Publications by authors named "Jaring S van der Zee"

37 Publications

Pulmonary challenge with carbon nanoparticles induces a dose-dependent increase in circulating leukocytes in healthy males.

BMC Pulm Med 2017 Sep 6;17(1):121. Epub 2017 Sep 6.

Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Room F-5-260, Amsterdam, The Netherlands.

Background: Inhalation of particulate matter, as part of air pollution, is associated with increased morbidity and mortality. Nanoparticles (< 100 nm) are likely candidates for triggering inflammatory responses and activation of coagulation pathways because of their ability to enter lung cells and pass bronchial mucosa. We tested the hypothesis that bronchial segmental instillation of carbon nanoparticles causes inflammation and activation of coagulation pathways in healthy humans in vivo.

Methods: This was an investigator-initiated, randomized controlled, dose-escalation study in 26 healthy males. Participants received saline (control) in one lung segment and saline (placebo) or carbon nanoparticles 10 μg, 50 μg, or 100 μg in the contra-lateral lung. Six hours later, blood and bronchoalveolar lavage fluid (BALF) was collected for inflammation and coagulation parameters.

Results: There was a significant dose-dependent increase in blood neutrophils (p = 0.046) after challenge with carbon nanoparticles. The individual top-dose of 100 μg showed a significant (p = 0.05) increase in terms of percentage neutrophils in blood as compared to placebo.

Conclusions: This study shows a dose-dependent effect of bronchial segmental challenge with carbon nanoparticles on circulating neutrophils of healthy volunteers. This suggests that nanoparticles in the respiratory tract induce systemic inflammation.

Trial Registration: Dutch Trial Register no. 2976. 11 July 2011. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2976.
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http://dx.doi.org/10.1186/s12890-017-0463-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588713PMC
September 2017

Soluble and cell-associated triggering receptor expressed on myeloid cells-1 and -2 in patients with pulmonary tuberculosis.

J Infect 2015 Dec 15;71(6):706-9. Epub 2015 Sep 15.

Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Division of Infectious Diseases, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jinf.2015.09.002DOI Listing
December 2015

Activated protein C inhibits neutrophil migration in allergic asthma: a randomised trial.

Eur Respir J 2015 Dec 17;46(6):1636-44. Epub 2015 Sep 17.

Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients.We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24 µg·kg(-1)·h(-1); n=12) or placebo (n=12) for 11 h. 4 h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8 h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF).rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways.Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.
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http://dx.doi.org/10.1183/13993003.00459-2015DOI Listing
December 2015

Expression of inhibitory regulators of innate immunity in patients with active tuberculosis.

BMC Infect Dis 2015 Feb 26;15:98. Epub 2015 Feb 26.

Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands.

Background: Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Toll-like-receptors (TLRs) are important for the recognition of the causative agent Mycobacterium tuberculosis. Negative regulation of TLRs is necessary to control deleterious inflammatory damage, but could provide a means of immune evasion by M. tuberculosis as well.

Methods: To obtain insight in the extent of expression of inhibitory regulators of immunity in patients with active TB, peripheral-blood-mononuclear-cells (PBMCs) and plasma were obtained from 54 TB patients and 29 healthy blood donors from Chittagong, Bangladesh. Bilateral alveolar macrophages were obtained from an infected versus a contralateral normal lung segment of 9 patients. Statistical analyses were performed using Mann-Whitney U and Wilcoxon matched pairs testing. Correlations were calculated using the Spearman rho test.

Results: PBMCs harvested from TB patients demonstrated increased mRNA expression of IL-1-receptor-associated-kinase-M, suppressor-of-cytokine-signalling-3 and Toll-interacting-protein. Flow cytometry revealed enhanced expression of IL-1-receptor-like-1 (ST2) on lymphocytes. Plasma soluble ST2 was elevated in patients with TB and correlated with established TB biomarkers, most strongly with soluble interleukin-2 receptor subunit α and interleukin-8. Alveolar macrophage mRNA expression of negative TLR regulators did not differ between the infected and contralateral lung side.

Conclusion: These results show enhanced expression of distinct negative regulators of innate immunity in PBMCs of patients with TB and identify plasma soluble ST2 as a potential novel biomarker for TB disease activity.
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http://dx.doi.org/10.1186/s12879-015-0833-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365962PMC
February 2015

Pulmonary tuberculosis induces a systemic hypercoagulable state.

J Infect 2015 Apr 29;70(4):324-34. Epub 2014 Oct 29.

Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Division of Infectious Diseases, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

Objectives: Human tuberculosis (TB) remains an important cause of death globally. Bangladesh is one of the most affected countries. We aimed to investigate the impact of pulmonary TB on pro- and anticoagulant mechanisms.

