35 results on '"Leusink-Muis T"'
Search Results
2. Airway hyper-responsiveness in allergic asthma in guinea-pigs is mediated by nerve growth factor via the induction of substance P: a potential role for trkA
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de Vries, A., Engels, F., Henricks, P. A. J., Leusink-Muis, T., McGregor, G. P., Braun, A., Groneberg, D. A., Dessing, M. C., Nijkamp, F. P., and Fischer, A.
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- 2006
3. Antibodies directed against nerve growth factor inhibit the acute bronchoconstriction due to allergen challenge in guinea-pigs
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De Vries, A, Engels, F, Henricks, P. A. J, Leusink-Muis, T, Fischer, A, and Nijkamp, F. P
- Published
- 2002
4. The development of allergic inflammation in a murine house dust mite asthma model is suppressed by synbiotic mixtures of non-digestible oligosaccharides and Bifidobacterium breve M-16V
- Author
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Verheijden, K A T, Willemsen, L E M, Braber, S, Leusink-Muis, T, Jeurink, P V, Garssen, J, Kraneveld, A D, Folkerts, G, Pharmacology, Sub Immunopharmacology, LS Pharma, Sub Airway in vivo Pharmacology, Sub General Pharmacology, Pharmacology, Sub Immunopharmacology, LS Pharma, Sub Airway in vivo Pharmacology, and Sub General Pharmacology
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0301 basic medicine ,Male ,Allergy ,Synbiotics ,ved/biology.organism_classification_rank.species ,Medicine (miscellaneous) ,Oligosaccharides ,Bifidobacterium breve ,Mice ,0302 clinical medicine ,immune system diseases ,Lung ,Mice, Inbred BALB C ,Nutrition and Dietetics ,biology ,Pyroglyphidae ,Original Contribution ,respiratory system ,medicine.symptom ,Bronchoalveolar Lavage Fluid ,Inflammation ,Allergic inflammation ,House dust mite ,03 medical and health sciences ,Interferon-gamma ,medicine ,Hypersensitivity ,Animals ,Asthma ,Chemokine CCL22 ,ved/biology ,business.industry ,Interleukins ,biology.organism_classification ,medicine.disease ,respiratory tract diseases ,Eosinophils ,Disease Models, Animal ,030104 developmental biology ,Immunology ,Chemokine CCL17 ,business ,030215 immunology - Abstract
PURPOSE: The incidence and severity of allergic asthma is rising, and novel strategies to prevent or treat this disease are needed. This study investigated the effects of different mixtures of non-digestible oligosaccharides combined with Bifidobacterium breve M-16V (BB) on the development of allergic airway inflammation in an animal model for house dust mite (HDM)-induced allergic asthma. METHODS: BALB/c mice were sensitized intranasally (i.n.) with HDM and subsequently challenged (i.n.) with PBS or HDM while being fed diets containing different oligosaccharide mixtures in combination with BB or an isocaloric identical control diet. Bronchoalveolar lavage fluid (BALF) inflammatory cell influx, chemokine and cytokine concentrations in lung homogenates and supernatants of ex vivo HDM-restimulated lung cells were analyzed. RESULTS: The HDM-induced influx of eosinophils and lymphocytes was reduced by the diet containing the short-chain and long-chain fructo-oligosaccharides and BB (FFBB). In addition to the HDM-induced cell influx, concentrations of IL-33, CCL17, CCL22, IL-6, IL-13 and IL-5 were increased in supernatants of lung homogenates or BALF and IL-4, IFN-γ and IL-10 were increased in restimulated lung cell suspensions of HDM-allergic mice. The diet containing FFBB reduced IL-6, IFN-γ, IL-4 and IL-10 concentrations, whereas the combination of galacto-oligosaccharides and long-chain fructo-oligosaccharides with BB was less potent in this model. CONCLUSION: These findings show that synbiotic dietary supplementation can affect respiratory allergic inflammation induced by HDM. The combination of FFBB was most effective in the prevention of HDM-induced airway inflammation in mice.
