Biomedical subjects

Tom van der Poll

Publications and source records attributed to Tom van der Poll.

At least 127 records · Page 7Linked to original sources

PubMed2003

Anticoagulant therapy for acute lung injury or pneumonia.

Pulmonary changes in thrombin formation in patients with acute lung injury or pneumonia are remarkably similar to systemic changes in coagulation observed in septic patients. Since anticoagulant therapy has proven to be successful in the treatment of patients with sepsis, the same therapeutic strategy may benefit patients with acute lung injury or pneumonia. Based on the fact that inflammation not only leads to dysregulation of the coagulation system, but vice versa, activation of coagulation amplifies inflammatory processes as well, it can be questioned whether the advantage of anticoagulant therapy is solely related to its influence on disturbed thrombin formation. In this paper we will discuss local changes in the haemostatic balance during acute lung injury, both in pre-clinical and clinical studies. Until now, pre-clinical studies have demonstrated that interventions aimed at correction of coagulation abnormalities may form an important strategy in patients with acute lung injury in the future. Pre-clinical studies on use of anticoagulants during pneumonia are presently performed and data are underway.

Animals↗

PubMed2002

Effects of IC14, an anti-CD14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans.

To determine the role of CD14 in lipopolysaccharide (LPS)-induced effects on coagulation and fibrinolysis in humans, 16 healthy subjects received an intravenous injection of LPS preceded by intravenous IC14, a recombinant chimeric monoclonal antibody against human CD14, or placebo. LPS-induced coagulation activation (tissue-factor mRNA in whole blood cells and plasma concentrations of F1+2) was not influenced by IC14, whereas the antibody reduced the increase in thrombin-antithrombin complexes and soluble fibrin. LPS injection also was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes), followed by an inhibitory response (plasminogen activator inhibitor type 1), which were attenuated by IC14. Furthermore, LPS reduced thrombin-activatable fibrinolysis-inhibitor antigen levels and increased soluble thrombomodulin levels, which were not influenced by IC14. These results suggest that different hemostatic responses during endotoxemia may proceed via CD14-dependent and -independent pathways.

Adult↗

PubMed2002

Diminished interferon-gamma production and responsiveness after endotoxin administration to healthy humans.

To obtain insight in the capacity of the lipopolysaccharide (LPS)-tolerant host to produce interferon (IFN)-gamma and to respond to this cytokine, whole blood was obtained from healthy humans before and 4 h after intravenous injection of LPS (4 ng/kg) and stimulated ex vivo. LPS exposure in vivo resulted in a diminished capacity to produce IFN-gamma after restimulation with LPS, together with a reduced ability to release the IFN-gamma-inducing cytokines interleukin (IL)-12 and IL-18 and with reduced responsiveness toward these cytokines. In addition, IFN-gamma responsiveness was strongly diminished after in vivo LPS exposure, as shown by the fact that blood obtained after LPS injection could not be primed by IFN-gamma for LPS-induced tumor necrosis factor-alpha release and that peripheral blood monocytes could not be stimulated by IFN-gamma to up-regulate major histocompatibility complex type II expression. Experimentally induced immunoparalysis is associated with strongly reduced IFN-gamma production and responsiveness.

Adult↗

PubMed2002

Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia.

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.

Animals↗

PubMed2002

Toll-like receptor 4 is not involved in host defense against pulmonary Legionella pneumophila infection in a mouse model.

Legionella pneumophila is a gram-negative microorganism that causes a severe pneumonia known as "legionnaires disease." Toll-like receptor 4 (TLR4) transduces the lipopolysaccharide signal and is therefore considered to play a role in host defense against gram-negative bacterial infection. To determine the role of TLR4 in L. pneumophila pneumonia, C3H/HeJ mice, which display a nonfunctional gene encoding TLR4 (TLR4), and wild-type (wt) C3H/HeN mice were intranasally inoculated with L. pneumophila serogroup 1. Infection proceeded in an identical way in TLR4 mutant and wt mice, as reflected by similar bacterial outgrowth in the lungs. In addition, the inflammatory responses to L. pneumophila infection-as assessed by histopathologic analysis, cell influx in bronchoalveolar lavage fluid, myeloperoxidase activity in lungs, and lung cytokine concentrations-were indistinguishable in TLR4 mutant and wt mice. These data suggest that, in this mouse model, TLR4 does not play a role in resistance to L. pneumophila.

Animals↗

PubMed2002

Differential role of interleukin-6 in lung inflammation induced by lipoteichoic acid and peptidoglycan from Staphylococcus aureus.