Methods: This prospective study was conducted in Chittagong, Bangladesh. We performed an in-depth analysis of coagulation activation and inhibition in plasma obtained from 64 patients with primary lung TB and 11 patients with recurrent lung TB and compared these with 37 healthy controls. Additionally, in nine patients coagulation activation was studied in bronchoalveolar lavage fluid (BALF) harvested from the site of infection and compared with BALF from a contralateral unaffected lung subsegment.

Results: Relative to uninfected controls, primary and recurrent TB were associated with a systemic net procoagulant state, as indicated by enhanced activation of coagulation (elevated plasma levels of thrombin-antithrombin complexes, D-dimer and fibrinogen) together with impaired anticoagulant mechanisms (reduced plasma levels of antithrombin, protein C activity, free protein S, and protein C inhibitor). Activation of coagulation did not correlate with plasma concentrations of established TB biomarkers. Coagulation activation could not be detected at the primary site of infection in a subset of TB patients.

Conclusions: Pulmonary TB is associated with a systemic hypercoagulable state.
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http://dx.doi.org/10.1016/j.jinf.2014.10.006DOI Listing
April 2015

Mast cell-deficient kit mice develop house dust mite-induced lung inflammation despite impaired eosinophil recruitment.

J Innate Immun 2014 18;6(2):219-26. Epub 2013 Oct 18.

Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Mast cells are implicated in allergic and innate immune responses in asthma, although their role in models using an allergen relevant for human disease is incompletely understood. House dust mite (HDM) allergy is common in asthma patients. Our aim was to investigate the role of mast cells in HDM-induced allergic lung inflammation.

Methods: Wild-type (Wt) and mast cell-deficient Kit(w-sh) mice on a C57BL/6 background were repetitively exposed to HDM via the airways.

Results: HDM challenge resulted in a rise in tryptase activity in bronchoalveolar lavage fluid (BALF) of Wt mice, indicative of mast cell activation. Kit(w-sh) mice showed a strongly attenuated HDM- induced recruitment of eosinophils in BALF and lung tissue, accompanied by reduced pulmonary levels of the eosinophil chemoattractant eotaxin. Remarkably, Kit(w-sh) mice demonstrated an unaltered capacity to develop lung pathology and increased mucus production in response to HDM. The increased plasma IgE in response to HDM in Wt mice was absent in Kit(w-sh) mice.

Conclusion: These data contrast with previous reports on the role of mast cells in models using ovalbumin as allergen in that C57BL/6 Kit(w-sh) mice display a selective impairment of eosinophil recruitment without differences in other features of allergic inflammation.
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http://dx.doi.org/10.1159/000354984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741476PMC
November 2015

Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation.

Innate Immun 2014 Aug 18;20(6):618-25. Epub 2013 Sep 18.

Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Protease-activated receptor-2 (PAR2) is abundantly expressed in the pulmonary compartment. House dust mite (HDM) is a common cause of allergic asthma and contains multiple PAR2 agonistic proteases. The aim of this study was to determine the role of PAR2 in HDM-induced allergic lung inflammation. For this, the extent of allergic lung inflammation was studied in wild type (Wt) and PAR2 knockout (KO) mice after repeated airway exposure to HDM. HDM exposure of Wt mice resulted in a profound influx of eosinophils in bronchoalveolar lavage fluid (BALF) and accumulation of eosinophils in lung tissue, which both were strongly reduced in PAR2 KO mice. PAR2 KO mice demonstrated attenuated lung pathology and protein leak in the bronchoalveolar space, accompanied by lower BALF levels of the anaphylatoxins C3a and C5a. This study reveals, for the first time, an important role for PAR2 in allergic lung inflammation induced by the clinically relevant allergens contained in HDM.
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http://dx.doi.org/10.1177/1753425913503387DOI Listing
August 2014

Systemic tryptophan and kynurenine catabolite levels relate to severity of rhinovirus-induced asthma exacerbation: a prospective study with a parallel-group design.

Thorax 2013 Dec 23;68(12):1122-30. Epub 2013 Jul 23.

Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, , Amsterdam, The Netherlands.

Background: Patients with allergic asthma have exacerbations which are frequently caused by rhinovirus infection. The antiviral tryptophan-catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is induced by interferon-γ and suppressed by Th2 mediators interleukin (IL)-4 and IL-13. We hypothesised that local IDO activity after viral airway infection is lower in patients with allergic asthma than in healthy controls.

Objective: To determine whether IDO activity differs between patients with allergic asthma and healthy individuals before and after rhinovirus infection.

Methods: Healthy individuals and patients with allergic asthma were experimentally infected with low-dose (10 TCID50) rhinovirus 16. Blood, bronchoalveolar lavage fluid and exhaled breath condensate (for mass spectrometry by UPLC-MS/MS) were obtained before and after rhinovirus challenge.