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- 2015
5. The development of allergic inflammation in a murine house dust mite asthma model is suppressed by synbiotic mixtures of non-digestible oligosaccharides and Bifidobacterium breve M-16V
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Pharmacology, Sub Immunopharmacology, LS Pharma, Sub Airway in vivo Pharmacology, Sub General Pharmacology, Verheijden, K A T, Willemsen, L E M, Braber, S, Leusink-Muis, T, Jeurink, P V, Garssen, J, Kraneveld, A D, Folkerts, G, Pharmacology, Sub Immunopharmacology, LS Pharma, Sub Airway in vivo Pharmacology, Sub General Pharmacology, Verheijden, K A T, Willemsen, L E M, Braber, S, Leusink-Muis, T, Jeurink, P V, Garssen, J, Kraneveld, A D, and Folkerts, G
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- 2016
6. Respiratory allergy and pulmonary irritation to trimellitic anhydride in Brown Norway rats
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Arts, J.H.E., Bloksma, N., Leusink-Muis, T., and Kuper, C.F.
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Airway irritation ,animal experiment ,sensitization ,immunoglobulin E ,animal tissue ,lung lavage ,immune system diseases ,methacholine ,Rats, Inbred BN ,acetylglucosaminidase ,Animals ,immunoglobulin blood level ,rat ,Nonspecific airway hyperresponsiveness ,lung injury ,Lung ,nonhuman ,Biology Nutrition ,Respiration ,Body Weight ,article ,lactate dehydrogenase ,Organ Size ,Allergens ,Respiratory allergy ,Rattus norvegicus ,respiratory tract diseases ,Rats ,Respiratory Function Tests ,female ,respiratory tract allergy ,Toxicology and Applied Pharmacology ,Phthalic Anhydrides ,irritant agent ,histopathology ,Immunization ,Brown Norway rats ,Trimellitic anhydride ,protein ,occupational asthma ,leukocyte ,Bronchoalveolar Lavage Fluid - Abstract
Occupational exposure to low-molecular-weight (LMW) allergens such as acid anhydrides can result in occupational asthma, an allergic disease characterized by episodic airway obstruction, airways inflammation, and non specific airways hyperresponsiveness. Since LMW irritants can provoke rather similar effects and since most, if not all, LMW allergens have irritant properties, this study addressed the distinction between allergenic and irritant effects of the respiratory allergen trimellitic anhydride (TMA). BN rats were sensitized by dermal application of TMA or vehicle alone and 3 weeks later were challenged by inhalation of a slightly irritating concentration of TMA or the vehicle. Lung function was measured before, during, and shortly after challenge. One day after challenge, in vivo and in vitro nonspecific airways hyperresponsiveness to methacholine was measured, and bronchoalveolar lavage was performed to measure total protein, lactate dehydrogenase, N-acetyl-glucosaminidase, and total and differential leukocyte numbers in the fluid. In addition, IgE measurements and histopathological examinations of the respiratory tract were carried out. TMA challenge of sensitized, but not sham-sensitized, BN rats reduced breathing frequency during challenge, elevated total and TMA-specific serum IgE levels, and caused a typical allergic asthma-associated airway pathology, as observed earlier. Vehicle challenge did not cause these effects, irrespective of sensitization. Hyperresponsiveness to methacholine was only seen in TMA-sensitized and -challenged rats. These rats also showed increased levels of the biochemical parameters and increased numbers of eosinophils and neutrophils in the lung lavage fluid; TMA challenge of sham-sensitized rats caused similar but markedly less pronounced effects. During TMA challenge of sham-sensitized rats, a breathing pattern typical of irritation was noticed but a clearly distinct pattern was seen upon TMA challenge of sensitized rats. In conclusion, TMA challenge of sensitized rats caused sensitization-dependent asthma-like early changes in breathing pattern that clearly could be distinguished from irritant-induced changes and non-specific airways hyperresponsiveness 24 h after challenge. Sensitization-dependent functional changes were accompanied by inflammatory changes characteristic of asthma and biochemical evidence of airway damage. © 2003 Elsevier Science (USA). All rights reserved.