Lipoteichoic acids (LTA) and peptidoglycans (PepG) are major components of the cell walls of gram-positive bacteria that trigger inflammatory responses in vitro. To study the in vivo effects of LTA and PepG from Staphylococcus aureus in lungs and to determine the role of interleukin (IL)-6 herein, these compounds were intranasally administered to IL-6 gene deficient (IL-6(-/-)) and wild type (IL-6(+/+)) mice. In IL-6(+/+) mice, LTA and PepG induced acute pulmonary inflammation in a dose-dependent way, characterized by neutrophilic influx and IL-6 production in the bronchoalveolar lavage fluid. Endogenously produced IL-6 attenuated inflammation induced by 10 microg LTA, as reflected by enhanced neutrophil influx, and increased tumor necrosis factor-alpha, macrophage inflammatory protein-1-alpha, and cytokine-induced neutrophil chemoattractant (KC) release into bronchoalveolar lavage fluid of IL-6(-/-) mice, compared with IL-6(+/+) mice. By contrast, pulmonary inflammation induced by 100 microg LTA was similar (neutrophil influx) or even tended to be attenuated (cytokine and chemokine release) in IL-6(-/-) mice. Endogenous IL-6 increased inflammation induced by PepG, as reflected by decreased neutrophil influx into lungs of IL-6(-/-) mice, compared with IL-6(+/+) mice. These data suggest that IL-6 plays an anti-inflammatory role during LTA-induced pulmonary inflammation, which is dependent on the severity of the inflammatory challenge, and a proinflammatory role in peptidoglycan-induced acute lung inflammation. Thus, the contribution of IL-6 to lung inflammation may vary with the stimulus used.

Administration, Intranasal↗

PubMed2002

Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.

The p38 mitogen-activated protein kinase (MAPK) participates in intracellular signaling cascades resulting in inflammatory responses. Therefore, inhibition of the p38 MAPK pathway may form the basis of a new strategy for treatment of inflammatory diseases. However, p38 MAPK activation during systemic inflammation in humans has not yet been shown, and its functional significance in vivo remains unclear. Hence, we exposed 24 healthy male subjects to an i.v. dose of LPS (4 ng/kg), preceded 3 h earlier by orally administered 600 or 50 mg BIRB 796 BS (an in vitro p38 MAPK inhibitor) or placebo. Both doses of BIRB 796 BS significantly inhibited LPS-induced p38 MAPK activation in the leukocyte fraction of the volunteers. Cytokine production (TNF-alpha, IL-6, IL-10, and IL-1R antagonist) was strongly inhibited by both low and high dose p38 MAPK inhibitor. In addition, p38 MAPK inhibition diminished leukocyte responses, including neutrophilia, release of elastase-alpha(1)-antitrypsin complexes, and up-regulation of CD11b with down-regulation of L-selectin. Finally, blocking p38 MAPK decreased C-reactive protein release. These data identify p38 MAPK as a principal mediator of the inflammatory response to LPS in humans. Furthermore, the anti-inflammatory potential of an oral p38 MAPK inhibitor in humans in vivo suggests that p38 MAPK inhibitors may provide a new therapeutic option in the treatment of inflammatory diseases.

Administration, Oral↗

PubMed2002

Expression of human immunodeficiency virus coreceptors CXC chemokine receptor 4 and CC chemokine receptor 5 on monocytes is down-regulated during human endotoxemia.

Lipopolysaccharide (LPS) can inhibit human immunodeficiency virus (HIV) infection in monocytes in vitro. To test the hypothesis that an LPS effect on CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5), known coreceptors for HIV, contributes to this effect, 8 healthy men were intravenously injected with Escherichia coli LPS (4 ng/kg), and monocyte CXCR4 and CCR5 expression was monitored by fluorescence-activated cell sorter analysis. LPS induced a decrease in the fraction of peripheral blood monocytes expressing CXCR4 and CCR5, reaching a nadir after 2 h (both P<.001 vs. baseline). In whole blood in vitro, not only LPS but also lipoarabinomannan (a cell wall component of Mycobacterium tuberculosis) and lipoteichoic acid (a cell wall component of Staphylococcus aureus) down-regulated the expression of CXCR4 and CCR5 on monocytes (all P<.05). Exposure of monocytes to (myco)bacterial agents may render them relatively resistant to infection with HIV by an effect on HIV coreceptors.

Adult↗

PubMed2002

IL-18 improves the early antimicrobial host response to pneumococcal pneumonia.