Results: IDO activity was not induced by rhinovirus infection in either group, despite increases in cold scores. However, baseline pulmonary IDO activity was lower in patients with allergic asthma than in healthy individuals. In contrast, systemic tryptophan and its catabolites were markedly higher in patients with allergic asthma. Moreover, systemic quinolinic acid and tryptophan were associated with eosinophil cationic protein (r=0.43 and r=0.78, respectively) and eosinophils (r=0.38 and r=0.58, respectively) in bronchoalveolar lavage fluid and peak asthma symptom scores after rhinovirus challenge (r=0.53 and r=0.64, respectively).

Conclusions: Rhinovirus infection by itself induces no IDO activity, but the reduced pulmonary IDO activity in patients with allergic asthma at baseline may underlie a reduced control of viral infections. Notably, the enhanced systemic catabolism of tryptophan in patients with allergic asthma was strongly related to the outcome of rhinovirus challenge in asthma and may serve as a prognostic factor.
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http://dx.doi.org/10.1136/thoraxjnl-2013-203728DOI Listing
December 2013

Lipopolysaccharide inhibits Th2 lung inflammation induced by house dust mite allergens in mice.

Am J Respir Cell Mol Biol 2013 Mar 13;48(3):382-9. Epub 2012 Dec 13.

Center of Infection and Immunity Amsterdam and Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, The Netherlands.

The complex biology of asthma compels the use of more relevant human allergens, such as house dust mite (HDM), to improve the translation of animal models into human asthma. LPS exposure is associated with aggravations of asthma, but the mechanisms remain unclear. Here, we studied the effects of increasing LPS doses on HDM-evoked allergic lung inflammation. To this end, mice were intranasally sensitized and challenged with HDM with or without increasing doses of LPS (0.001-10 μg). LPS dose-dependently inhibited HDM-induced eosinophil recruitment into the lungs and mucus production in the airways. LPS attenuated the production of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) in HDM-challenged lungs, while enhancing the HDM-induced release of IL-17, IL-33, IFN-γ, and TNF-α. The shift toward a Th1 inflammatory response was further illustrated by predominant neutrophilic lung inflammation after LPS administration at higher doses. LPS did not influence HDM-induced plasma IgE concentrations. Although LPS did not significantly affect the activation of coagulation or complement in HDM-challenged lungs, it reduced HDM-initiated endothelial cell activation. This study is the first to provide insights into the effects of LPS in an allergic lung inflammation model making use of a clinically relevant allergen without a systemic adjuvant, revealing that LPS dose-dependently inhibits HDM-induced pulmonary Th2 responses.
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http://dx.doi.org/10.1165/rcmb.2012-0331OCDOI Listing
March 2013

Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses.

Eur Respir J 2013 Jul 11;42(1):188-97. Epub 2012 Oct 11.

Center of Experimental and Molecular Medicine, Academic Medical Center/University ofAmsterdam, Amsterdam, The Netherlands.

Intravenous administration of activated protein C (APC) inhibits coagulation and inflammation in the lungs of humans and animals. Investigations in rodents demonstrated that direct intrapulmonary delivery of APC also exerts anticoagulant and anti-inflammatory effects. The effect of intrabronchial administration of recombinant human (rh)APC on lipopolysaccharide (LPS)-induced haemostatic and inflammatory alterations in the bronchoalveolar space of humans was studied. Eight subjects received rhAPC via intrabronchial instillation by bronchoscope, while in a contralateral subsegment subjects received saline; all subjects were challenged bilaterally with LPS in the same lung subsegments. Four additional subjects received rhAPC (75 μg), with saline as a control in the contralateral subsegment, while they were bilaterally "challenged" with saline. After 6 h a bronchoalveolar lavage was performed and coagulation and inflammatory parameters were measured. rhAPC enhanced LPS-induced coagulation activation in the bronchoalveolar space, when compared with the control side. In addition, rhAPC amplified LPS-induced pro-inflammatory responses, as indicated by higher concentrations of cytokines and chemokines. rhAPC alone did not have procoagulant or pro-inflammatory effects. Locally administered rhAPC has unexpected procoagulant and pro-inflammatory effects in LPS-challenged lung subsegments. These data argue against a role for intrapulmonary delivery of rhAPC as a treatment strategy for lung inflammatory disorders in humans.
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http://dx.doi.org/10.1183/09031936.00057112DOI Listing
July 2013

Gene expression profiles in alveolar macrophages induced by lipopolysaccharide in humans.

Mol Med 2012 Dec 6;18:1303-11. Epub 2012 Dec 6.

Joint Unit Hospices Civils de Lyon - bioMérieux, Hôpital Edouard Herriot, Lyon, France.

Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo, we conducted a study in eight healthy humans, in which we instilled sterile saline into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later, a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals. LPS induced differential expression of 2,932 genes in alveolar macrophages; 1,520 genes were upregulated, whereas 1,440 genes were downregulated. A total of 26 biological functions were overrepresented in LPS-exposed macrophages; 44 canonical pathways affected by LPS were identified, among which the genes associated with the role of pattern recognition receptors in recognition of bacteria and viruses represented the top pathway. Other pathways included cellular immune response, signaling by tumor necrosis factor (receptor) family members, cytokine signaling and glucocorticoid receptor signaling. These results reveal for the first time a large number of functional pathways influenced by the biologically relevant challenge provided by LPS administered into the airways. These data can assist in identifying novel targets for therapeutic intervention in pulmonary diseases associated with LPS exposure, including pneumonia, asthma and chronic obstructive pulmonary disease.
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http://dx.doi.org/10.2119/molmed.2012.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521791PMC
December 2012

Endogenous MCP-1 promotes lung inflammation induced by LPS and LTA.

Mol Immunol 2011 Jul 6;48(12-13):1468-76. Epub 2011 May 6.

Center for Infection and Immunity Amsterdam, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Monocyte chemoattractant protein 1 (MCP-1) plays an important role in leukocyte recruitment to sites of infection and inflammation. In addition, MCP-1 may attenuate inflammation by virtue of its capacity to inhibit the production of proinflammatory cytokines. We here investigated the role of MCP-1 in lung inflammation induced by lipopolysaccharide (LPS) or lipoteichoic acid (LTA), constituents of the gram-negative and gram-positive bacterial cell wall, respectively. Healthy humans demonstrated elevated MCP-1 concentrations in their bronchoalveolar lavage fluid (BALF) 6h after inhalation of LPS. Similarly, intranasal administration of LPS or LTA to mice resulted in a rise in BALF MCP-1 levels. Murine alveolar macrophage-like cells released significant amounts of MCP-1 upon stimulation with LPS or LTA in vitro. Compared to Wt mice, MCP-1(-/-) mice demonstrated lower TNF-α levels and a diminished neutrophil influx into their bronchoalveolar space after either LPS or LTA instillation. After intrapulmonary delivery of LPS MCP-1(-/-) mice had decreased interleukin-6 and KC concentrations and less severe lung inflammation upon histopathological examination. Remarkably, MCP-1 deficiency was associated with an early enhancement of interleukin-10 release in BALF after both LPS and LTA instillation. These data suggest that MCP-1 is a proinflammatory mediator during pulmonary inflammation induced by either LPS or LTA.
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http://dx.doi.org/10.1016/j.molimm.2011.04.001DOI Listing
July 2011

Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial.

Thorax 2011 Jun 7;66(6):514-20. Epub 2011 Apr 7.

Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, F5-260, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.

Background: In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown.

Objective: To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FE(NO)) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worsening asthma control or asthma-related quality of life.

Methods: In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n=43) or guided by a novel internet-based monitoring system (internet strategy) (n=52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV1), exacerbations, hospitalisations and patient's satisfaction with the tapering strategy.

Results: Median cumulative sparing of prednisone was 205 (25-75th percentile -221 to 777) mg in the internet strategy group compared with 0 (-497 to 282) mg in the conventional treatment group (p = 0.02). Changes in prednisone dose (mixed effect regression model) from baseline were -4.79 mg/day and +1.59 mg/day, respectively (p < 0.001). Asthma control, asthma-related quality of life, FEV1, exacerbations, hospitalisations and satisfaction with the strategy were not different between groups.

Conclusions: An internet-based management tool including home monitoring of symptoms, lung function and FE(NO) in severe asthma is superior to conventional treatment in reducing total corticosteroid consumption without compromising asthma control or asthma-related quality of life. Clinical trial registration number Clinical trial registered with http://www.trialregister.nl (Netherlands Trial Register number 1146).
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http://dx.doi.org/10.1136/thx.2010.153411DOI Listing
June 2011

Priming of alveolar macrophages upon instillation of lipopolysaccharide in the human lung.

Am J Respir Cell Mol Biol 2010 Mar 15;42(3):349-56. Epub 2009 May 15.

Academic Medical Center, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

The airways are continuously exposed to respiratory pathogens, which may result in bacterial pneumonia, one of the most common infectious diseases and the leading cause of sepsis. Considering that recurrent exposure to microbial products can lead to tolerance of immune cells, and that this might contribute to the susceptibility to nosocomial infection, we investigated the effect of in vivo lipopolysaccharide (LPS) instillation on the responsiveness of alveolar macrophages. In eight healthy humans, sterile saline was instilled into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung; 6 hours later, a bilateral bronchoalveolar lavage was performed, and purified alveolar macrophages were ex vivo stimulated with LPS or lipoteichoic acid (LTA), triggering Toll-like receptor (TLR)-4 and -2, respectively. In vivo LPS-exposed alveolar macrophages were primed, as reflected by increased ex vivo LPS- and LTA-induced IL-1 beta and IL-6 gene expression and production compared with in vivo saline-exposed alveolar macrophages. LPS instillation did not influence the surface expression of TLR4 or TLR2. Furthermore, LPS instillation did not impact on the expression of a number of extracellular and intracellular regulators of TLR signaling. However, p38 mitogen-activated protein kinase remained phosphorylated in alveolar macrophages upon LPS instillation. The current data demonstrate that LPS instillation in the human lung primes alveolar macrophages for further stimulation with either LPS or LTA, possibly by sustained p38 mitogen-activated protein kinase activation.
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http://dx.doi.org/10.1165/rcmb.2008-0362OCDOI Listing
March 2010

Associations between pre-employment immunologic and airway mucosal factors and the development of occupational allergy.