- Published
- 2003
7. Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice
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Ten Broeke, R, Crom, Rini, van Haperen, Rien, Verweij, V, Leusink-Muis, T, van Ark, I, De Clerck, F, Nijkamp, FP, Folkerts, G, Ten Broeke, R, Crom, Rini, van Haperen, Rien, Verweij, V, Leusink-Muis, T, van Ark, I, De Clerck, F, Nijkamp, FP, and Folkerts, G
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- 2006
8. Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice
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De Clerck Fred, Van Ark Ingrid, Leusink-Muis Thea, Verweij Vivienne, Van Haperen Rien, De Crom Rini, Broeke Robert, Nijkamp Frans P, and Folkerts Gert
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Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Asthma is associated with airway hyperresponsiveness and enhanced T-cell number/activity on one hand and increased levels of exhaled nitric oxide (NO) with expression of inducible NO synthase (iNOS) on the other hand. These findings are in paradox, as NO also relaxes airway smooth muscle and has immunosuppressive properties. The exact role of the endothelial NOS (eNOS) isoform in asthma is still unknown. We hypothezised that a delicate regulation in the production of NO and its bioactive forms by eNOS might be the key to the pathogenesis of asthma. Methods The contribution of eNOS on the development of asthmatic features was examined. We used transgenic mice that overexpress eNOS and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin. Results eNOS overexpression resulted in both increased eNOS activity and NO production in the lungs. Isolated thoracic lymph nodes cells from eNOS overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines IFN-γ, IL-5 and IL-10. No difference in serum IgE levels could be found. Further, there was a 50% reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals. Finally, airway hyperresponsiveness to methacholine was abolished in eNOS overexpressing mice. Conclusion These findings demonstrate that eNOS overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma. We suggest that a delicate balance in the production of bioactive forms of NO derived from eNOS might be essential in the pathophysiology of asthma.
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- 2006
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9. Synbiotics, a promising approach for alleviating exacerbated allergic airway immune responses in offspring of a preclinical murine pollution model.
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Dehghani A, Wang L, Garssen J, Styla E, Leusink-Muis T, Van Ark I, Folkerts G, Van Bergenhenegouwen J, and Braber S
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- Animals, Female, Pregnancy, Pyroglyphidae immunology, Immunoglobulin E blood, Gastrointestinal Microbiome drug effects, Mice, Inbred BALB C, Bronchoalveolar Lavage Fluid immunology, Bronchoalveolar Lavage Fluid cytology, Mice, Lung immunology, Lung drug effects, Male, Maternal Exposure adverse effects, Disease Models, Animal, Prenatal Exposure Delayed Effects immunology, Immunoglobulin G blood, Th2 Cells immunology, Th2 Cells drug effects, Synbiotics administration & dosage, Asthma immunology, Asthma chemically induced
- Abstract
Exposure to pollutants like environmental cigarette smoke (CS) poses a major global health risk, affecting individuals from an early age. Therefore, this study explores how postnatal synbiotic supplementation affects allergic asthma symptoms in house-dust-mite (HDM)- challenged offspring maternally exposed to CS. In HDM-allergic offspring of CS-exposed dams, lung resistance was elevated, but synbiotic supplementation effectively reduced this resistance. Elevated eosinophil BALF counts following HDM challenge were intensified in pups maternally exposed to CS. Similarly, Th2 cell activation and serum IgE and IgG1 levels were more pronounced in HDM-allergic offspring of CS-exposed mothers. Synbiotics reduced eosinophil numbers and serum IgE and IgG1, and tended to decrease Th2 cell infiltration and activation. Synbiotics promoted beneficial gut bacteria like Bifidobacterium and Akkermansia. In conclusion, early-life synbiotic intervention mitigated allergic asthma associated with maternal air pollution exposure, highlighting the potential of synbiotics for clinical evaluation as a strategy to prevent allergy development in offspring., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johan Garssen reports financial support was provided by Danone Nutricia Research. Jeroen van Bergenhenegouwen reports a relationship with Danone Nutricia Research that includes: employment. Johan Garssen reports a relationship with Danone Nutricia Research that includes: employment. Saskia Braber reports a relationship with Danone Nutricia Research that includes: employment. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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10. Electrical vagus nerve stimulation is a promising approach to reducing pulmonary complications after an esophagectomy: an experimental rodent model.
