Nico A Maris

University of Amsterdam, Amsterdam, North Holland, Netherlands

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Publications (14)71.42 Total impact

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    ABSTRACT: Various lung diseases are associated with local activation of coagulation and concurrent inhibition of fibrinolysis. Although salmeterol, a beta2-adrenoceptor agonist with profound bronchodilatory properties, has been studied extensively, the effects of this compound on the pulmonary hemostatic balance are not elucidated. A single-blinded, placebo-controlled study. University hospital and laboratory. A total of 32 human volunteers. Subjects inhaled 100 microg of salmeterol or placebo (t = -30 mins) followed by 100 microg of lipopolysaccharide (LPS) or normal saline (t = 0 mins; n = 8 per group). Measurements were performed in bronchoalveolar lavage fluid obtained 6 hrs postchallenge. Inhalation of LPS enhanced pulmonary coagulation as determined by an increase in the concentrations of thrombin-antithrombin complexes, factor VIIa, and soluble tissue factor in bronchoalveolar lavage fluid (all p < .05 vs. saline). LPS concurrently inhibited pulmonary fibrinolysis, as reflected by a decrease in bronchoalveolar lavage fluid plasminogen activator activity together with an increase in plasminogen activator inhibitor type 1 (both p < .05 vs. saline). Moreover, LPS inhalation was associated with a suppression of the anticoagulant protein C pathway, as indicated by an increase in soluble thrombomodulin and decreases in protein C and activated protein C levels in bronchoalveolar lavage fluid (all p < .05 vs. saline). Salmeterol, either with or without LPS inhalation, enhanced fibrinolysis (plasminogen activator activity and tissue-type and urokinase-type plasminogen activator levels) but did not influence LPS-induced changes in coagulation or the protein C pathway. Salmeterol has profibrinolytic properties in the normal lung and when applied in a model of sterile pulmonary inflammation.
    Critical Care Medicine 01/2007; 35(1):57-63. · 6.12 Impact Factor
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    ABSTRACT: Intravenous administration of recombinant human activated protein C (rhAPC) is known to reduce lipopolysaccharide (LPS)-induced pulmonary inflammation by attenuating neutrophil chemotaxis towards the alveolar compartment. Ideally, one would administer rhAPC in pulmonary inflammation at the site of infection to minimize the risk of systemic bleeding complications. In this study, we therefore assessed the effect of inhaled rhAPC in a murine model of acute lung injury. Mice were exposed to LPS (0.5 mg kg(-1): intranasally) to induce acute lung injury. 30 minutes before and 3 hours after LPS exposure mice were subjected to vehicle or rhAPC inhalation (25 or 100 microg per mouse in each nebulization). In order to establish whether rhAPC inhalation affects neutrophil recruitment, neutrophil migration was determined in vitro using a trans-well migration assay. rhAPC inhalation dose-dependently decreased LPS-induced coagulation and inflammation markers in bronchoalveolar lavage fluid (BALF), reduced protein leakage into the alveolar space and improved lung function. In contrast, rhAPC did not prevent LPS-induced neutrophil recruitment into the alveolar space. Neutrophil migration in vitro towards FCS or interleukin (IL)-8 was significantly inhibited by pretreatment with rhAPC (0.01-10 microg ml(-1)], whereas rhAPC (10 microg ml(-1)) added to the chemoattractant (modelling for topical rhAPC administration) did not affect neutrophil migration towards FCS or IL-8. rhAPC inhalation significantly diminished LPS-induced pulmonary inflammation. The benefit of inhaled rhAPC appeared not to involve attenuation of neutrophil recruitment, in contrast to its effects after intravenous administration.
    British Journal of Pharmacology 12/2006; 149(6):740-6. · 5.07 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) are pattern-recognition receptors that have been implicated in the initiation of innate immune responses upon the first encounter with invading pathogens. The airways are frequently exposed to various types of lipopolysaccharide (LPS) from the environment or from pathogens. The current study was designed to determine the effect of LPS on TLR gene expression in human alveolar macrophages in vivo. In total, 16 healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg LPS or normal saline (n = 8 per group). Measurements were performed in alveolar macrophages purified from bronchoalveolar lavage fluid obtained 6 h post-challenge. Inhalation of LPS by healthy human volunteers resulted in enhanced alveolar macrophage expression of mRNAs encoding TLRs 1, 2, 7, 8 and CD14, and reduced expression of mRNAs encoding TLR4 and lymphocyte antigen 96. In conclusion, lipopolysaccharide differentially influences the toll-like receptor mRNA expression profile in human alveolar macrophages in vivo.