To determine the role of endogenous IL-18 during pneumonia, IL-18 gene-deficient (IL-18(-/-)) mice and wild-type (WT) mice were intranasally inoculated with Streptococcus pneumoniae, the most common causative agent of community-acquired pneumonia. Infection with S. pneumoniae increased the expression of IL-18 mRNA and was associated with elevated concentrations of both precursor and mature IL-18 protein within the lungs. IL-18(-/-) mice had significantly more bacteria in their lungs and were more susceptible for progressing to systemic infection at 24 and 48 h postinoculation. Similarly, treatment of WT mice with anti-IL-18 was associated with enhanced outgrowth of pneumococci. In contrast, the clearance of pneumococci from lungs of IL-12(-/-) mice was unaltered when compared with WT mice. Furthermore, anti-IL-12 did not influence bacterial clearance in either IL-18(-/-) or WT mice. These data suggest that endogenous IL-18, but not IL-12, plays an important role in the early antibacterial host response during pneumococcal pneumonia.

Animals↗

PubMed2002

Animal and human models for sepsis.

Several preclinical models for sepsis have been used in the last decades to successfully unravel the pathophysiologic processes during sepsis. Furthermore, these models for sepsis revealed promising immunomodulating agents for the treatment of sepsis. Nevertheless, several clinical trials evaluating the efficacy of these new anti-inflammatory agents in septic patients showed disappointing results. In this article the advantages and disadvantages of different models for sepsis are discussed. Most models for sepsis lack an infectious focus. Importantly, investigations studying the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis lacking an infectious focus and when using models for sepsis with a more natural route of infection. These differences will be discussed in this article. In general, it is advised to use a combination of models to test a new therapeutic agent, before starting a clinical study evaluating this new therapy.

Adjuvants, Immunologic↗

PubMed2002

Endothelium: interface between coagulation and inflammation.

OBJECTIVE: To review the involvement of endothelial cells in the pathogenesis of coagulation abnormalities during severe infection, the differential role of proinflammatory cytokines in these mechanisms, and the cross talk between coagulation and inflammation. DATA SOURCES: Published articles on experimental studies of coagulation activation during inflammation and clinical studies of patients with sepsis and associated hemostatic abnormalities. DATA SYNTHESIS AND CONCLUSION: The endothelium plays a central role in all major pathways involved in the pathogenesis of the hemostatic derangement observed during severe inflammation (i.e., initiation and regulation of thrombin generation and inhibition of fibrinolysis). Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross talk in which the endothelium seems to play a pivotal role.

Animals↗

PubMed2002

CpG oligodeoxynucleotides enhance host defense during murine tuberculosis.

Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs activate immune cells to produce cytokines. CpG ODNs protect mice against infections with intracellular bacteria by the induction of a T helper 1 (Th1) response. To determine the effect of CpG ODNs in pulmonary tuberculosis, mice were treated with CpG ODNs or control ODNs at the time of intranasal infection. CpG ODNs reduced mycobacterial outgrowth for up to 5 weeks after Mycobacterium tuberculosis infection and were associated with a decrease in inflammation in lung tissue. CpG treatment was also associated with elevated levels of gamma interferon (IFN-gamma) and decreased levels of interleukin 4 in the lungs and an increased capacity of splenocytes to secrete Th1-type cytokines. CpG ODNs given 2 weeks after infection were still able to reduce mycobacterial outgrowth and to enhance a Th1 response 5 weeks postinfection. Administration of CpG ODNs to IFN-gamma-gene-deficient mice failed to reduce mycobacterial outgrowth. These data suggest that CpG ODNs improve host defense during pulmonary tuberculosis by an IFN-gamma-dependent mechanism.

Adjuvants, Immunologic↗

PubMed2002

Role of interleukin-1 in the pulmonary immune response during Pseudomonas aeruginosa pneumonia.

Pneumonia is associated with elevated concentrations of the proinflammatory cytokine interleukin (IL)-1 in the pulmonary compartment. To study the role of IL-1 in the pathogenesis of Pseudomonas pneumonia, IL-1 receptor type 1 gene-deficient (IL-1R -/-) mice and wild-type mice were intranasally inoculated with Pseudomonas aeruginosa. The absence of the IL-1 signal attenuated the outgrowth of Pseudomonas in lungs, as reflected by an increasing number of colony-forming units (cfu) during Pseudomonas pneumonia in wild-type mice and a concurrently decreasing number of cfu during pulmonary infection in IL-1R -/- mice (P < 0.05, IL-1R -/- mice vs. wild-type mice). Influx of neutrophils was decreased in bronchoalveolar lavage fluids in IL-1R -/- mice compared with wild-type mice. Similarly, lung levels of cytokines (tumor necrosis factor-alpha, IL-6) and chemokines (macrophage inflammatory protein-2 and KC) were lower in IL-1R -/- mice 24 h postinoculation. Consistent with results obtained in IL-1R -/- mice, treatment of wild-type mice with IL-1R antagonist also diminished outgrowth of Pseudomonas when compared with wild-type mice treated with vehicle (P < 0.05). These results demonstrate that an absence or reduction in endogenous IL-1 activity improves host defense against Pseudomonas pneumonia while suppressing the inflammatory response.