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Janssen HJB, Geraedts TCM, Fransen LFC, van Ark I, Leusink-Muis T, Folkerts G, Garssen J, Ruurda JP, Nieuwenhuijzen GAP, van Hillegersberg R, and Luyer MDP
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- Animals, Rats, Male, Postoperative Complications immunology, Postoperative Complications prevention & control, Postoperative Complications etiology, Vagus Nerve surgery, Vagotomy, Rats, Sprague-Dawley, Bronchoalveolar Lavage Fluid immunology, Lung pathology, Lung immunology, Lung Injury etiology, Lung Injury prevention & control, Neutrophils immunology, Humans, Esophagectomy adverse effects, Vagus Nerve Stimulation methods, Cytokines metabolism, Disease Models, Animal, Lipopolysaccharides
- Abstract
After esophagectomy, an imbalanced inflammatory response increases the risk of postoperative morbidity. The vagus nerve modulates local and systemic inflammatory responses, but its pulmonary branches are transected during esophagectomy as part of the oncological resection, which may account for the high incidence of postoperative (pulmonary) complications. This study investigated the effect of electrical vagus nerve stimulation (VNS) on lipopolysaccharide (LPS)-induced lung injury in rats. Rats (n = 60) were randomly assigned to a non-vagotomy or cervical vagotomy group, with VNS or without (NOSTIM). There were four non-vagotomy groups: NOSTIM and bilateral VNS with 100, 50, or 10 µA. The four vagotomy groups were NOSTIM and VNS with fixed amplitude (50 µA) bilaterally before (VNS-50-before) or after bilateral vagotomy (VNS-50-after), or unilaterally (left) before ipsilateral vagotomy (VNS-50-unilaterally). LPS was administered intratracheally after surgery. Pulmonary function, pro-inflammatory cytokines in serum, broncho-alveolar lavage fluid (BALF), and histopathological lung injury (LIS) were assessed 180 min post-procedure. In non-vagotomized rats, neutrophil influx in BALF following intra-tracheal LPS (mean 30 [± 23]; P = 0.075) and LIS (mean 0.342 [± 0.067]; P = 0.142) were similar after VNS-100, compared with NOSTIM. VNS-50 reduced neutrophil influx (23 [± 19]; P = 0.024) and LIS (0.316 [± 0.093]; P = 0.043). VNS-10 reduced neutrophil influx (15 [± 6]; P = 0.009), while LIS (0.331 [± 0.053]; P = 0.088) was similar. In vagotomized rats, neutrophil influx (52 [± 37]; P = 0.818) and LIS (0.407 [SD ± 0.037]; P = 0.895) in VNS-50-before were similar compared with NOSTIM, as well as in VNS-50-after (neutrophils 30 [± 26]; P = 0.090 and LIS 0.344 [± 0.053]; P = 0.073). In contrast, VNS-50-unilaterally reduced neutrophil influx (26 [± 10]; P = 0.050) and LIS (0.296 [± 0.065]; P = 0.005). Systemic levels of cytokines TNF-α and IL-6 were undetectable in all groups. Pulmonary function was not statistically significantly affected. In conclusion, VNS limited influx of neutrophils in lungs in non-vagotomized rats and may attenuate LIS. Unilateral VNS attenuated lung injury even after ipsilateral vagotomy. This effect was absent for bilateral VNS before and after bilateral vagotomy. It is suggested that the effect of VNS is dependent on (partially) intact vagus nerves and that the level of the vagotomy during esophagectomy may influence postoperative pulmonary outcomes., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)
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- 2024
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11. Exploring the Modulatory Effect of High-Fat Nutrition on Lipopolysaccharide-Induced Acute Lung Injury in Vagotomized Rats and the Role of the Vagus Nerve.
