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Tom van der Poll

Publications and source records attributed to Tom van der Poll.

At least 73 records · Page 4Linked to original sources
PubMed2005

Aspiration pneumonitis primes the host for an exaggerated inflammatory response during pneumonia.

OBJECTIVE: Nosocomial pneumonia is a feared complication in the critically ill patient. Aspiration pneumonitis is frequently complicated by infections. The objective of this study was to determine the influence of aspiration pneumonitis on the host response to a common nosocomial respiratory pathogen. DESIGN: Controlled, in vivo laboratory study. SETTING: Research laboratory of a health sciences university. SUBJECTS: Female C57Bl/6 mice. INTERVENTIONS: Mice received hydrochloric acid or saline intratracheally followed 16 hrs later by Klebsiella pneumoniae. MEASUREMENTS AND MAIN RESULTS: Hydrochloric acid induced a mild aspiration pneumonitis. Nonetheless, hydrochloric acid aspiration resulted in a markedly increased inflammatory response in the lung on infection with K. pneumoniae. This enhanced inflammatory reaction was accompanied by a greatly increased outgrowth of K. pneumoniae in lungs of mice previously exposed to hydrochloric acid. Preexisting aspiration pneumonitis also triggered mouse lungs in vivo and alveolar macrophages ex vivo for enhanced release of proinflammatory mediators on stimulation with Klebsiella lipopolysaccharide. Inhibition of tumor necrosis factor-alpha resulted in an increased inflammatory reaction and enhanced bacterial outgrowth in mice with primary K. pneumoniae pneumonia, whereas it had no effect in mice with preexisting aspiration pneumonitis. CONCLUSIONS: These data indicate a) that aspiration pneumonitis renders the host more susceptible to respiratory tract infection with K. pneumoniae, concurrently priming the lung for an exaggerated inflammatory response; and b) that although tumor necrosis factor-alpha plays a major role in the host response to primary infection, it does not affect lung inflammation or defense after aspiration pneumonitis.

Analysis of Variance↗
PubMed2005

Endogenous interleukin-12 improves the early antimicrobial host response to murine Escherichia coli peritonitis.

Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a p35 and a p40 subunit. To determine the role of IL-12 in abdominal sepsis, p35 gene-deficient (IL-12 knockout, KO) mice and normal wild-type (WT) mice were injected intraperitoneally with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-12 p40 and IL-12 p75 concentrations in peritoneal fluid and plasma. Whereas at 6 h postinfection, IL-12 KO and WT mice displayed similar bacterial counts, at 20 hours IL-12 KO mice had significantly more bacteria in liver homogenates and were more susceptible to progressing to systemic infection. In addition, IL-12 KO mice demonstrated higher levels of proinflammatory cytokines in peritoneal fluid and increased lung and liver injury. IL-12 deficiency did not influence the recruitment of cells to the site of the infection. These data suggest that endogenous IL-12 is involved in the early antibacterial host response during abdominal sepsis.

Animals↗
PubMed2005

Preclinical models of shock and sepsis: what can they tell us?

The goal of translational research is to transform biologic knowledge into new treatments for human disease. Although preclinical models replicate some of the features of the disease process modeled, they invariably fail to reproduce the complexity of human illness, and by their very experimental nature, they are readily manipulated to maximize evidence of efficacy. The result is that successful translation from preclinical models to clinically effective therapy is uncommon, and that clinical trials are often undertaken without a comprehensive and realistic preclinical portfolio of studies to optimize their design. The lethal and morbid human conditions of sepsis and shock are attractive targets for new therapies and enormously challenging processes to translate because they entail considerable clinical heterogeneity, require emergent effective intervention, and are shaped not only by the initial insult, but by approaches to subsequent resuscitation and support. A colloquium jointly sponsored by the Shock Society and the International Sepsis Forum in June 2004 addressed the challenges of translational research in shock and sepsis. Through a comprehensive review of a broad variety of model approaches, and vigorous debate about the merits of differing strategies, a series of common themes emerged. We concluded that there is no single ideal model of shock or sepsis, but rather a large number of complementary models that recapitulate some discrete features of the disorders while minimizing others. Consequently, successful preclinical investigation mandates the use of a panel of preclinical studies consciously designed to address specific questions of relevance to the clinical setting. A corollary of this conclusion is that preclinical studies can shape concepts of disease and can be used to refine decisions regarding optimal patient populations for therapeutic interventional trials. We further recognized that the design and reporting of preclinical studies is highly variable, thereby limiting effective data interpretation and integration between studies. Hence, greater model standardization would aid in interpreting data and in pooling results into systematic data syntheses: such efforts should be promoted and undertaken.

