The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps.

The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity.

Systemic inflammation and antibodies to citrullinated peptides in hand osteoarthritis.

OBJECTIVES: To investigate systemic inflammation and autoimmune response to citrullinated peptides in patients with erosive and non erosive 'lone' hand osteoarthritis (HOA) with no hip/knee involvement and their relationship with radiographic structural damage. METHODS: Sera were obtained from a total of 99 patients with HOA (52 patients with erosive HOA and 47 patients with non-erosive HOA) and from 50 control subjects (NC). Hand radiographs were obtained from all patients and scored for joint damage according to the Kellgren-Lawrence and the Kallman scores. Serum levels of high-sensitivity CRP (hsCRP), IL-6, pentraxin-3 (PTX-3), anti-CCP and anti-modified citrullinated vimentin (MCV) antibodies were evaluated by a sandwich ELISA. RESULTS: Circulating levels of inflammatory biomarkers hsCRP, IL-6 and PTX3 were not significantly different in the two groups of patients with erosive and non-erosive HOA compared to NC and no significant difference was seen between non-erosive and erosive HOA. Anti-CCP positivity was detected respectively in 1 patient (2.1%) with non-erosive HOA and 1 patient (1.9%) with erosive HOA. Anti-MCV antibodies were present in 4 patients (8.5%) with non-erosive HOA, and 4 patients (7.7%) with erosive HOA. In the control group, one subject (2%) was positive for anti-CCP and 2 subjects (4%) had anti-MCV antibodies. Significant correlation was obtained only between body mass index and hsCRP concentration (r=0.4071; p<0.0001). No correlation between inflammation markers/autoantibodies and disease duration and radiological scores was found. CONCLUSIONS: Our study underlines the lack of systemic inflammation and autoimmunity in 'lone' HOA and confirms the association between BMI and CRP levels.

Dexamethasone prophylaxis in pediatric open heart surgery is associated with increased blood long pentraxin PTX3: potential clinical implications.

Glucocorticoid administration before cardiopulmonary bypass (CPB) can reduce the systemic inflammatory response and improve clinical outcome. Long pentraxin PTX3 is a novel inflammatory parameter that could play a protective cardiovascular role by regulating inflammation. Twenty-nine children undergoing open heart surgery were enrolled in the study. Fourteen received dexamethasone (1st dose 1.5 mg/Kg i.v. or i.m. the evening before surgery; 2nd dose 1.5 mg/kg i.v. before starting bypass) and fifteen children served as control. Blood PTX3, short pentraxin C-reactive protein (CRP), interleukin-1 receptor II (IL-1RII), fibrinogen and partial thromboplastin time (PTT) were assayed at different times. PTX3 levels significantly increased during CPB in dexamethasone-treated (+D) and dexamethasone-untreated (-D) subjects, but were significantly higher in +D than -D patients. CRP levels significantly increased both in +D and -D patients in the postoperative days, with values significantly higher in -D than +D patients. Fibrinogen and PTT values were significantly higher in -D than +D patients in the 1st postoperative day. IL-1RII plasma levels increased in the postoperative period in both groups. Dexamethasone prophylaxis in pediatric patients undergoing CPB for cardiac surgery is associated with a significant increase of blood PTX3 that could contribute to decreasing inflammatory parameters and improving patient clinical outcome.

Pentraxin 3 in acute respiratory distress syndrome: an early marker of severity.