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Seesing MFJ, Janssen HJB, Geraedts TCM, Weijs TJ, van Ark I, Leusink-Muis T, Folkerts G, Garssen J, Ruurda JP, Nieuwenhuijzen GAP, van Hillegersberg R, and Luyer MDP
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- Rats, Animals, alpha7 Nicotinic Acetylcholine Receptor metabolism, Vagus Nerve metabolism, Vagotomy, Lipopolysaccharides metabolism, Acute Lung Injury metabolism
- Abstract
During esophagectomy, the vagus nerve is transected, which may add to the development of postoperative complications. The vagus nerve has been shown to attenuate inflammation and can be activated by a high-fat nutrition via the release of acetylcholine. This binds to α7 nicotinic acetylcholine receptors (α7nAChR) and inhibits α7nAChR-expressing inflammatory cells. This study investigates the role of the vagus nerve and the effect of high-fat nutrition on lipopolysaccharide (LPS)-induced lung injury in rats. Firstly, 48 rats were randomized in 4 groups as follows: sham (sparing vagus nerve), abdominal (selective) vagotomy, cervical vagotomy and cervical vagotomy with an α7nAChR-agonist. Secondly, 24 rats were randomized in 3 groups as follows: sham, sham with an α7nAChR-antagonist and cervical vagotomy with an α7nAChR-antagonist. Finally, 24 rats were randomized in 3 groups as follows: fasting, high-fat nutrition before sham and high-fat nutrition before selective vagotomy. Abdominal (selective) vagotomy did not impact histopathological lung injury (LIS) compared with the control (sham) group ( p > 0.999). There was a trend in aggravation of LIS after cervical vagotomy ( p = 0.051), even after an α7nAChR-agonist ( p = 0.090). Cervical vagotomy with an α7nAChR-antagonist aggravated lung injury ( p = 0.004). Furthermore, cervical vagotomy increased macrophages in bronchoalveolar lavage (BAL) fluid and negatively impacted pulmonary function. Other inflammatory cells, TNF-α and IL-6, in the BALF and serum were unaffected. High-fat nutrition reduced LIS after sham ( p = 0.012) and selective vagotomy ( p = 0.002) compared to fasting. vagotomy. This study underlines the role of the vagus nerve in lung injury and shows that vagus nerve stimulation using high-fat nutrition is effective in reducing lung injury, even after selective vagotomy.
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- 2023
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12. Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation.
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Pelgrim CE, van Ark I, van Berkum RE, Schuitemaker-Borneman AM, Flier I, Leusink-Muis T, Janbazacyabar H, Diks MAP, Gosker HR, Kelders MCJM, Langen RCJ, Schols AMWJ, Hageman RJJ, Braber S, Garssen J, Folkerts G, van Helvoort A, and Kraneveld AD
- Abstract
One cluster of the extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) is related to the brain, which includes anxiety, depression and cognitive impairment. Brain-related comorbidities are related to worsening of symptoms and increased mortality in COPD patients. In this study, a murine model of COPD was used to examine the effects of emphysema and repetitive pulmonary inflammatory events on systemic inflammatory outcomes and brain function. In addition, the effect of a dietary intervention on brain-related parameters was assessed. Adult male C57Bl/6J mice were exposed to elastase or vehicle intratracheally (i.t.) once a week on three consecutive weeks. Two weeks after the final administration, mice were i.t. exposed to lipopolysaccharide (LPS) or vehicle for three times with a 10 day interval. A dietary intervention enriched with omega-3 PUFAs, prebiotic fibers, tryptophan and vitamin D was administered from the first LPS exposure onward. Behavior and cognitive function, the degree of emphysema and both pulmonary and systemic inflammation as well as blood-brain barrier (BBB) integrity and neuroinflammation in the brain were assessed. A lower score in the cognitive test was observed in elastase-exposed mice. Mice exposed to elastase plus LPS showed less locomotion in the behavior test. The enriched diet seemed to reduce anxiety-like behavior over time and cognitive impairments associated with the presented COPD model, without affecting locomotion. In addition, the enriched diet restored the disbalance in splenic T-helper 1 (Th1) and Th2 cells. There was a trend toward recovering elastase plus LPS-induced decreased expression of occludin in brain microvessels, a measure of BBB integrity, as well as improving expression levels of kynurenine pathway markers in the brain by the enriched diet. The findings of this study demonstrate brain-associated comorbidities - including cognitive and behavioral impairments - in this murine model for COPD. Although no changes in lung parameters were observed, exposure to the specific enriched diet in this model appeared to improve systemic immune disbalance, BBB integrity and derailed kynurenine pathway which may lead to reduction of anxiety-like behavior and improved cognition., Competing Interests: Authors AH, JG, and RH were employed by Danone Nutricia Research, Utrecht, Netherlands. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pelgrim, van Ark, van Berkum, Schuitemaker-Borneman, Flier, Leusink-Muis, Janbazacyabar, Diks, Gosker, Kelders, Langen, Schols, Hageman, Braber, Garssen, Folkerts, van Helvoort and Kraneveld.)
- Published
- 2022
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13. Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies.
