Pavel Kunes

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.

CD200/CD200R Paired Potent Inhibitory Molecules Regulating Immune and Inflammatory Responses; part I: CD200/CD200R Structure, Activation, and Function

CD200/CD200R are highly conserved type I paired membrane glycoproteins that belong to the Ig superfamily containing a two immunoglobulin-like domain (V, C). CD200 is broadly distributed in a variety of cell types, whereas CD200R is primarily expressed in myeloid and lymphoid cells. They fulfill multiple functions in regulating inflammation. The interaction between CD200/CD200R results in activation of the intracellular inhibitory pathway with RasGAP recruitment and thus contributes to effector cell inhibition. It was confirmed that the CD200R activation stimulates the differentiation ofT cells to the Treg subset, upregulates indoleamine 2,3-dioxygenase activity, modulates cytokine environment from a Thl to a Th2 pattern, and facilitates an antiinflammatory IL-10 and TGF-beta synthesis. CD200/CD200R are required for maintaining self-tolerance. Many studies have demonstrated the importance of CD200 in controlling autoimmunity, inflammation, the development and spread of cancer, hypersensitivity, and spontaneous fetal loss.

The long pentraxin 3 in cardiac surgery: distinct responses in "on-pump" and "off-pump" patients.

Objective. Pentraxin 3 (PTX3) is a newly identified acute phase reactant with non-redundant functions in innate immunity. The purpose of this study was to assess the kinetics of release of PTX3 in cardiac surgical patients, operated on either with or without the use of cardiopulmonary bypass (CPB). Design. Thirty-four patients, seventeen in each group, were randomly assigned to CABG surgery performed either with (“on-pump”) or without (“off-pump”) CPB. Blood samples were collected both during and after the operation up to the 7th day. Results. In patients operated on with the use of CPB, PTX3 levels increased throughout the operation. Compared to baseline levels the highest PTX3 value (p<0.000) was attained on the 1st postoperative day in both “on-pump” and “off-pump” patients. In contrast to CPB patients, however, PTX3 levels in the latter group declined slowly, remaining elevated as long as the 3rd postoperative day (p<0.042). Conclusions. Operations performed with the use of CPB are associated with a more pronounced release of PTX3 immediatelly after operation.

Early Expression of FcRI (CD64) on Monocytes of Cardiac Surgical Patients and Higher Density of Monocyte Anti-Inflammatory Scavenger CD163 Receptor in “On-Pump” Patients

Objective. Activation of innate immunity cells is inseparably linked to cardiac surgical operation. The aim of this study was to assess the kinetics in the expression of receptor for Fc part of IgG, FcγRI (CD64), and scavenger receptor CD163 on peripheral blood cells of cardiac surgical patients and to examine the effect of cardiac bypass as a separable influence on the systemic acute inflammatory response. Methods. Forty patients, twenty in each group, were randomly assigned to CABG surgery performed either with “on-pump” or without “off-pump” cardiopulmonary bypass. Standardized quantitative flow cytometry method was used to determine the expression of surface markers. Results. The density of CD64 molecule on monocytes reached maximum on the 1st postoperative day (P<.001) whereas the peak for CD64 molecule expression on granulocytes was postponed to the 3rd postoperative day (P<.001). The expression of CD163 scavenger molecule on monocytes reached maximum on the 1st postoperative day (P<.001). The density of CD163 molecule on monocytes on the 1st postoperative day is significantly higher in “on-pump” patients in comparison with “off-pump” patients (P<.001). Conclusion. In cardiac surgical patients the expression of activation marker FcγR1 (CD64) on monocytes is increased earlier in comparison with granulocytes in both “on-pump” and “off-pump” patients. The expression of scavenger molecule CD163 on monocytes is significantly higher in “on-pump” patients.

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-1β 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 hosts 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 hosts 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.

Serum level of sCD163, a soluble receptor for hemoglobin, is influenced by cardiac surgery