OBJECTIVE: Pentraxin 3 is a fluid phase receptor involved in innate immunity. It belongs to the Pentraxins family, as C-reactive protein does. Pentraxin 3 is produced by a variety of tissue cells, whereas only the liver produces C-reactive protein. Pentraxin 3 plays a unique role in the regulation of inflammation. Acute lung injury and acute respiratory distress syndrome are characterized by an important inflammatory reaction. We investigated the role of pentraxin 3 as a marker of severity and outcome predictor of acute lung injury and acute respiratory distress syndrome. DESIGN: We measured circulating pentraxin 3 and C-reactive protein levels within 24 hrs from intubation (day 1), after 24 hrs from the first sample, then every 3 days for the first month and then once a week, until discharge from the intensive care unit. Pentraxin 3 was also measured in bronchoalveolar lavages, performed when clinically indicated. SETTING: One university medical center general intensive care unit. PATIENTS: The study included 21 patients affected by acute lung injury and acute respiratory distress syndrome (1994 Consensus Conference criteria). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pentraxin 3 plasma levels were high with a peak on the first day (median 71.05 ng/mL, interquartile range 52.37-117.38 ng/mL, normal values <2 ng/mL), declining thereafter. C-reactive protein peaked later and remained at relatively high values. Out of several day 1 parameters, pentraxin 3 was the only significant difference between survivors and nonsurvivors. Pentraxin 3 levels were positively correlated with lung injury score values (p < 0.001) and number of organ failures (p < 0.001). Pentraxin 3 was present in bronchoalveolar lavages fluids (5.03 ng/mL, interquartile range 1.52-8.48 ng/mL) and bronchoalveolar lavages positive to bacterial culture were associated with significantly higher pentraxin 3 values (p < 0.05). CONCLUSIONS: The results presented here show that pentraxin 3 is elevated in acute lung injury and acute respiratory distress syndrome and that its levels correlate with parameters of lung injury and systemic involvement. The clinical and pathophysiological significance of pentraxin 3 in acute lung injury and acute respiratory distress syndrome deserves further scrutiny.

PTX3 as a potential novel tool for the diagnosis and monitoring of pulmonary fungal infections in immuno-compromised pediatric patients.

Pentraxin-3 (PTX3) is a member of the long pentraxin superfamily and has a nonredundant role in mediating resistance to fungal pathogens. Serial monitoring of PTX3 plasmatic levels was performed in 10 pediatric leukemia patients affected by pulmonary fungal infections. When compared with values of a control pediatric cohort, PTX3 showed significantly higher plasmatic values. Moreover, the response to the antifungal therapy correlated with normalization of PTX3 values. PTX3 may represent a useful tool for the diagnosis and monitoring of fungal infections in immuno-compromised children.

The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells.

Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 (MART-1) tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.

Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-gamma.

The protopypic long pentraxin 3 (PTX3) is a unique, humoral pattern-recognition receptor, which plays a nonredundant function in innate resistance to pathogens. Dendritic cells (DC) of myelomonocytic origin, but not plasmacytoid DC, are a major source of PTX3 in response to Toll-like receptor (TLR) engagement. The present study was designed to explore the regulation of PTX3 production in DC. PTX3 production was induced by TLR ligands, CD40 ligand, and interleukin (IL)-1beta and was suppressed by dexamethasone, 1alpha, 25-dihydroxivitamin D3, and prostaglandin E2. It was unexpected that lipopolysaccharide (LPS)-stimulated PTX3 production was enhanced by IL-10 and inhibited by IL-4 and interferon-gamma (IFN-gamma). Enhancement of PTX3 production by IL-10 was also evident when Pam3 Cys-Ser-(Lys)4.3HCl, a TLR2-TLR1 agonist, polyionisicpolycytidylic acid, a TLR3 agonist, and IL-1beta were used as stimuli. The effect of IL-10 was blocked by an anti-IL-10 monoclonal antibody (mAb) or an anti-IL-10 receptor alpha mAb, which also reduced the LPS-induced production. Thus, production of PTX3 in DC is subjected to a distinct regulatory network, with inhibition by IFN-gamma and enhancement by IL-10. The amplification by IL-10 of production of a nonredundant component of fluid-phase innate immunity mirrors the IL-10 stimulatory function on B cells in adaptive immunity. As PTX3 is also an extracellular matrix component, IL-10-enhanced PTX3 production may play a role in orchestration of tissue remodeling in chronic inflammation.

Interferon-activated neutrophils store a TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) intracellular pool that is readily mobilizable following exposure to proinflammatory mediators.