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Wang L, van Iersel LEJ, Pelgrim CE, Lu J, van Ark I, Leusink-Muis T, Gosker HR, Langen RCJ, Schols AMWJ, Argilés JM, van Helvoort A, Kraneveld AD, Garssen J, Henricks PAJ, Folkerts G, and Braber S
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- Animals, Cytokines metabolism, Fatty Acids metabolism, Interleukin-1beta metabolism, Mice, Tumor Necrosis Factor-alpha metabolism, Adipose Tissue metabolism, Adipose Tissue pathology, Cigarette Smoking, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Smoke adverse effects
- Abstract
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.
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- 2022
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14. Changes in intestinal homeostasis and immunity in a cigarette smoke- and LPS-induced murine model for COPD: the lung-gut axis.
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Wang L, Pelgrim CE, Peralta Marzal LN, Korver S, van Ark I, Leusink-Muis T, van Helvoort A, Keshavarzian A, Kraneveld AD, Garssen J, Henricks PAJ, Folkerts G, and Braber S
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- Animals, Bronchoalveolar Lavage Fluid, Disease Models, Animal, Homeostasis, Immunoglobulin A adverse effects, Immunoglobulin A metabolism, Immunoglobulin A, Secretory metabolism, Immunoglobulin A, Secretory pharmacology, Lipopolysaccharides adverse effects, Lung metabolism, Mice, Nicotiana, Cigarette Smoking adverse effects, Pulmonary Disease, Chronic Obstructive metabolism
- Abstract
Chronic obstructive pulmonary disease (COPD) is often associated with intestinal comorbidities. In this study, changes in intestinal homeostasis and immunity in a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD model were investigated. Mice were exposed to cigarette smoke or air for 72 days, except days 42 , 52 , and 62 on which the mice were treated with saline or LPS via intratracheal instillation. Cigarette smoke exposure increased the airway inflammatory cell numbers, mucus production, and different inflammatory mediators, including C-reactive protein (CRP) and keratinocyte-derived chemokine (KC), in bronchoalveolar lavage (BAL) fluid and serum. LPS did not further impact airway inflammatory cell numbers or mucus production but decreased inflammatory mediator levels in BAL fluid. T helper (Th) 1 cells were enhanced in the spleen after cigarette smoke exposure; however, in combination with LPS, cigarette exposure caused an increase in Th1 and Th2 cells. Histomorphological changes were observed in the proximal small intestine after cigarette smoke exposure, and addition of LPS had no effect. Cigarette smoke activated the intestinal immune network for IgA production in the distal small intestine that was associated with increased fecal sIgA levels and enlargement of Peyer's patches. Cigarette smoke plus LPS decreased fecal sIgA levels and the size of Peyer's patches. In conclusion, cigarette smoke with or without LPS affects intestinal health as observed by changes in intestinal histomorphology and immune network for IgA production. Elevated systemic mediators might play a role in the lung-gut cross talk. These findings contribute to a better understanding of intestinal disorders related to COPD.
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- 2022
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15. Increased exploration and hyperlocomotion in a cigarette smoke and LPS-induced murine model of COPD: linking pulmonary and systemic inflammation with the brain.
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Pelgrim CE, Wang L, Peralta Marzal LN, Korver S, van Ark I, Leusink-Muis T, Braber S, Folkerts G, Garssen J, van Helvoort A, and Kraneveld AD
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- Animals, Brain metabolism, Disease Models, Animal, Inflammation pathology, Lipopolysaccharides adverse effects, Lung metabolism, Mice, Mice, Inbred C57BL, Nicotiana, Cigarette Smoking adverse effects, Pulmonary Disease, Chronic Obstructive pathology
- Abstract
Brain-related comorbidities are frequently observed in chronic obstructive pulmonary disease (COPD) and are related to increased disease progression and mortality. To date, it is unclear which mechanisms are involved in the development of brain-related problems in COPD. In this study, a cigarette smoke and lipopolysaccharide (LPS) exposure murine model was used to induce COPD-like features and assess the impact on brain and behavior. Mice were daily exposed to cigarette smoke for 72 days, except for days 42 , 52 , and 62 , on which mice were intratracheally exposed to the bacterial trigger LPS. Emphysema and pulmonary inflammation as well as behavior and brain pathology were assessed. Cigarette smoke-exposed mice showed increased alveolar enlargement and numbers of macrophages and neutrophils in bronchoalveolar lavage. Cigarette smoke exposure resulted in lower body weight, which was accompanied by lower serum leptin levels, more time spent in the inner zone of the open field, and decreased claudin-5 and occludin protein expression levels in brain microvessels. Combined cigarette smoke and LPS exposure resulted in increased locomotion and elevated microglial activation in the hippocampus of the brain. These novel findings show that systemic inflammation observed after combined cigarette smoke and LPS exposure in this COPD model is associated with increased exploratory behavior. Findings suggest that neuroinflammation is present in the brain area involved in cognitive functioning and that blood-brain barrier integrity is compromised. These findings can contribute to our knowledge about possible processes involved in brain-related comorbidities in COPD, which is valuable for optimizing and developing therapy strategies.