J Allergy Clin Immunol 2009 Mar 7;123(3):694-700, 700.e1-3. Epub 2009 Feb 7.

Department of Pulmonology, Academic Medical Center, University of Amsterdam, The Netherlands.

Background: Sensitization to occupational allergens is frequently found in laboratory animal workers (LAWs) and can cause serious health problems. Atopy is a major risk factor for sensitization, but it is considered insufficient to advise against working with animals.

Objective: We investigated whether immunologic measures, including serology and cytokine production profiles of blood cells, and parameters for airway inflammation are associated with the development of occupational sensitization.

Methods: In a prospective cohort study 110 starting LAWs were followed for 2 years. At inclusion, results of health questionnaires, skin test results, lung function measures, methacholine threshold levels, and nasal lavage fluid were obtained. Blood was taken for measuring total IgE and allergen-specific IgE antibodies. Cytokine production profiles were measured in whole blood.

Results: Twenty-two new cases of sensitization were identified during follow-up. In multivariate logistic regression analysis a model including atopy and total IgE level predicted sensitization best. This was corroborated in a separate validation cohort. Parameters for airway inflammation or cytokine production profiles did not further contribute to the prediction of sensitization. Based on these results, pre-employment counseling aimed at applicant LAWs with atopy and a total IgE level of greater than 100 IU/mL might be able to reduce occupational sensitization by up to 45% to 50% with less than 10% false-positive predictions.

Conclusion: The combination of atopy and total IgE level offered the best model to predict development of occupational sensitization. Other immunologic parameters and parameters of airway inflammation did not contribute significantly.
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http://dx.doi.org/10.1016/j.jaci.2008.12.021DOI Listing
March 2009

Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide.

Crit Care Med 2009 Feb;37(2):619-25

Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Pneumonia is characterized by an acute inflammatory response in the lung, which is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. Here, we compared the effects of lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria, and lipopolysaccharide (LPS), in the human bronchoalveolar space.

Design: Controlled in vivo volunteer study.

Setting: Clinical research unit.

Subjects: Twenty-three healthy nonsmoking male volunteers.

Interventions: Sterile saline was instilled into a lung subsegment followed by bronchoscopic instillation of either LTA (Staphylococcus aureus, at a dose of 4, 20, or 100 ng/kg body weight) or LPS (Escherichia coli, 4 ng/kg body weight) into the contralateral lung. Bronchoalveolar lavage fluid was obtained 6 hours thereafter.

Measurements And Main Results: Bronchial instillation of LTA- or LPS-activated bronchoalveolar coagulation, as reflected by increases in the levels of thrombin-antithrombin complexes, d-dimer, and soluble tissue factor. Concurrently, LTA and LPS inhibited anticoagulant mechanisms, as indicated by reductions in antithrombin, Protein C, and Activated Protein C concentrations together with elevated levels of soluble thrombomodulin. Both LTA and LPS administration was associated with an inhibition of pulmonary fibrinolysis, as measured by a reduction in plasminogen activator activity and elevated levels of plasminogen activator inhibitor type I.

Conclusions: This study is the first to describe the effects of LTA on hemostasis in humans, demonstrating that LTA induces similar changes in the human bronchoalveolar space as LPS, characterized by activation of coagulation with concurrent inhibition of anticoagulant and fibrinolytic pathways.
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http://dx.doi.org/10.1097/CCM.0b013e31819584f9DOI Listing
February 2009

Lung inflammation induced by lipoteichoic acid or lipopolysaccharide in humans.

Am J Respir Crit Care Med 2008 Jul 10;178(1):34-41. Epub 2008 Apr 10.

Center for Infection and Immunity Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.

Rationale: Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways.

Objectives: We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria).

Methods: Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation-dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured.

Measurements And Main Results: Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release.

Conclusions: This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infection.
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http://dx.doi.org/10.1164/rccm.200708-1261OCDOI Listing
July 2008

Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats.

Crit Care Med 2008 Jan;36(1):204-10

Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We investigated the role of these natural anticoagulants in Streptococcus pneumoniae pneumonia.

Design: A controlled in vivo laboratory study.

Setting: Research laboratory of a university hospital.

Subjects: Total of 98 male Sprague-Dawley rats.