Animals↗
PubMed2005

Pneumonia models and innate immunity to respiratory bacterial pathogens.

Preclinical sepsis models have been used for decades to study the pathophysiologic processes during sepsis and shock. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in patients with sepsis were disappointing. The main reason for this unsatisfactory experience might be that unlike the clinical situation, most of these preclinical models are devoid of a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when sepsis models with a more natural route of infection, such as pneumonia, were used. In this review, we will give insights into pneumonia models and discuss results and differences in the innate immune responses during distinct pulmonary infection models.

Animals↗
PubMed2005

Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers.

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.

Administration, Inhalation↗
PubMed2005

Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney.

TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R injury using TLR2-/- and TLR2+/+ mice, TLR2 antisense oligonucleotides, and chimeric mice deficient in leukocyte or renal TLR2. Tubular cells needed TLR2 to produce significant cytokine and chemokine amounts upon ischemia in vitro. TLR2 played a proinflammatory and detrimental role in vivo after I/R injury, as reflected by a reduction in the amount of local cytokines and chemokines, leukocytes, and the level of renal injury and dysfunction in TLR2-/- mice compared with controls. Analysis of chimeric mice suggested that TLR2 expressed on renal parenchyma plays a crucial role in the induction of inflammation and injury. TLR2-antisense treatment protected mice from renal dysfunction, neutrophil influx, and tubular apoptosis after I/R injury compared with nonsense treatment. In summary, we identified renal-associated TLR2 as an important initiator of inflammatory responses leading to renal injury and dysfunction in I/R injury. These data imply that TLR2 blockade could provide a basis for therapeutic strategies to treat or prevent renal ischemic injury.

Animals↗
PubMed2004

Cutting edge: expression patterns of surface and soluble triggering receptor expressed on myeloid cells-1 in human endotoxemia.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified molecule involved in the amplification of inflammation. To determine the regulation of TREM-1, we studied TREM-1 expression and soluble TREM-1 plasma levels upon i.v. LPS challenge in healthy humans in vivo and in vitro. Granulocyte TREM-1 expression was high at baseline and immediately down-regulated upon LPS exposure along with an increase in soluble TREM-1. Monocytes displayed a gradual up-regulation of TREM-1 upon LPS in vivo and in vitro. In vitro studies extended these findings to highly purified lipoteichoic acid and Streptococcus pneumoniae. Nonbacterial TLR ligands such as polyinosine-polycytidylic acid and imidazoquinoline, as well as the TLR9 ligand CpG, did not impact TREM-1 expression. The LPS-induced alterations in TREM-1 surface expression were not a result of increased TNF-alpha or IL-10. Inhibitor studies disclosed a PI3K-dependent pathway in LPS-induced up-regulation of TREM-1 on monocytes, whereas MAPK played a limited role.

Cell Separation↗
PubMed2004

Macrophages play a dual role during pulmonary tuberculosis in mice.

Pulmonary macrophages provide the preferred hiding and replication site of Mycobacterium tuberculosis but display antimicrobial functions. This raises questions regarding the role of macrophages during tuberculosis. We depleted lungs of activated macrophages (activated macrophage(-) mice) and compared this with nonselective macrophage depletion (macrophage(-) mice). Although nonselective depletion of macrophages after infection improved clinical outcome, depletion of activated macrophages led to impaired resistance, reflected by enhanced mycobacterial outgrowth. The production of tumor necrosis factor- alpha and numbers of granuloma decreased after depletion of activated macrophages. Both macrophage(-) and activated macrophage(-) mice showed polarized production of interferon- gamma by splenocytes and lymph-node cells and were able to attract and activate T cells in the lung. These data demonstrate that the dual role of macrophages is associated with the activation state of macrophages and that extensive apoptosis found in patients with tuberculosis could be part of a host defense strategy, as long as these cells are not activated.

Animals↗
PubMed2004

LPS-binding protein-deficient mice have an impaired defense against Gram-negative but not Gram-positive pneumonia.