Background:The scavenger receptor for complexes hemoglobin-haptoglobin (CD163), which is expressed on monocytes/ macrophages, is shed to the body fluids in a soluble form (sCD163). Objectives: To evaluate the dynamics of sCD163 in the blood of patients undergoing cardiac surgery. Patients and Methods: Sixty-one adult patients who underwent coronary artery bypass grafting (CABG) were enrolled in the study. They were assigned to undergo CABG using either cardiopulmonary bypass (CPB), “on-pump”, (22 patients), modified CPB, mini “on-pump”, (17 patients) or without CPB, “off-pump”, (22 patients) surgery. Serum levels of sCD163 in venous blood samples taken before and after surgery, and during an early postoperative period, were evaluated by Macro 163TM diagnostic kit (IQ Products, Groningen, NL). Results: Compared to the preoperative levels (“on-pump”; 344 ng/mL, “off-pump”; 314.5 ng/mL, mini-invasive “on-pump”; 336.5 ng/mL) serum levels were elevated at the finish of surgery, reaching maximum at the 1st postoperative day (“onpump”; 658 ng/mL; p<0.05, “off-pump”; 810.5 ng/mL; p<0.01; mini-invasive “on-pump”; 663 ng/mL; non-significant). No significant differences regarding the serum levels of sCD163 between different surgical approaches were found. Conclusion: Serum level of sCD163 scavenger molecule for hemoglobin is elevated at the end of surgery and at the 1st postoperative day, being little influenced by cardiopulmonary bypass.

Lipopolysaccharide Binding Protein and sCD14 are Not Produced as Acute Phase Proteins in Cardiac Surgery

Objectives. The changes in the serum levels of lipopolysaccharide binding protein (LBP) and sCD14 during cardiac surgery were followed in this study. Design. Thirty-four patients, 17 in each group, were randomly assigned to coronary artery bypass grafting surgery performed either with (“on-pump”) or without (“off-pump”) cardiopulmonary bypass. LBP and sCD14 were evaluated by ELISA. Results. The serum levels of LBP were gradually increased from the 1st postoperative day and reached their maximum on the 3rd postoperative day in both “on-pump” and “off-pump” patients (30.33±9.96 μg/mL; 37.99±16.58 μg/mL), respectively. There were no significant differences between “on-pump” and “off-pump” patients regarding LBP. The significantly increased levels of sCD14 from the 1st up to the 7th postoperative day in both “on-pump” and “off-pump” patients were found with no significant differences between these groups. No correlations between LBP and sCD14 and IL-6, CRP and long pentraxin PTX3 levels were found. Conclusions. The levels of LBP and sCD14 are elevated in cardiac surgical patients being similar in both groups. These molecules are not produced as acute phase proteins in these patients.

Expression of CD200/CD200R regulatory molecules on granulocytes and monocytes is modulated by cardiac surgical operation

Aims: Cardiac surgical operation is inseparably linked to the induction of an inflammatory response. Both humoral and cellular regulatory mechanisms are operating to maintain body homeostasis. We followed the changes in the expression of CD200/CD200R regulatory molecules on monocytes and granulocyte of cardiac surgical patients operated on using either standard (OP) or modified “mini-invasive” cardiopulmonary bypass (MOP). Methods: Expression of CD200/CD200R regulatory molecules was determined by flow cytometry. Results: The expression of CD200R on granulocytes was increased after surgery in both groups of patients, but the increase was statistically significant only in OP patients (p<0.01). At this time point, there was a significant difference in CD200R expression on granulocytes when comparing OP to MOP patients, being higher in the former group (p<0.01). The expression of CD200R on monocytes was diminished after surgery and during an early postoperative period in both groups of patients. The expression of CD200 on monocytes was significantly diminished after surgery in both groups (p<0.01). Nonetheless, we observed an increase in CD200 expression in OP patients at the 3rd postoperative day. There was a statistically significantly increased CD200 expression on monocytes of OP patients (p<0.001) at the 3rd postoperative day when we compared OP and MOP groups. The expression of CD200 on granulocytes was significantly higher after surgery and at the 3rd postoperative day in OP when compared to MOP patients. Conclusions: CD200R expression on granulocytes was significantly increased, while CD200 and CD200R expression on monocytes was decreased after cardiac surgery.

The Effect of Conventional and Mini-Invasive Cardiopulmonary Bypass on Neutrophil Activation in Patients Undergoing Coronary Artery Bypass Grafting

Interleukin-10 (IL-10) is considered to be a cytokine with potent anti-inflammatory properties, which have been previously linked to increased incidence of sepsis. The level of IL-10 is elevated by cardiac surgery when cardiopulmonary bypass (CPB) and methylprednisolone are used. In our study, we compare the level of IL-10, IL-10 Receptor (IL-10R), and percentage of neutrophils between two groups of cardiac surgical patients undergoing Coronary Artery Bypass Grafting, both of which were not given methylprednisolone. The first group was operated with conventional CPB, while the second group was operated with minimally invasive CPB (mini-CPB). We detected enhanced level of IL-10 during surgery and at the end of surgery in both groups of patients. While no correlation between IL-10 and IL10R was found, IL-10 was positively correlated with increased percentage of neutrophils at the time points when the level of IL-10 peaked.