Interventions: Rats were challenged intratracheally with S. pneumoniae (serotype 3, 10(6) colony forming units), inducing pneumonia. Rats were randomized to intravenous treatment with normal saline, activated protein C, antithrombin, tissue factor pathway inhibitor, heparin, or tissue-type plasminogen activator.

Measurements And Main Results: Rats infected with S. pneumoniae had increased thrombin-antithrombin complexes in bronchoalveolar lavage fluid, with decreased levels of antithrombin activity and fibrin degradation products. Administration of activated protein C, antithrombin, and tissue factor pathway inhibitor significantly limited these procoagulant changes. Furthermore, antithrombin treatment resulted in less bacterial outgrowth of S. pneumoniae and less histopathologic damage in lungs.

Conclusions: Anticoagulant treatment attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. Antithrombin seems to exert significant lung-protective effects in pneumococcal pneumonia in rats.
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http://dx.doi.org/10.1097/01.CCM.0000292012.87482.F4DOI Listing
January 2008

Recombinant major urinary proteins of the mouse in specific IgE and IgG testing.

Int Arch Allergy Immunol 2007 23;144(4):296-304. Epub 2007 Jul 23.

Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Recombinant allergens are preferred over natural allergen extracts in measuring antibodies. We tested the use of recombinant variants of the major mouse allergen Mus m 1 in detection of mouse-specific antibodies in sera of laboratory animal workers and children.

Methods: Six recombinant major urinary proteins (MUPs) were produced and antibody-binding capacity was compared to natural Mus m 1 and to mouse urine extract. In a specific subset, cross-reactivity of MUP with Mus m 1 and between the different recombinant MUPs was determined.

Results: For IgE antibodies, MUP8 showed high cross-reactivity with Mus m 1. MUP8-specific IgE was found in 55% of the mouse urine IgE-positive sera. Specific IgG and IgG4 antibodies against natural Mus m 1 correlated strongly with antibodies against recombinant MUP8 and were cross-reactive. IgG4 levels against MUP8 and mouse urine extract correlated, but detection of mouse urine-specific IgG4 in the absence of MUP-specific IgG4 was not uncommon. Cross-reactivity of IgG antibodies between MUP8 and Mus m 1 as well as between the different MUPs was high and inhibition varied between 54 and 99%.

Conclusion: The mouse allergen Mus m 1 can be replaced in antibody testing by recombinant MUP8. Other MUPs, except MUP4, are interchangeable with MUP8. However, mouse urine extract showed better detection of both mouse-specific IgE and IgG4 levels. Other components in the mouse urine, like mouse albumin and other yet unidentified components, also induce IgE and IgG4 antibodies.
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http://dx.doi.org/10.1159/000106318DOI Listing
December 2007

Salmeterol enhances pulmonary fibrinolysis in healthy volunteers.

Crit Care Med 2007 Jan;35(1):57-63

Center for Experimental and Molecular Medicine Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: 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.

Design: A single-blinded, placebo-controlled study.

Setting: University hospital and laboratory.

Subjects: A total of 32 human volunteers.

Interventions: 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 And Main Results: 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.

Conclusions: Salmeterol has profibrinolytic properties in the normal lung and when applied in a model of sterile pulmonary inflammation.
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http://dx.doi.org/10.1097/01.CCM.0000249827.29387.4EDOI Listing
January 2007

Spreading of occupational allergens: laboratory animal allergens on hair-covering caps and in mattress dust of laboratory animal workers.

Occup Environ Med 2007 Apr 19;64(4):267-72. Epub 2006 Oct 19.

Department Of Pulmonology, Academic Medical Center, Amsterdam, The Netherlands.

Background: Family members of laboratory animal workers are at risk of developing allergy to laboratory animals. Little is known about the spreading of laboratory animal allergens outside the animal facilities.

Objective: To assess the presence of laboratory animal allergens in dust collected from mattresses of laboratory animal workers and unexposed controls.

Methods: Mouse and rat urinary proteins were measured in samples of mattress dust collected by laboratory animal workers and unexposed controls. In addition, rat and mouse allergens were determined in extracts of hair-covering caps, used during laboratory animal work, to estimate spreading of allergen through dust captured on hair. Allergen concentrations on hair caps were compared with exposure measured by personal airborne dust sampling.

Results: Levels of rat urinary allergens (RUA) and mouse urinary allergens (MUA) and mouse urinary protein (MUP) 8, a specific pheromone-binding mouse allergen, were significantly higher in mattress samples of laboratory animal workers than in those of controls. Hair-covering caps used in animal facilities harboured large amounts of RUA and MUA, which correlated significantly with exposure measured by the personal sampling technique in the animal facility.

Conclusions: Occupational laboratory animal allergens are detectable in mattress dust of laboratory animal workers. Transfer of allergens via uncovered hair of animal workers is likely contributing to this phenomenon. This study stresses the importance of using hair caps to prevent spreading of occupational allergens.
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http://dx.doi.org/10.1136/oem.2006.028845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078456PMC
April 2007

Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia.