LPS-binding protein (LBP) can facilitate the transfer of cell wall components of both Gram-negative bacteria (LPS) and Gram-positive bacteria (lipoteichoic acid) to inflammatory cells. Although LBP is predominantly produced in the liver, recent studies have indicated that this protein is also synthesized locally in the lung by epithelial cells. To determine the role of LBP in the immune response to pneumonia, LBP gene-deficient (-/-) and normal wild-type (WT) mice were intra-nasally infected with either Streptococcus pneumoniae or Klebsiella pneumoniae, common Gram-positive and Gram-negative pathogens, respectively. Pneumococcal pneumonia was associated with a 7-fold rise in LBP concentrations in bronchoalveolar lavage fluid of WT mice; LBP-/- mice infected with S. pneumoniae showed a similar survival and a similar bacterial burden in their lungs 48 h post-infection. In Klebsiella pneumonia, however, LBP-/- mice demonstrated a diminished survival together with an enhanced bacterial outgrowth in their lungs. These data suggest that LBP is important for a protective immune response in Klebsiella pneumonia, but does not contribute to an effective host response in pneumococcal pneumonia.

Acute-Phase Proteins↗
PubMed2004

Non-mannose-capped lipoarabinomannan induces lung inflammation via toll-like receptor 2.

Non-mannose-capped lipoarabinomannan (AraLAM) is part of the cell membrane of atypical mycobacteria. To determine the capacity of AraLAM to induce lung inflammation in vivo and to determine the signaling receptors involved herein, wild-type (WT) mice, lipopolysaccharide binding protein knockout mice, CD14-deficient (CD14 KO) mice, Toll-like receptor (TLR) 4 mutant mice, or TLR2 KO mice were intranasally inoculated with purified AraLAM. AraLAM induced high lung levels of tumor necrosis factor, interleukin-1beta, interleukin-6, and cytokine-induced neutrophil chemoattractant (KC) and an influx of neutrophils into the pulmonary compartment of WT mice. Lipopolysaccharide binding protein knockout, CD14 KO, and TLR4 mutant mice displayed similar inflammatory responses as WT mice, whereas in TLR2 KO mice, AraLAM-induced lung inflammation was strongly diminished. In addition, TLR2 KO mice, but not CD14 KO or TLR4 mutant mice, displayed a delayed clearance of pulmonary infection with the atypical AraLAM expressing Mycobacterium smegmatis. These data indicate that TLR2 is the signaling receptor for purified AraLAM in the lung in vivo and that this receptor contributes to an effective clearance of M. smegmatis from the pulmonary compartment.

Animals↗
PubMed2004

IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection.

Secondary pneumococcal pneumonia is a serious complication during and shortly after influenza infection. We established a mouse model to study postinfluenza pneumococcal pneumonia and evaluated the role of IL-10 in host defense against Streptococcus pneumoniae after recovery from influenza infection. C57BL/6 mice were intranasally inoculated with 10 median tissue culture infective doses of influenza A (A/PR/8/34) or PBS (control) on day 0. By day 14 mice had regained their normal body weight and had cleared influenza virus from the lungs, as determined by real-time quantitative PCR. On day 14 after viral infection, mice received 10(4) CFU of S. pneumoniae (serotype 3) intranasally. Mice recovered from influenza infection were highly susceptible to subsequent pneumococcal pneumonia, as reflected by a 100% lethality on day 3 after bacterial infection, whereas control mice showed 17% lethality on day 3 and 83% lethality on day 6 after pneumococcal infection. Furthermore, 1000-fold higher bacterial counts at 48 h after infection with S. pneumoniae and, particularly, 50-fold higher pulmonary levels of IL-10 were observed in influenza-recovered mice than in control mice. Treatment with an anti-IL-10 mAb 1 h before bacterial inoculation resulted in reduced bacterial outgrowth and markedly reduced lethality during secondary bacterial pneumonia compared with those in IgG1 control mice. In conclusion, mild self-limiting influenza A infection renders normal immunocompetent mice highly susceptible to pneumococcal pneumonia. This increased susceptibility to secondary bacterial pneumonia is at least in part caused by excessive IL-10 production and reduced neutrophil function in the lungs.

Animals↗
PubMed2004

Inhibition of the tissue factor/factor VIIa pathway does not influence the inflammatory or antibacterial response to abdominal sepsis induced by Escherichia coli in mice.