Animals↗

PubMed2002

Modulation of pulmonary innate immunity during bacterial infection: animal studies.

Both the increasing number of immunocompromised patients susceptible to pneumonia and the development of bacterial resistance are significant problems related to the treatment of pneumonia. The primary outcome of treatment for pneumonia is to tip the balance towards a successful host response. An ideal approach would be a combination of immunomodulation and conventional antimicrobial therapy. It is of increasing importance to understand the components of innate immunity, before immunomodulatory therapy can be applied to patients. Much of our knowledge of the role of alveolar macrophages, cytokines and chemokines in the pathogenesis of pneumonia is derived from animal studies on experimental pneumonia. This article summarizes current information on the role of an alveolar macrophage (AM) and AM-derived mediators in host defense against pneumonia.

Animals↗

PubMed2002

Therapeutic intervention in disseminated intravascular coagulation: have we made any progress in the last millennium?

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC. Thrombin generation proceeds via the (extrinsic) tissue factor/activated factor VII route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin and the protein C and protein S system. Also, impaired fibrin degradation, due to high circulating levels of plasminogen activator inhibitor type-I, contributes to enhanced intravascular fibrin deposition. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or (activated) protein C.

Anticoagulants↗

PubMed2001

Roles of interleukin-6 and macrophage inflammatory protein-2 in pneumolysin-induced lung inflammation in mice.

Pneumolysin (PLY), a toxin synthesized by Streptococcus pneumoniae, is an important virulence factor in pneumococcal disease. This study evaluated the effects of PLY in lungs of mice. Intranasal inoculation with PLY was associated with a dose-dependent influx of polymorphonuclear leukocytes (PMNL) in bronchoalveolar lavage fluid (BALF) and increased concentrations of interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, and KC in BALF. PLY mutants with either reduced cytolytic activity or reduced cytolytic and complement-activating activities were less potent in inducing PMNL recruitment to the lung (P<.05), which suggests that PLY cytolytic activity is very important for the inflammatory response. IL-6 and MIP-2 also played a role in PLY-induced PMNL recruitment; this response was partially diminished in IL-6 gene-deficient mice and in mice treated with anti-MIP-2 antiserum. PLY may play an important role in the induction of an inflammatory response in the pulmonary compartment in the early phase of pneumococcal pneumonia.

Animals↗

PubMedDate not supplied

Sepsis and disseminated intravascular coagulation.

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may deplete platelets and coagulation factors, which may in turn cause bleeding. Recent insights into important pathogenetic mechanisms that may lead to DIC have resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of PAI-1, contributes to enhanced intravascular fibrin deposition. Supportive strategies aimed at the inhibition of coagulation activation may be justified on theoretical grounds and have been found to be beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or recombinant human activated protein C.

Anticoagulants↗

PubMedDate not supplied

Effect of IC14, an anti-CD14 antibody, on plasma and cell-associated chemokines during human endotoxemia.

To determine the role of CD14 in lipopolysaccharide (LPS)-induced release of chemokines, 16 humans were injected with LPS (4 ng/kg) preceded (-2 h) by intravenous IC14, an anti-human CD14 monoclonal antibody, or placebo. LPS elicited increases in interleukin (IL)-8 concentrations in plasma and in lysates of red blood cell (RBC), polymorphonuclear cell and mononuclear cell fractions, which were all reduced by IC14. LPS also induced rises in the plasma and RBC levels of monocyte chemoattractant protein (MCP)-1, which were diminished by IC14. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, chemokines that in contrast to IL-8 and MCP-1 can not bind to the Duffy antigen receptor for chemokines on RBCs, were only detected in plasma. IC14 attenuated the LPS-induced release of MIP-1beta, but not of MIP-1alpha. IL-8 and MCP-1, but not MIP-1alpha and MIP-1b, circulate in RBC-associated form during endotoxemia. LPS-induced chemokine release is, in part, mediated by an interaction with CD14.

Adult↗