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Biomedical subjects

Tom van der Poll

Publications and source records attributed to Tom van der Poll.

At least 91 records · Page 5Linked to original sources
PubMed2004

Inhibition of plasmin activity by tranexamic acid does not influence inflammatory pathways during human endotoxemia.

OBJECTIVE: Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems. METHODS AND RESULTS: To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-alpha2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both P<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-alpha1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release. CONCLUSIONS: These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during human endotoxemia.

Adult↗
PubMed2004

Salmeterol, a beta2-receptor agonist, attenuates lipopolysaccharide-induced lung inflammation in mice.

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.

Administration, Inhalation↗
PubMed2004

The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense.

The epidermal growth factor-seven transmembrane (EGF-TM7) family is a group of seven-span transmembrane receptors predominantly expressed by cells of the immune system. Family members CD97, EGF module-containing mucin-like receptor (EMR) 1, EMR2, EMR3, EMR4, and EGF-TM7-latrophilin-related protein are characterized by an extended extracellular region with a variable number of N-terminal EGF-like domains. EGF-TM7 receptors bind cellular ligands as demonstrated by the interaction of CD97 with decay accelerating factor (CD55) and dermatan sulfate. Investigating the effect of newly generated mAb on the migration of neutrophilic granulocytes, we here report for the first time in vivo data on the function of CD97. In dextran sulfate sodium-induced experimental colitis, we show that homing of adoptively transferred neutrophils to the colon was significantly delayed when cells were preincubated with CD97 mAb. The consequences of this defect in neutrophil migration for host defense are demonstrated in a murine model of Streptococcus pneumoniae-induced pneumonia. Mice treated with CD97 mAb to EGF domain 1 (1B2) and EGF domain 3 (1C5) displayed a reduced granulocytic inflammatory infiltrate at 20 h after inoculation. This was associated with a significantly enhanced outgrowth of bacteria in the lungs at 44 h and a strongly diminished survival. Together, these findings indicate an essential role for CD97 in the migration of neutrophils.

Animals↗
PubMed2004

Differential expression of interferon-gamma and interferon-gamma-inducing cytokines in Thai patients with scrub typhus or leptospirosis.

Interferon (IFN)-gamma plays an important role in the induction of a type 1 immune response against intracellular pathogens. We compared the plasma levels of IFN-gamma and IFN-gamma-inducing cytokines in adult Thai patients with scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, and leptospirosis, caused by extracellular Leptospira interrogans. IFN-gamma, interleukin (IL)-18, and IL-15 levels were elevated only in patients with scrub typhus, whereas IL-12p40 and tumor necrosis factor-alpha concentrations were elevated in both patient groups, although more so in scrub typhus. These data suggest a role for a cell-mediated immune response in host defense against O. tsutsugamushi.

Adolescent↗
PubMed2004

P38 mitogen activated protein kinase is involved in the downregulation of granulocyte CXC chemokine receptors 1 and 2 during human endotoxemia.

Chemokine receptors CXC receptor (CXCR) 1 and 2, and their ligands interleukin (IL)-8 and growth-related oncogene alpha (GRO alpha), are principal regulators of neutrophil activation and migration. To investigate the role of p38 mitogen activated protein kinase (MAPK) in the regulation of CXCR expression during an inflammatory response in vivo, 24 healthy volunteers received an intravenous injection with lipopolysaccharide (LPS) preceded (-3 hr) by a specific p38 MAPK inhibitor (BIRB 796 BS) at a high dose (600 mg) or a low dose (50 mg) or a placebo. The LPS-induced reduction of neutrophil CXCR 1 and 2 expression, as determined by fluorescence-activated cell sorter analysis, was inhibited in volunteers receiving the high dose of the p38 MAPK inhibitor. The kinase inhibitor also dose dependently diminished the LPS-induced rises in plasma IL-8 and GRO alpha levels. These results indicate a principal role for p38 MAPK in regulating factors essential for neutrophil activation and chemotaxis in vivo.

Chemokine CXCL1↗
PubMed2004

Increased expression of HIV co-receptor CXCR4 on CD4+ T-cells in patients with active visceral leishmaniasis.

Enhanced expression of the human immunodeficiency virus (HIV) co-receptor CXCR4 renders T-lymphocytes more susceptible for infection with HIV. We demonstrate that patients with active visceral leishmaniasis have a higher proportion of circulating CD4+ T-cells expressing CXCR4 than healthy controls, suggesting that Leishmania may facilitate HIV infection of CD4+ lymphocytes.

Adolescent↗
PubMed2004

New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology.