BACKGROUND: Anticoagulants have gained increasing attention for the treatment of sepsis. Inhibition of the tissue factor (TF)/factor (F) VIIa pathway has been shown to attenuate the activation of coagulation and to prevent death in a primate model of sepsis caused by gram-negative bacteria. METHODS: To determine the role of the TF/FVIIa complex in the host response to peritonitis, mice received an intraperitoneal injection of live Escherichia coli with or without concurrent treatment with recombinant nematode anticoagulant protein c2 (rNAPc2), a selective inhibitor of the TF/FVIIa pathway. RESULTS: Peritonitis was associated with an increase in the expression of TF at the tissue level and activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes and by increased fibrin(ogen) deposition in the liver and lungs. rNAPc2 strongly attenuated this procoagulant response but did not influence the inflammatory response (histopathology, leukocyte recruitment to the peritoneal cavity, and cytokine and chemokine levels). Moreover, rNAPc2 did not alter bacterial outgrowth locally or dissemination of the infection, and survival was not different between rNAPc2-treated mice and control mice. CONCLUSIONS: These data suggest that TF/FVIIa activity contributes to the activation of coagulation during E. coli peritonitis but does not play a role in the inflammatory response or antibacterial host defense.

Animals↗
PubMed2004

Activation of neutrophils and inhibition of the proinflammatory cytokine response by endogenous granulocyte colony-stimulating factor in murine pneumococcal pneumonia.

Granulocyte colony-stimulating factor (G-CSF) is considered to improve host defense during infection, via increased recruitment of and enhanced performance of neutrophils and subsequent inhibition of potentially harmful proinflammatory mediators. The present study sought to determine the role of endogenous G-CSF in host defense against pneumococcal pneumonia. Patients with unilateral community-acquired pneumonia demonstrated elevated concentrations of G-CSF in bronchoalveolar lavage fluid obtained from the infected, but not from the contralateral, site. Treatment of mice with pneumococcal pneumonia with an anti-G-CSF antibody reduced neutrophil counts in lung tissue and diminished CD11b expression on pulmonary neutrophils but increased the lung concentrations of tumor necrosis factor- alpha, interleukin-1 beta, and cytokine-induced neutrophil chemoattractant. Treatment with anti-G-CSF did not influence the outgrowth of pneumococci in lungs, the dissemination of the infection, or survival in murine pneumonia. During pneumococcal pneumonia, G-CSF is produced locally at the site of the infection, where it exerts both pro- and anti-inflammatory effects.

Adult↗
PubMed2004

Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense.

Toll-like receptors (TLR) are crucial pattern recognition receptors in innate immunity. The importance of TLR2 in host defense against Gram-positive bacteria has been suggested by the fact that this receptor recognizes major Gram-positive cell wall components, such as peptidoglycan and lipoteichoic acid. To determine the role of TLR2 in pulmonary Gram-positive infection, we first established that TLR2 is indispensable for alveolar macrophage responsiveness toward Streptococcus pneumoniae. Nonetheless, TLR2 gene-deficient mice intranasally inoculated with S. pneumoniae at doses varying from nonlethal (with complete clearance of the infection) to lethal displayed only a modestly reduced inflammatory response in their lungs and an unaltered antibacterial defense when compared with normal wild-type mice. These data suggest that TLR2 plays a limited role in the innate immune response to pneumococcal pneumonia, and that additional pattern recognition receptors likely are involved in host defense against this common respiratory pathogen.

Animals↗
PubMed2004

Coagulation in sepsis: all bugs bite equally.

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. There is compelling evidence from clinical and experimental studies that disseminated intravascular coagulation is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. Data from the PROWESS phase III clinical trial of recombinant activated protein C in patients with severe sepsis confirm this notion and demonstrate that the vast majority of patients with severe sepsis have increased markers for systemic coagulation activation, decreased physiological anticoagulant proteins and depressed fibrinolysis. There is no correlation between the type of microorganism that has caused the infection and the presence or severity of the coagulation disorder.

Biomarkers↗
PubMed2004

Improved host defense against pneumococcal pneumonia in platelet-activating factor receptor-deficient mice.

Platelet-activating factor (PAF) is a phospholipid with proinflammatory properties that binds to a specific receptor (PAF receptor [PAFR]) that is expressed on many different cell types. PAFR is able to bind phosphorylcholine, which is present in both PAF and the pneumococcal cell wall. Activation of respiratory epithelial cells in vitro results in up-regulation of PAFR, which, in turn, facilitates invasion of Streptococcus pneumoniae. To determine the role of PAFR in host defense against pneumococcal pneumonia, PAFR-deficient (PAFR(-/-)) and wild-type (wt) mice were inoculated intranasally with S. pneumoniae. PAFR(-/-) mice were relatively resistant to pneumococcal pneumonia, as indicated by delayed and reduced mortality, diminished outgrowth of pneumococci in lungs, and reduced dissemination of the infection (all P<.05, vs. wt mice). PAFR(-/-) mice also had less pulmonary inflammation. These data provide evidence that PAFR is used by S. pneumoniae to induce lethal pneumonia.

Animals↗