Neutrophils are versatile cells, which play a role, not only in inflammatory processes but also in immune and antitumoral responses. Recently, we have reported that interferon (IFN)-activated neutrophils are able to release biologically active tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2 ligand), a molecule exerting selective, apoptotic activities toward tumor and virus-infected cells, as well as immunoregulatory functions on activated T lymphocytes. Herein, we show that only a minor fraction of the total TRAIL, newly synthesized by IFN-activated neutrophils within 24 h, is released outside, the rest being retained intracellularly, mainly in secretory vesicles and light membrane fractions. We demonstrate that the intracellular pool of TRAIL present in IFN-pretreated neutrophils is rapidly mobilizable to the cell surface and can be secreted following exposure to proinflammatory mediators such as TNF-alpha, lipopolysaccharide, formyl-methionyl-leucyl-phenylalanine, CXC chemokine ligand 8/interleukin-8, insoluble immunocomplexes, and heat shock protein Gp96. These various proinflammatory agonists functioned as effective secretagogue molecules only, in that they failed to augment TRAIL mRNA expression or TRAIL de novo synthesis in freshly isolated neutrophils or cultured with or without IFN. In addition, supernatants from IFN-treated neutrophils stimulated with proinflammatory mediators induced the apoptosis of target cells more effectively than supernatants from neutrophils activated with IFNs alone. Collectively, our results uncover a novel mechanism, whereby the release of soluble TRAIL by neutrophils can be greatly amplified and further reinforce the notion that neutrophils are important cells in tumor surveillance and immunomodulation.

FGF2-induced upregulation of DNA polymerase-delta p12 subunit in endothelial cells.

p12 represents the smallest, so far poorly characterized subunit of the mammalian DNA polymerase delta (pol delta) heterotetramer. Previously, to gain a molecular understanding of endothelial cell activation by fibroblast growth factor-2 (FGF2), we identified an upregulated transcript in FGF2-overexpressing murine aortic endothelial cells (FGF2-T-MAE cells) showing 89% identity with human p12. Here, we cloned the open reading frame of the murine p12 cDNA and confirmed the capacity of overexpressed or exogenously added FGF2 to upregulate p12 mRNA and protein in endothelial and NIH3T3 cells with no effect on the other pol delta subunits. p12 expression was instead unaffected by serum and different mitogens. Also, anti-p12 antibodies decorated FGF2-T-MAE cell nuclei and their chromosome outline during metaphase. Small interfering RNA-mediated knockdown of p12 caused a significant decrease in FGF2-driven proliferation rate of FGF2-T-MAE cells, in keeping with a modulatory role of p12 in pol delta activity. Immunoistochemistry of FGF2-embedded Matrigel plugs and FGF2-overexpressing tumor xenografts demonstrated a nuclear p12 staining of angiogenic CD31(+) endothelium. p12 immunoreactivity was also observed in the CD45(+)/CD11b(+) inflammatory infiltrate. Thus, FGF2 upregulates p12 expression in endothelial cells in vitro and in vivo. p12 expression in infiltrating inflammatory cells may suggest additional, cell proliferation-unrelated functions for this pol delta subunit.

The long pentraxin PTX3 in vascular pathology.

Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition proteins characterized by a cyclic multimeric structure. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver in response to IL-6, while PTX3 is produced by a variety of tissues and cells and in particular by innate immunity cells in response to proinflammatory signals and Toll-like receptor (TLR) engagement. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes, acting as a predecessor of antibodies. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor acting as a non-redundant component of the humoral arm of innate immunity and involved in tuning inflammation, in matrix deposition and female fertility.

Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction.

BACKGROUND: Inflammation has a pathogenetic role in acute myocardial infarction (MI). Pentraxin-3 (PTX3), a long pentraxin produced in response to inflammatory stimuli and highly expressed in the heart, was shown to peak in plasma approximately 7 hours after MI. The aim of this study was to assess the prognostic value of PTX3 in MI compared with the best-known and clinically relevant biological markers. METHODS AND RESULTS: In 724 patients with MI and ST elevation, PTX3, C-reactive protein (CRP), creatine kinase (CK), troponin T (TnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed at entry, a median of 3 hours, and the following morning, a median of 22 hours from symptom onset. With respect to outcome events occurring over 3 months after the index event, median PTX3 values were 7.08 ng/mL in event-free patients, 16.12 ng/mL in patients who died, 9.12 ng/mL in patients with nonfatal heart failure, and 6.88 ng/mL in patients with nonfatal residual ischemia (overall P<0.0001). Multivariate analysis including CRP, CK, TnT, and NT-proBNP showed that only age > or =70 years (OR, 2.11; 95% CI, 1.04 to 4.31), Killip class >1 at entry (OR, 2.20; 95% CI, 1.14 to 4.25), and PTX3 (>10.73 ng/mL) (OR, 3.55; 95% CI, 1.43 to 8.83) independently predicted 3-month mortality. Biomarkers predicting the combined end point of death and heart failure in survivors were the highest tertile of PTX3 and of NT-proBNP and a CK ratio >6. CONCLUSIONS: In a representative contemporary sample of patients with MI with ST elevation, the acute-phase protein PTX3 but not the liver-derived short pentraxin CRP or other cardiac biomarkers (NT-proBNP, TnT, CK) predicted 3-month mortality after adjustment for major risk factors and other acute-phase prognostic markers.

Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation.

We investigated the capacity of human islets to produce monocyte chemoattractant protein-1 (MCP-1). Primary cultures of pancreatic islets expressed and secreted MCP-1, as determined by Northern blot, immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. The produced MCP-1 was biologically active as it attracted monocytes in chemotaxis assay, and chemotactic activity was almost abrogated by a neutralizing anti-MCP-1 monoclonal antibody. Expression of MCP-1 was increased by primary inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha) and lipopolysaccharide at both the mRNA and protein levels but not by glucose. However, MCP-1 did not modulate insulin secretion. MCP-1 secreted by pancreatic islets plays a relevant role in the clinical outcome of islet transplant in patients with type 1 diabetes. In fact, low MCP-1 secretion resulted as the most relevant factor for long-lasting insulin independence. This finding opens new approaches in the management of human islet transplantation. Finally, the finding that MCP-1 appears constitutively present in normal human islet beta-cells (immunohistochemistry and in situ hybridization), in the absence of an inflammatory infiltrate, suggests that this chemokine could have functions other than monocyte recruitment and opens a new link between the endocrine and immune systems.

IFN-gamma-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection.

IFN-gamma-inducible protein 10 (IP-10/CXCL10) is a chemokine involved in delayed-type hypersensitivity and attraction of monocytes and activated T lymphocytes at inflammatory foci, whereas pentraxin 3 (PTX3) is part of the innate immune response. In the Republic of Guinea, 220 newly diagnosed, HIV-negative, pulmonary tuberculosis (TB) patients were studied together with 220 healthy household controls and 220 community controls. CXCL10 and PTX3 blood levels were assessed by ELISA at diagnosis, after 2 months and at the end of treatment. In untreated patients, both CXCL10 and PTX3 levels were higher (P < 0.0001) than in controls, although household controls had higher (P < 0.0001) CXCL10 and PTX3 levels than community controls, but lower (P < 0.0001) than those of patients. At the end of treatment, 186 cured patients showed reduction (P < 0.0001) in both CXCL10 and PTX3 levels. In 34 patients with treatment failure, both CXCL10 and PTX3 levels increased further. In five previously healthy households who developed TB during the follow-up and in two patients who relapsed after treatment, a remarkable increase in both CXCL10 and PTX3 plasma levels was observed. Active TB is associated with increased CXCL10 and PTX3 levels in the plasma. Although not specific for TB, measurement of these proteins may help the monitoring of disease activity and efficacy of therapy.

Long pentraxin PTX3 upregulates tissue factor expression in human endothelial cells: a novel link between vascular inflammation and clotting activation.

Inflammation is a major contributing factor to atherosclerotic plaque development and ischemic heart disease. PTX3 is a long pentraxin that was recently found to be increased in patients with acute myocardial infarction. Because tissue factor (TF), the in vivo trigger of blood coagulation, plays a dominant role in thrombus formation after plaque rupture, we tested the possibility that PTX3 could modulate TF expression. Human umbilical vein endothelial cells, incubated with endotoxin (lipopolysaccharide) or the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha, expressed TF. The presence of PTX3 increased TF activity and antigen severalfold in a dose-dependent fashion. PTX3 exerted its effect at the transcription level, inasmuch as the increased levels of TF mRNA, mediated by the stimuli, were enhanced in its presence. The increase in mRNA determined by PTX3 originated from an enhanced nuclear binding activity of the transacting factor c-Rel/p65, which was mediated by the agonists and measured by electrophoretic mobility shift assay. The mechanism underlying the increased c-Rel/p65 activity resided in an enhanced degradation of the c-Rel/p65 inhibitory protein IkappaBalpha. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. Our results suggest that PTX3, by increasing TF expression, potentially plays a role in thrombogenesis and ischemic vascular disease.

High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration.