A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. 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 result in depletion of platelets and coagulation factors, which may cause bleeding. Recent understanding of important pathogenetic mechanisms that may lead to DIC has 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 the fibrinolytic inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular fibrin deposition. Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive 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, for example by means of the administration of recombinant human activated protein C.

Anticoagulants↗
PubMed2004

Beyond sepsis: activated protein C and ischemia-reperfusion injury.

OBJECTIVE: To review potential clinical situations beyond sepsis in which activated protein C might be an effective treatment. DATA SOURCE: Published articles between 1970 and 2003 on experimental and clinical studies of activation of both coagulation and inflammation in various disease states. DATA SYNTHESIS AND CONCLUSION: The efficacy of activated protein C in sepsis might rely on the fact that it can modulate both coagulation and inflammation. Therefore, administration of activated protein C could be beneficial in disease states that are also characterized by the simultaneous activation of these systems. Ischemia-reperfusion injury of various organs may represent such a state. Indeed, the involvement of the protein C system has been demonstrated in various experimental studies of ischemia-reperfusion, including studies in renal ischemia-reperfusion syndromes, coronary atherosclerosis and acute coronary syndromes, and intestinal ischemia and reperfusion. In some of these models, activated protein C administration, or other interventions in the protein C system, was shown to be beneficial.

Animals↗
PubMed2004

Acute pancreatitis in mice impairs bacterial clearance from the lungs, whereas concurrent pneumonia prolongs the course of pancreatitis.

OBJECTIVE: Nosocomial pneumonia is a feared complication in the critically ill patient. Serious acute pancreatitis is frequently complicated by infections. The objectives of this study were to determine the influence of acute pancreatitis on host defense against Pseudomonas pneumonia and to determine the influence of Pseudomonas pneumonia on the severity of concurrent pancreatitis. DESIGN: A controlled, in vivo laboratory study. SETTING: Research laboratory of a health sciences university. SUBJECTS: Female C57Bl/6 mice. INTERVENTIONS: Pancreatitis was induced by 12 hourly intraperitoneal injections of cerulein (pancreatitis) or saline (sham) immediately followed by intranasal administration of Pseudomonas aeruginosa (to induce pneumonia) or saline (controls). Mice were killed 24 hrs later. Hence, four groups were studied: sham/control, pancreatitis/control, sham/pneumonia, and pancreatitis/pneumonia mice. MEASUREMENTS AND MAIN RESULTS: When compared with sham/pneumonia mice, pancreatitis/pneumonia mice demonstrated exaggerated lung inflammation, higher bacterial counts in lungs and pancreas, and enhanced dissemination of the infection. Concurrently, pneumonia prolonged the course of pancreatitis, as reflected by histopathology and higher plasma amylase and relative pancreas weights (all p < .05 for the difference between pancreatitis/pneumonia and pancreatitis/control mice), which was associated with the localization of Pseudomonas in the pancreas. CONCLUSIONS: Acute pancreatitis impairs host defense against Pseudomonas pneumonia, whereas pneumonia prolongs the course of pancreatitis.

Acute Disease↗
PubMed2004

Platelet-activating factor receptor-deficient mice show an unaltered clearance of nontypeable Haemophilus influenzae from their respiratory tract.

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.

Animals↗
PubMed2004

Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice.

To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low- or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.

Animals↗
PubMed2004

Modulation of innate immune responses in the treatment of sepsis and pneumonia.

In the last decades several preclinical models for sepsis have been used to study the pathophysiologic processes during sepsis. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in septic patients were disappointing. It should be realized that most of the preclinical models for sepsis lack a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis with a more natural route of infection, such as pneumonia, and when using models for sepsis lacking an infectious focus. In this review we will compare models for sepsis and models for pneumonia. We advise to use a combination of models, including models for sepsis and models for localized infections, to test new immunomodulating strategies before starting any clinical trial evaluating a new immunomodulating therapy.

Adjuvants, Immunologic↗
PubMed2004

Elevated plasma levels of interferon (IFN)-gamma, IFN-gamma inducing cytokines, and IFN-gamma inducible CXC chemokines in visceral leishmaniasis.

