oxidative stress and/or by chemical modification of self molecules. Danger signals are identified by several families of molecules which are expressed on the surfaces of innate immunity cells. Among them the TLR receptors family which is associated with intracellular signaling pathway NF-kappaB is one of the most important. The inflammatory response is induced via activated NF-kappaB transcription factor.