    European Respiratory Journal 10/2006; 28(3):622-6. · 6.36 Impact Factor
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    ABSTRACT: Nontypable Haemophilus influenzae (NTHi) is a common bacterial pathogen causing human respiratory tract infections under permissive conditions such as chronic obstructive pulmonary disease. Inhalation of beta2-receptor agonists is a widely used treatment in patients with chronic obstructive pulmonary disease. The aim of this study was to determine the effect of inhalation of beta2 agonists on the host immune response to respiratory tract infection with NTHi. Mouse alveolar macrophages were stimulated in vitro with NTHi in the presence or absence of the beta2 receptor agonists salmeterol or salbutamol. In addition, mice received salmeterol or salbutamol by inhalation and were intranasally infected with NTHi. End points were pulmonary inflammation and bacterial loads. Both salmeterol and salbutamol inhibited NTHi induced tumor necrosis factor-alpha (TNFalpha) release by mouse alveolar macrophages in vitro by a beta receptor dependent mechanism. In line, inhalation of either salmeterol or salbutamol was associated with a reduced early TNFalpha production in lungs of mice infected intranasally with NTHi, an effect that was reversed by concurrent treatment with the beta blocker propranolol. The clearance of NTHi from the lungs was impaired in mice treated with salmeterol or salbutamol, an adverse effect that was prevented by propranolol and independent of the reduction in TNFalpha. These data suggest that inhalation of salmeterol or salbutamol may negatively influence an effective clearance of NTHi from the airways.
    Respiratory research 02/2006; 7:57. · 3.64 Impact Factor
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    ABSTRACT: TLRs are important for the recognition of conserved motifs expressed by invading bacteria. TLR4 is the signaling receptor for LPS, the major proinflammatory component of the Gram-negative cell wall, whereas CD14 serves as the ligand-binding part of the LPS receptor complex. Triggering of TLR4 results in the activation of two distinct intracellular pathways, one that relies on the common TLR adaptor MyD88 and one that is mediated by Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF). Nontypeable Haemophilus influenzae (NTHi) is a common Gram-negative respiratory pathogen that expresses both TLR4 (LPS and lipooligosaccharide) and TLR2 (lipoproteins) ligands. To determine the roles of CD14, TLR4, and TLR2 during NTHi pneumonia, the following studies were performed: 1) Alveolar macrophages from CD14 and TLR4 knockout (KO) mice were virtually unresponsive to NTHi in vitro, whereas TLR2 KO macrophages displayed a reduced NTHi responsiveness. 2) After intranasal infection with NTHi, CD14 and TLR4 KO mice showed an attenuated early inflammatory response in their lungs, which was associated with a strongly reduced clearance of NTHi from the respiratory tract; in contrast, in TLR2 KO mice, lung inflammation was unchanged, and the number of NTHi CFU was only modestly increased at the end of the 10-day observation period. 3) MyD88 KO, but not TRIF mutant mice showed an increased bacterial load in their lungs upon infection with NTHi. These data suggest that the MyD88-dependent pathway of TLR4 is important for an effective innate immune response to respiratory tract infection caused by NTHi.
    The Journal of Immunology 12/2005; 175(9):6042-9. · 5.52 Impact Factor
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    ABSTRACT: Salmeterol is a beta2-adrenoreceptor agonist used in the treatment of obstructive pulmonary disease. Salmeterol inhibits inflammatory responses by neutrophils and mononuclear cells in vitro and in mouse models of lung inflammation in vivo. To determine the effect of salmeterol on LPS-induced lung inflammation in humans.Methods: Thirty-two healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg salmeterol or placebo (t=-0.5 h) followed by 100 microg LPS or normal saline (t=0 h; n=8/group). Measurements were performed in bronchoalveolar lavage fluid and purified alveolar macrophages obtained 6 h post-challenge. Inhalation of LPS was associated with neutrophil influx, neutrophil degranulation (myeloperoxidase, bactericidal/permeability-increasing protein and elastase), release of cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines (interleukin 8, epithelial cell-derived neutrophil attractant 78, macrophage inflammatory proteins 1alpha and 1beta), activation of alveolar macrophages (upregulation of HLA-DR and CD71; enhanced expression of mRNAs for 13 different mediators of inflammation), and protein leakage (all p<0.05 vs. placebo/saline). Pretreatment with salmeterol inhibited LPS-induced neutrophil influx, neutrophil degranulation (myeloperoxidase), tumor necrosis factor alpha release, and HLA-DR expression (all p<0.05 vs. placebo/LPS), while not significantly influencing other responses. Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.