Crit Care Med 2006 Jun;34(6):1725-30

Center of Infection and Immunity Amsterdam, Laboratory of Experimental Internal Medicine, Department of Pulmonology, University of Amsterdam, the Netherlands.

Objective: The tissue factor (TF)-factor VIIa (FVIIa) complex not only is essential for activation of blood coagulation but also affect the inflammatory response during sepsis. The objective of this study was to determine the role of TF-FVIIa in pneumonia caused by Streptococcus pneumoniae, the most important causative organism in community-acquired pneumonia and a major cause of sepsis.

Design: A controlled, in vivo laboratory study.

Setting: Research laboratory of a health sciences university.

Patients And Subjects: Patients with unilateral community-acquired pneumonia and female BALB/c mice.

Interventions: Bilateral bronchoalveolar lavage was performed in patients with community-acquired pneumonia. In mice, pneumonia was induced by intranasal inoculation with S. pneumoniae with or without concurrent inhibition of TF-FVIIa by subcutaneous injections of recombinant nematode anticoagulant protein (rNAPc2).

Measurements And Main Results: Patients with unilateral community-acquired pneumonia demonstrated elevated concentrations of FVIIa, soluble TF, and thrombin-antithrombin complexes in bronchoalveolar lavage fluid obtained from the infected site compared with the uninfected site. Mice with S. pneumoniae pneumonia displayed increased TF expression and fibrin deposits in lungs together with elevated thrombin-antithrombin complex levels in bronchoalveolar lavage fluid; inhibition of TF-FVIIa by rNAPc2 attenuated the procoagulant response in the lung but did not affect host defense, as reflected by an unaltered outgrowth of pneumococci and an unchanged survival.

Conclusions: These data suggest that TF-FVIIa activity contributes to activation of coagulation in the lung during pneumococcal pneumonia but does not play an important role in the antibacterial host defense in this murine model.
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http://dx.doi.org/10.1097/01.CCM.0000218807.20570.C2DOI Listing
June 2006

Clinically masked increases in bronchial inflammation in guideline-treated persistent asthma.

Pulm Pharmacol Ther 2006 18;19(6):397-403. Epub 2005 Nov 18.

Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Current guidelines generally recommend a combination of inhaled corticosteroids and a Beta2-agonist for persistent asthma. The adjustment of anti-inflammatory therapy in persistent asthma is advised to be guided mainly by the presence of symptoms.

Objective: To investigate whether clinically masked increases in bronchial inflammation occur in guideline-treated, persistent asthma following allergen exposure.

Methods: After a 4-week steroid-run-in period (fluticasone 250 microg twice daily) 48 allergic patients with persistent asthma underwent a bronchial challenge with a single dose of allergen, after inhalation of salbutamol (400 microg, nebulized dose). FEV1 and sputum markers of bronchial inflammation were measured before and after allergen challenge. Furthermore, additional rescue-salbutamol usage was recorded following allergen challenge.

Results: After allergen challenge there was a significant increase in sputum eosinophil numbers (geometric mean number x 10(4)/g [95% CI]: 0.5 [0.3; 1.0] before, and 2.4 [1.3; 4.2] after challenge, p=0.01). The mean change in FEV1 between 4 and 8h after challenge relative to baseline was -0.04% [95% CI-2.3; 2.2], p>0.9. None of the patients took additional rescue salbutamol over 8 h after allergen challenge.

Conclusions: Clinically masked increases in bronchial inflammation occur in guideline-treated, persistent asthma following allergen exposure. This finding underscores the need for additional guides for the adjustment of anti-inflammatory therapy in persistent asthma.
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http://dx.doi.org/10.1016/j.pupt.2005.10.002DOI Listing
December 2006

Adding salmeterol to an inhaled corticosteroid reduces allergen-induced serum IL-5 and peripheral blood eosinophils.

J Allergy Clin Immunol 2005 Nov 3;116(5):1007-13. Epub 2005 Oct 3.

Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Adding a long-acting beta(2)-agonist to inhaled corticosteroids results in better symptomatic asthma control than increasing the dose of inhaled corticosteroids.

Objective: Investigating whether adding the long-acting beta(2)-agonist salmeterol to the inhaled corticosteroid fluticasone propionate has an effect on allergen-induced allergic inflammation in asthma.

Methods: Bronchial allergen challenges were performed in 26 patients with allergic asthma, pretreating them with a single dose of either fluticasone/salmeterol (100/50 microg) or fluticasone alone (100 microg), in a double-blind, randomized, cross-over design. Sputum and serum markers of bronchial inflammation were measured after allergen challenge, as well as lung function parameters. Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein.