Interferon (IFN)- gamma plays an important role during immune responses against leishmaniasis. Production of IFN-gamma is regulated by interleukin (IL)-12, IL-18, and IL-15. Interferon-gamma-inducible protein (IP)-10 and monokine induced by IFN-gamma (Mig) are CXC chemokines, the production of which, at least in part, is IFN-gamma dependent. A follow-up study of individuals infected with Leishmania donovani was undertaken in an area of Ethiopia endemic for visceral leishmaniasis (VL). Plasma levels of IFN-gamma, IL-12p40, IL-18, IL-15, IP-10, and Mig were markedly elevated in symptomatic VL patients (n = 70) compared with individuals with asymptomatic Leishmania infections (n = 39), malaria patients (n = 13), and healthy controls from the endemic area (n = 12). A significant decrease of IFN-gamma and all mediators was observed after treatment of VL patients (n = 33). These data show that increased plasma levels of IFN-gamma, as well as the mediators involved in the production and the activity of this cytokine, are characteristic of active VL in humans, and may play an important immunopathogenic role. The data also suggest that in patients with VL, the production of type 1 cytokines is not depressed, but there appears to be an unresponsiveness to the stimuli of type 1 cytokines. The underlying causes of immunologic unresponsiveness remain a subject of further investigation.

Adolescent↗
PubMed2003

Compartmentalisation of cytokines and cytokine inhibitors in ventilator-associated pneumonia.

OBJECTIVE: To examine whether cytokine concentrations change in the pulmonary compartment during the development of ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage (NBL) was performed every 48 h in critically ill mechanically ventilated patients. Serial measurements of the cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1alpha, IL-1beta, IL-6, and IL-10 and the cytokine inhibitors soluble TNFalpha receptor type I (sTNFalphaRI), IL-1 receptor antagonist (IL-1Ra) and soluble IL-1 receptor II (sIL-1RII) were performed on the NBL fluid and matching plasma samples by ELISA. SETTING: An adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and nineteen patients who did not develop VAP served as controls. INTERVENTIONS: None. RESULTS: Plasma concentrations of the measured cytokines and cytokine inhibitors did not change significantly in any patients. In control patients, NBL fluid concentrations of sIL-1RII decreased significantly over time (P=0.01). In patients who developed VAP, NBL fluid concentrations of TNFalpha, sTNFalphaRI, IL-1alpha, and IL-1beta increased significantly (P=0.002, P=0.03, P=0.04 and P=0.02, respectively). Furthermore, NBL fluid/plasma concentration ratios for TNFalpha, sTNFalphaRI, IL-1alpha, IL-1Ra and IL-6 increased significantly as VAP developed (P=0.001, P=0.001, P=0.04, P=0.03, and P=0.04, respectively). CONCLUSION: Our results suggest that the production of important cytokines and cytokine inhibitors is compartmentalised within the lung in critically ill mechanically ventilated patients who develop VAP.

Adult↗
PubMed2003

Cholestatic interleukin-6-deficient mice succumb to endotoxin-induced liver injury and pulmonary inflammation.

Circulating and hepatic interleukin (IL)-6 levels are strongly increased during clinical and experimental cholestasis. Cholestatic liver injury is associated with increased susceptibility to endotoxin-induced toxicity. To determine the role of IL-6 herein, extrahepatic cholestasis was induced by bile duct ligation (BDL) in IL-6-gene deficient (IL-6(-/-)) and normal (IL-6(+/+)) mice. BDL elicited increased levels of hepatic IL-6 mRNA and protein in normal mice. Hepatocellular injury 2 weeks after BDL was similar in IL-6(-/-) and IL-6(+/+) mice as demonstrated by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice 2 weeks after BDL was associated with enhanced cytokine release, severe liver damage, and death when compared with sham-operated mice. Effects of endotoxin were largely similar in sham-operated IL-6(-/-) and IL-6(+/+) mice, but cholestatic IL-6(-/-) mice were more susceptible to the toxic effects of endotoxin, as reflected by increased cytokine release, more profound liver injury and lung inflammation, and higher mortality. Although endogenous IL-6 is not important in the development of liver injury after experimentally induced obstructive jaundice, this cytokine plays an important role in decreasing hypersensitivity to endotoxin in cholestatic mice.

Animals↗
PubMed2003

Toll-like receptor 4 is not involved in host defense against respiratory tract infection with Sendai virus.

Toll-like receptors (TLR) induce innate immune responses upon stimulation by a wide variety of pathogens. TLR4 has been implicated in innate immunity against respiratory syncytial virus (RSV) by an interaction with the viral envelope fusion (F) protein. Sendai virus (mouse parainfluenza type 1) shares many features with RSV, including a structurally and functionally similar F protein. To determine the role of TLR4 in host defense against Sendai virus respiratory tract infection, TLR4 mutant and wildtype mice were intranasally infected with Sendai virus. Sendai infection resulted in an increase in viral RNA copies in lung homogenates peaking on day 4. Pulmonary viral loads, histopathology, cytokine levels and leukocyte influx were similar in TLR4 mutant and wildtype mice. In spite of the structural similarities shared by the F proteins of Sendai virus and RSV, TLR4 is not involved in host defense against respiratory tract infection with Sendai virus.

Animals↗