The objective of this study was to evaluate whether the interleukin (IL)-1 decoy receptor (R), a negative pathway of regulation of IL-1, is correlated with severity of infection in critically ill patients and reflects the activation of anti-inflammatory pathways by glucocorticoid hormones. Plasma samples were obtained from 101 consecutive, critically ill patients admitted to the intensive care unit with different severities of microbial infection, as defined by standardized criteria. Here, we report that the IL-1 type II decoy R(II) is elevated in critically ill patients, especially in severe, systemic infection and culture-positive infections. In patients with a marked systemic inflammatory response syndrome 4, a pronounced, sepsis-induced further increase of circulating IL-1 decoy RII levels was evident. Thirty-six patients treated with glucocorticoid hormones had significantly higher levels of IL-1 decoy RII, but lower IL-6 and C-reactive protein, than 67 untreated subjects. The usefulness of IL-1RII, in particular as a potential marker for the activation of anti-inflammatory pathways or for responsiveness to anti-inflammatory agents such as glucocorticoid hormones, deserves further analysis.

The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation.

Pentraxin-3 (PTX3), an acute-phase protein that belongs to the family of the PTXs, is found elevated in septic shock and increased in patients with acute myocardial infarction. As tissue factor (TF) plays a key role in thrombosis and inflammation associated with atherosclerosis and as we have recently reported that PTX3 increases TF synthesis in endothelial cells, we tested whether PTX3 could modulate TF expression in monocytes. Monocytes from peripheral blood of healthy donors were incubated with highly purified PTX3 with or without lipopolysaccharide (LPS). Cells were then disrupted, and procoagulant activity was assessed by a one-stage clotting time. PTX3 enhanced TF activity and antigen from LPS-stimulated monocytes in a dose-dependent way. The effect was specific, as other PTXs, such as C-reactive protein and serum amyloid P component, were ineffective. Moreover, the increase in activity was specific for LPS, as in the presence of other TF-inducing agents such as interleukin-1beta and tumor necrosis factor alpha, PTX3 was not effective. The increase in TF activity requires mRNA synthesis, as assessed by polymerase chain reaction. The mechanism by which PTX3 modulates TF synthesis resides in an enhanced IkappaB, alpha phosphorylation and degradation and increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by Western blot and electro-mobility shift assay. These results show that PTX3 is an enhancer of the expression of TF by mononuclear cells. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. PTX3 increases TF expression, thus potentially playing a role in thrombogenesis and wound healing.

Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells.

Inflammation is a critical contributing factor to the development and the progression of atherosclerosis. Recently, the acute-phase protein pentraxin-3 (PTX3), which has C-terminal sequence homology with the classic pentraxin C-reactive protein (CRP), was described to be increased in patients with myocardial infarction. In this study, we have investigated the capacity of human primary vascular smooth muscle cells (VSMC), derived from arterial specimens of ten different patients, to express PTX3 after incubation with atherogenic lipoproteins. Enzymatically degraded LDL (E-LDL), which is present in human early lesions, mediated a rapid cholesterol loading and foam cell transformation of primary VSMC, which was paralleled by a marked dose- and time-dependent expression of PTX3 mRNA and release of the acute-phase protein. Expression of PTX3 mRNA was delayed and remained almost undetectable for up to 6 h of incubation with E-LDL. However, during extended exposure to E-LDL for more than 24 h, PTX3 mRNA expression increased by more than 15-fold in VSMC foam cells, which was reflected by a concomitant release of up to 211 ng/ml PTX3 protein. We provide evidence for marked expression of PTX3 by VSMC induced by degraded lipoproteins, which may lead to an in situ vascular acute-phase reaction, contributing to the inflammatory pathogenesis of atherosclerosis.

Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm.

