Spyros Fotopoulos

Aghia Sophia Children’s Hospital, Athínai, Attica, Greece

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Publications (11)22.49 Total impact

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    ABSTRACT: Background:Activin-A is a cytokine with a critical role in infections and associated inflammation in experimental models and humans. Still, the effects of activin-A on neonatal infections remain elusive. Here, we investigated the expression of activin-A in the serum of septicaemic preterm and term neonates and in peripheral blood leukocytes stimulated with inflammatory agents in vitro. The role of activin-A in the regulation of inflammatory responses by neonatal leukocytes was delineated.Methods:Peripheral blood was obtained from 37 septicaemic neonates between the 1(st)-5(th) day post-infection and 35 healthy controls. Isolated monocytes and lymphocytes were stimulated with lipopolysaccharide (LPS) or phytohemaglutinin (PHA) in vitro in the presence of activin-A. Cell proliferation, cytokine and chemokine release were investigated.Results:Activin-A was significantly increased in the serum of preterm septicaemic neonates. Neonatal leukocytes secreted copious amounts of activin-A following stimulation, pointing to these cells as an essential source of activin-A in the circulation. Importantly, treatment of neonatal leukocytes with activin-A during PHA and LPS stimulation, resulted in significantly decreased IL-1β, IL-6 and CXCL8 production, concomitant with a striking increase in the anti-inflammatory mediator, IL-10.Conclusion:Our findings uncover activin-A as a novel immunomodulatory agent critical for the control of inflammatory responses in septicaemic neonates.Pediatric Research (2013); doi:10.1038/pr.2013.159.
    Pediatric Research 09/2013; · 2.67 Impact Factor
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    ABSTRACT: During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4- and anti-CD14-blocking antibodies and stimulated with LPS. Cytokine and chemokine levels were measured in supernatants. TLR4, CD14 expression, and LPS-induced CXCL8 release were higher in neonates, possibly contributing to aberrant inflammation. TLR4 blockade resulted in approximately 3-fold greater suppression of LPS-induced CXCL8 release in preterm neonates (38%) than in adults (14%). CD14 blockade (approximately 80%) in neonates induced approximately 3-fold greater inhibition of CXCL8 release, compared with anti-TLR4 (approximately 30%). Anti-TLR4 partly (50-60%) inhibited IL-10 and TNF-alpha, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, apart from TLR4/CD14-mediated signaling, is regulated by LPS interactions with other TLRs and/or immune receptors. IL-10 and TNF-alpha release depends on LPS binding not only to CD14/TLR4 but also to CD14 associated with another TLR. Our findings reveal the contribution of TLR4 and CD14 in neonatal cytokine and chemokine release and could aid in design of antagonists to prevent harmful inflammation.
    Pediatric Research 05/2009; 66(2):179-84. · 2.67 Impact Factor
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    ABSTRACT: Inflammation due to perinatal infection (PI) and perinatal asphyxia (PA) may cause damage to various tissues and very often to the immature brain of the fetus and the newborn. Previously, we have shown that the neonatal immune system has the ability to produce increased chemokine protein levels in the serum during the inflammatory response caused by PI and PA. The aim of our present study was to investigate mRNA levels of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) in peripheral blood leukocytes from infected and asphyxiated neonates. Forty-two premature neonates were studied; 11 with PI, 16 with PA and 15 without PA and PI, were used as controls. IL-8 and MCP-1 mRNA levels were investigated in whole blood and in phytohemagglutinin-activated lymphocytes using semi-quantitative polymerase chain reaction and real-time polymerase chain reaction, respectively. IL-8 mRNA levels were significantly increased in whole blood both during PA and PI, while MCP-1 mRNA levels were not. In vitro activated lymphocytes expressed significantly increased IL-8 mRNA levels during PI, whereas no increase was observed during PA. MCP-1 mRNA levels were significantly increased in activated lymphocytes during PA, while no increase was observed during PI. Our data show that chemokine mRNA levels expressed by activated lymphocytes during inflammation caused by PIs are different to those expressed during PAs. These findings might have important implications during the administration of specific chemokine antagonists in order to prevent or reduce tissue damage caused by inflammation.
    Neonatology 02/2007; 91(2):107-13. · 2.57 Impact Factor
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    ABSTRACT: The inflammatory response induced by perinatal infections and asphyxia is considered to participate in neonatal brain damage. Inflammatory responses are characterized by the expression of chemokines. Although chemokine levels have been investigated in healthy newborns, their role during neonatal pathological conditions has not been studied. The aim of our study was to examine chemokine serum levels in asphyxiated and infected neonates. Peripheral blood samples were obtained from perinatally asphyxiated and infected neonates during the first days of life and from neonates who developed nosocomial infections. Serum levels of interleukin-8 (IL-8), interferon-gamma-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and regulated upon activation, normal T cells expressed and secreted (RANTES) were determined. In perinatally asphyxiated neonates, IL-8 levels were significantly elevated on the 1st day of life. In perinatally infected neonates, IL-8 and IP-10 levels were significantly increased on the 1st day of life, while RANTES levels were significantly lower and remained so until the 4th day. In nosocomially infected neonates, IL-8, IP-10 and MIP-1alpha levels were significantly increased on diagnosis of infection. The neonatal immune system is able to produce chemokines for the induction of an inflammatory response during perinatal asphyxia and perinatal or nosocomial infections. Blockade of inflammatory chemokines could possibly contribute to the prevention of brain damage.