Results: Asthmatic responses after allergen challenge were significantly reduced after pretreatment with fluticasone/salmeterol relative to fluticasone alone. Sputum inflammatory markers after allergen challenge were not significantly affected by fluticasone/salmeterol pretreatment. By contrast, serum IL-5 was significantly reduced (geometric mean serum IL-5 [SEM]: 0.5 [0.3] vs 1.1 [0.3] pg/mL 1 hour and 0.6 [0.3] vs 1.1 [0.3] pg/mL 6 hours after challenge with fluticasone/salmeterol vs fluticasone alone pretreatment, respectively; P values < .05). Also, peripheral blood eosinophils were significantly reduced (geometric mean number x 10(6)/L [SEM]: 172 [0.1] vs 237 [0.1] at 6 hours and 271 [0.1] vs 351 [0.1] at 24 hours with fluticasone/salmeterol vs fluticasone alone pretreatment, respectively; P < .05).

Conclusion: Adding salmeterol to fluticasone reduces allergen-induced serum IL-5 and peripheral blood eosinophils. This phenomenon may contribute to the improved clinical outcomes that result from adding a long-acting beta(2)-agonist to inhaled corticosteroids.
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http://dx.doi.org/10.1016/j.jaci.2005.08.016DOI Listing
November 2005

Antiinflammatory effects of salmeterol after inhalation of lipopolysaccharide by healthy volunteers.

Am J Respir Crit Care Med 2005 Oct 30;172(7):878-84. Epub 2005 Jun 30.

Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.

Rationale: 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.

Objective: 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.

Measurements And Main Results: 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.

Conclusion: Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.
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http://dx.doi.org/10.1164/rccm.200503-451OCDOI Listing
October 2005

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

Thromb Haemost 2005 Jun;93(6):1036-40

Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1160/TH04-08-0492DOI Listing
June 2005

Clustering of allergic outcomes within families and households in areas endemic for helminth infections.

Int Arch Allergy Immunol 2005 Apr 2;136(4):356-64. Epub 2005 Mar 2.

Department of Parasitology, Hasanuddin University, Makassar, Indonesia.

Background: Allergy and helminth infections share key immunological features in terms of Th2 responses. Although in industrialized countries clustering of allergic disorders within families has been frequently reported, such information is lacking from areas where helminth infections are endemic.

Methods: A total of 466 subjects from 29 families and 112 households participated in this study. Filarial infection, skin test reactivity and IgE to mite as well as total IgE were measured in all samples. Clustering of the allergy-related outcomes due to genetic and household factors was tested.

Results: Genetic factors contributed significantly to the clustering of total IgE and allergen-specific IgE, whereas only household factors contributed to the clustering of SPT positivity.

Conclusion: Similar to several studies conducted in western populations, total IgE and allergen-specific IgE are influenced by genetic factors in a population resident in a helminth endemic area. However, clustering of SPT positivity due to genetic factors was not significant in the current study raising the question of whether the presence of helminth infections may override genes that are associated with the expression of tissue reactivity to allergens in the west.
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http://dx.doi.org/10.1159/000084255DOI Listing
April 2005

Accuracy of specific IgE in the prediction of asthma: development of a scoring formula for general practice.

Br J Gen Pract 2005 Feb;55(511):125-31

Department of General Practice, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: For the diagnosis of asthma in young children, GPs have to rely on history taking and physical examination, as spirometry is not possible. The additional diagnostic value of specific immunoglobulin E (IgE) to inhalent allergens remains unclear.

Aim: To assess the predictive accuracy of specific IgE to cat, dog, and/or house dust mites in young children for the subsequent development of asthma at the age of 6 years.

Design Of Study: Prospective follow-up study.

Setting: Seventy-two general practices.

Method: A total of 654 children, aged 1-4 years, visiting their GPs for persistent coughing (>/= 5 days), were tested for IgE antibodies by radio allergosorbent testing (RAST). Parents completed a questionnaire on potential risk indicators. Those children who showed an IgE-positive status (12.7%) and a random sample of those with an IgE-negative status (<0.5 U/ml) were followed up to the age of 6 years when the asthma status was established. The main outcome measure was asthma at the age of 6 years (combination of both symptoms and/or use of asthma medication, and impaired lung function).

Results: Addition of RAST results to a prediction model based on age, wheeze, and family history of pollen allergy increased the area under the receiver operating characteristic (ROC) curve from 0.76 to 0.87. Furthermore, RAST improved patient differentiation as indicated by a change in the range of asthma probabilities from 6-75% before the IgE test, to 1-95% after the IgE-test.

Conclusion: Sensitisation to inhalant allergens in 1-4-year-olds, as shown by RAST, is a useful diagnostic indicator for the presence of asthma at the age of 6 years, even after a clinical history has been obtained. This model should preferably be validated in a new population before it can be applied in practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463187PMC
February 2005

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

J Infect Dis 2004 Apr 29;189(8):1506-15. Epub 2004 Mar 29.

Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1086/382962DOI Listing
April 2004
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