PURPOSE: To investigate plasma and cerebrospinal fluid (CSF) concentrations of pentraxin 3 (PTX3), a prototypic long pentraxin protein induced by proinflammatory signals, in subarachnoid hemorrhage (SAH), and its relation with SAH-associated vasospasm. METHODS: Serial plasma and CSF samples were collected from 38 consecutive SAH patients admitted to the Neurosurgical Intensive Care. PTX3 concentrations were analyzed in relation to clinical status and clinical vasospasm (defined as neuro-worsening and angiographic confirmation of vessel narrowing). Since neutrophils are an important source of preformed PTX3, myeloperoxidase (MPO) in CSF was measured to assess the correlation with CSF PTX3 and establish whether blood contamination was the determinant of PTX3 increase. RESULTS: PTX3 was elevated in all SAH patients both in plasma and CSF. Acute peak (first 48 h after SAH) CSF PTX3 was significantly higher in patients who later developed vasospasm [median 13.6 (range 2.3-51.9) ng/ml] compared to those who did not [3.2 (0.1-50.5) ng/ml, p = 0.03]. The temporal pattern of CSF PTX3 in patients with vasospasm was triphasic with a peak during the first 48 h after SAH, a subsequent decrease in the following 48-96 h and a secondary significant increase with the occurrence of vasospasm. A loose correlation between CSF PTX3 and MPO was observed (r(2) = 0.13), indicating that following SAH there is a brain production of PTX3. CONCLUSIONS: Acute increased concentrations of PTX3 in CSF but not in plasma are related to the occurrence of vasospasm, indicating that measurement of CSF PTX3 associated with the clinical evaluation can improve early diagnosis of this complication.

Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality.

PURPOSE: Pentraxin 3 (PTX3) is an inflammatory mediator produced by neutrophils, macrophages, myeloid dendritic and endothelial cells. During sepsis a massive inflammatory activation and coagulation/fibrinolysis dysfunction occur. PTX3, as a mediator of inflammation, may represent an early marker of severity and outcome in sepsis. METHODS: This study is based on a prospective trial regarding the impact of glycemic control on coagulation in sepsis. Ninety patients admitted to three general intensive care units were enrolled when severe sepsis or septic shock was diagnosed. At enrollment, we recorded sepsis signs, disease severity, coagulation activation [prothrombin fragments 1 + 2 (F(1+2))] and fibrinolysis inhibition [plasminogen activator inhibitor-1 (PAI-1)]. We measured plasma PTX3 levels at enrollment, everyday until day 7, then at days 9, 11, 13, 18, 23 and 28. Mortality was recorded at day 90. RESULTS: Although not different on day 1, PTX3 remained significantly higher in non-survivors than in survivors over the first 5 days (p = 0.002 by general linear model). On day 1, PTX3 levels were higher in septic shock than in severely septic patients (p = 0.029). Day 1 PTX3 was significantly correlated with platelet count (p < 0.001), SAPS II score (p = 0.006) and SOFA score (p < 0.001). Day 1 PTX3 was correlated with F(1+2) concentration and with PAI-1 activity and concentration (p < 0.05 for all). CONCLUSIONS: Persisting high levels of circulating PTX3 over the first days from sepsis onset may be associated with mortality. PTX3 correlates with severity of sepsis and with sepsis-associated coagulation/fibrinolysis dysfunction.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial.

BACKGROUND: Inflammation may play a significant role in the pathogenesis of atrial fibrillation (AF). OBJECTIVES: To examine the roles of three systemic inflammatory markers in predicting recurrent AF. METHODS: The association between the plasma concentrations of high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6) and pentraxin-3 (PTX3) with echocardiographic parameters and with the time to first recurrence of AF was tested in 382 patients with a history of AF but in sinus rhythm at randomisation, enrolled in the GISSI-AF biohumoral study. RESULTS: Baseline PTX3 was related to left atrial, but not to left ventricular chamber volume. During one year of follow-up, 204 patients (53.1%) had a recurrent AF. There were no significant differences in baseline median [Q1-Q3] plasma concentrations of IL-6, hsCRP and PTX3 among patients with (2.11 [1.47-3.74] pg/ml, 3.30 [1.40-6.80] mg/l and 4.66 [3.27-6.97] ng/ml, respectively) or without recurrent AF (2.09 [1.37-2.90] pg/ml, p=0.182; 3.00 [1.10-6.20] mg/l, p=0.333; 5.09 [3.22-7.98] ng/ml, p=0.637). At 6 and 12 months follow-up, AF patients had significantly higher concentrations of IL-6 and PTX3 than those in sinus rhythm, and those with most recent episodes of AF had higher hsCRP. Baseline levels of IL-6, hsCRP or PTX3 were not significantly associated with a higher risk of recurrence of AF. CONCLUSION: In patients with a history of AF, but without significant left ventricular dysfunction or heart failure, inflammatory biomarkers may be raised but are, at best, weak predictors of the risk for first recurrence of AF.