    Acta Paediatrica 07/2005; 94(6):800-6. · 1.97 Impact Factor
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    ABSTRACT: Sepsis related morbidity in neonates is mediated through innate inflammatory responses. The initial step in inflammation is the recognition of the invading microorganisms by immune cells which leads to their activation and the clearance of pathogens. Toll-like receptors expressed on immune cells bind to pathogens and trigger the release of pro-inflammatory cytokines. Aim: To investigate the innate immune response to Gram negative bacteria in healthy neonates and adults by evaluating the effect of in vitro LPS administration on: a) TLR4 surface expression on peripheral blood monocytes and b) IL-8 and TNF-alpha release from blood cultures. Materials and Methods: Peripheral blood from 10 preterm, 10 term neonates and 10 adults was incubated for 4 hours with or without 100ng/ml LPS. For blocking experiments, blood was pre-incubated with anti-TLR4 antibody for 30 minutes. Double staining with anti-CD14 and anti-TLR4 antibodies was performed by FACS and TLR4% expression as well as mean fluorescence intensity were estimated. IL-8 and TNFalpha release were assessed by ELISA in culture's supernatant. Results:TLR4 surface expression on monocytes before LPS stimulation was significantly higher in preterm neonates as compared to adults. Following LPS administration, TLR4 expression increased in all three groups, however the increase in adults was significantly higher to that found in preterms. TNF-alpha release was similar in all three groups. IL-8 release was significantly higher in full terms and preterm neonates as compared to adults. Blocking experiments with anti-TLR4 antibody partially decreased LPS-induced IL-8 release. Conclusions: Preterm neonates have higher baseline expression of TLR4 than adults and thus may be more susceptible to bacterial infections. Although TLR4 increase following LPS was lower in preterms as compared to adults, IL-8 release was higher. The partial inhibition of TLR4 by blocking antibody suggests that IL-8 production in newborns is also mediated through TLR4 independent pathways.
    Pediatric Research 01/2005; 58(2). · 2.67 Impact Factor
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    ABSTRACT: To determine serum levels of interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1) and C-reactive protein (CRP) in asphyxiated neonates and compare these inflammatory factors with those found in neonates with perinatal infection. 88 neonates were studied, of whom 36 were asphyxiated, 18 were infected and the remaining 34 were controls. Peripheral blood samples were obtained on the 1st, 3rd and 5th postnatal days. Cytokines IL-6 and IL-1beta as well as sICAM-1 serum levels did not differ between asphyxiated and infected neonates; however, at most time periods, their values were significantly higher than controls. TNF-alpha was similar in the three groups of neonates. CRP serum values were significantly higher in the infected neonates than in the asphyxiated or control subjects. Among the 54 asphyxiated and infected neonates, 15 were considered as severe cases and 39 as mild. The severe cases, at most time periods, had significantly higher IL-6, IL-1beta and sICAM-1 levels compared with the mild ones. Through receiver operating characteristic curves the cut-off points, sensitivities, and specificities for distinguishing neonates at risk or at high risk for brain damage were established. Similar increases in serum levels of IL-6, IL-1beta and sICAM-1 were found in perinatally asphyxiated and infected neonates. As these increases correlated with the severity of the perinatal insults, neonates at high risk for brain damage might be detected.
    Acta paediatrica (Oslo, Norway: 1992). Supplement 02/2002; 91(438):92-7.
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    ABSTRACT: We studied 57 low-birth-weight premature neonates, of whom 29 suffered from perinatal asphyxia and/or infection, while the remaining 28 did not and served as controls. We measured peripheral nucleated red blood cell (NRBC) absolute numbers as well as interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha cytokine serum levels at 24 h postnatally and on days 3 and 7 following birth. Fourteen of the asphyxiated/infected neonates and 12 controls had neurologic assessments at the corrected postnatal age of 18 months. We found NRBC absolute numbers and serum IL-1beta and IL-6 cytokine levels at 24 h postnatally to be significantly higher in neonates with perinatal asphyxia/infection than in the controls (p = 0.022, p = 0.036 and p = 0.037, respectively). TNF-alpha levels did not differ. Neurologic examination at the corrected postnatal age of 18 months showed 8 out of the 14 children who had been asphyxiated/infected as neonates to have abnormal findings, while 12 children who were used as controls during their neonatal period were normal. Abnormal neurologic findings correlated with high NRBC counts and IL-1beta and IL-6 levels at 24 h postnatally. In conclusion, increased NRBC counts and proinflammatory cytokine levels in asphyxiated/infected neonates represent early markers for subsequent neurologic impairment.
    Biology of the Neonate 02/2001; 79(3-4):213-8. · 1.90 Impact Factor
  • Pediatric Research - PEDIAT RES. 01/1999; 45(6).
  • Pediatric Research 01/1999; 45(6). · 2.67 Impact Factor
  • Pediatric Research 01/1999; 45. · 2.67 Impact Factor
  • Pediatric Research 01/1997; 41(5). · 2.67 Impact Factor