    American Journal of Respiratory and Critical Care Medicine 10/2005; 172(7):878-84. · 11.04 Impact Factor
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    ABSTRACT: Pneumonia is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. To determine the effect of lipopolysaccharide (LPS) on the hemostatic balance in the human lung, six healthy subjects inhaled nebulized LPS or saline in a randomized cross-over study and bronchoalveolar lavage fluid was obtained six hours thereafter. LPS induced soluble tissue factor and thrombin-antithrombin complexes and inhibited plasminogen activator activity in BALF. Additionally plasminogen activator inhibitor type 1 production was upregulated after LPS inhalation. LPS also elicited local activation of neutrophils (release of elastase, myeloperoxidase and bactericidal/permeability increasing protein) and secretion of interleukin (IL)-6 and IL-8. Inhalation of LPS by healthy humans reproduces major features of the procoagulant response to inflammatory and infectious lung diseases and may be used as a novel model to evaluate pathogenetic mechanisms and new interventions.
    Thrombosis and Haemostasis 07/2005; 93(6):1036-40. · 5.76 Impact Factor
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    ABSTRACT: Platelet-activating factor (PAF), a glycerophospholipid with proinflammatory properties, exerts its biological effects by interacting with the PAF receptor (PAFR) expressed on many different cell types. The PAFR specifically binds phosphorylcholine, the biologically active component of PAF. However, phosphorylcholine is also a component of the cell wall of nontypeable Haemophilus influenzae (NTHi). In recently published in vitro experiments, the invasion of respiratory epithelial cells by NTHi was mediated by the PAFR. To determine the role of the PAFR in host defense against pneumonia induced by NTHi, PAFR-deficient (PAFR-/-) and normal wild-type mice were intranasally inoculated with NTHi. The absence of a functional PAFR was associated with a normal innate immune response as indicated by similar bacterial counts, myeloperoxidase activity, and inflammation within the pulmonary compartment of PAFR-/- and wild-type mice. These data indicate that the PAFR does not interfere with the clearance of NTHi from the respiratory tract.
    Shock 01/2005; 22(6):543-7. · 2.61 Impact Factor
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    ABSTRACT: Lipopolysaccharide is ubiquitously present in the environment. To determine the effect of salmeterol, a long-acting beta(2)-receptor agonist, on lipopolysaccharide-induced lung inflammation, mice received lipopolysaccharide (10 microg) intranasally with or without salmeterol intraperitoneally (5 mg/kg) 30 min earlier and 12 h thereafter. Salmeterol dose- and time-dependently inhibited the lipopolysaccharide-induced influx of neutrophils into bronchoalveolar lavage fluid and lung tissue, and these pulmonary neutrophils displayed a reduced expression of CD11b at their surface. To determine the contribution of the salmeterol effect on neutrophil CD11b in the attenuated neutrophil recruitment, we treated mice intranasally exposed to lipopolysaccharide with salmeterol with or without a blocking anti-CD11b antibody. Anti-CD11b profoundly reduced lipopolysaccharide-induced neutrophil influx in bronchoalveolar lavage fluid, an effect that was modestly enhanced by concurrent salmeterol treatment. These data suggest that salmeterol inhibits lipopolysaccharide-induced neutrophil recruitment to the lungs by a mechanism that possibly in part is mediated by an effect on neutrophil CD11b.
    AJP Lung Cellular and Molecular Physiology 07/2004; 286(6):L1122-8. · 3.52 Impact Factor
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    Gut 04/2003; 52(3):452-3; author reply 453. · 10.73 Impact Factor
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    ABSTRACT: Alveolar macrophages (AMs) are considered major effector cells in host defense against respiratory tract infections by virtue of their potent phagocytic properties. In addition, AMs may regulate the host inflammatory response to infection by production of cytokines and by their capacity to phagocytose apoptotic polymorphonuclear cells (PMNs). To elucidate the in vivo contribution of AM to host defense against pneumococcal pneumonia, we depleted mice of AMs via pulmonary application of liposomal dichloromethylene-bisphosphonate (AM- mice) before inoculation with Streptococcus pneumoniae; control mice received saline (AM+sal) or liposomal phosphate-buffered saline (AM+lip) before bacterial inoculation. AM- mice displayed a significantly higher mortality compared with AM+ control mice, whereas bacterial clearance did not differ. Poor outcome of AM- mice was accompanied by a pronounced increase of local proinflammatory cytokine production as well as strongly elevated and prolonged pulmonary PMN accumulation. Closer examination of infiltrating PMN in AM- mice disclosed high proportions of apoptotic and secondary necrotic cells, reflecting the lack of efficient clearance mechanisms in the absence of AMs. Furthermore, caspase-3 staining showed only slightly higher activity in AM- mice, arguing against accelerated apoptosis per se. These data suggest that AMs are indispensable in the host response to pneumococcal pneumonia by means of their capacity to modulate inflammation, possibly via elimination of apoptotic PMNs.
    American Journal of Respiratory and Critical Care Medicine 02/2003; 167(2):171-9. · 11.04 Impact Factor
  • Lancet. 01/2003; 52(3):452-453.
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