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- 2022
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16. Intratracheal administration of solutions in mice; development and validation of an optimized method with improved efficacy, reproducibility and accuracy.
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Pelgrim CE, van Ark I, Leusink-Muis T, Brans MAD, Braber S, Garssen J, van Helvoort A, Kraneveld AD, and Folkerts G
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- Animals, Bronchoalveolar Lavage Fluid, Disease Models, Animal, Female, Lipopolysaccharides, Lung, Mice, Mice, Inbred BALB C, Reproducibility of Results, Intubation, Intratracheal, Research Design
- Abstract
Animal models are still vital in the field of respiratory disease research. To improve the accuracy and consistency of the dose of specific compounds administered specifically in the respiratory tract, it is important to optimize and to compare the technique to currently available techniques. In this study, an optimized intubation-mediated intratracheal administration (IMIT) technique is described and compared to oropharyngeal aspiration (OA). Adult female Balb/c mice were treated with Evans Blue using IMIT or OA and sacrificed after a short recovery to observe the distribution of solutions throughout the lungs. Additionally, mice were treated with increasing doses of lipopolysaccharide (LPS) or saline to compare efficacy of both techniques. Inflammatory cell numbers in bronchoalveolar lavage were quantified 24 h post-administration. Evans Blue staining revealed a more homogeneous distribution and less variability among animals treated using IMIT as compared to OA. Higher inflammatory cell numbers were observed in IMIT mice compared to OA mice after exposure to vehicle or the lowest LPS concentration. This study shows that the optimized IMIT is superior to OA with regards to efficacy, reproducibility and accuracy. This IMIT method can be deployed to refine 3R animal welfare aspects of the experimental design and improve the reproducibility of respiratory disease mouse models., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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17. Prenatal and Postnatal Cigarette Smoke Exposure Is Associated With Increased Risk of Exacerbated Allergic Airway Immune Responses: A Preclinical Mouse Model.
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Janbazacyabar H, van Bergenhenegouwen J, Garssen J, Leusink-Muis T, van Ark I, van Daal MT, Folkerts G, and Braber S
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- Animals, Antigens, Dermatophagoides immunology, Cytokines metabolism, Disease Models, Animal, Disease Progression, Female, Humans, Male, Maternal Exposure adverse effects, Mice, Mice, Inbred BALB C, Prenatal Exposure Delayed Effects etiology, Pyroglyphidae immunology, Risk, Cigarette Smoking adverse effects, Hypersensitivity immunology, Lung immunology, Pregnancy immunology, Prenatal Exposure Delayed Effects immunology, Respiratory Hypersensitivity immunology, Th2 Cells immunology
- Abstract
Increased exposure to household air pollution and ambient air pollution has become one of the world's major environmental health threats. In developing and developed countries, environmental cigarette smoke (CS) exposure is one of the main sources of household air pollution (HAP). Moreover, results from different epidemiological and experimental studies indicate that there is a strong association between HAP, specifically CS exposure, and the development of allergic diseases that often persists into later life. Here, we investigated the impact of prenatal and postnatal CS exposure on offspring susceptibility to the development of allergic airway responses by using a preclinical mouse model. Pregnant BALB/c mice were exposed to either CS or air during pregnancy and lactation and in order to induce allergic asthma the offspring were sensitized and challenged with house dust mite (HDM). Decreased lung function parameters, like dynamic compliance and pleural pressure, were observed in PBS-treated offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. Maternal CS exposure significantly increased the HDM-induced airway eosinophilia and neutrophilia in the offspring. Prenatal and postnatal CS exposure increased the frequency of Th2 cells in the lungs of HDM-treated offspring compared to offspring born to air-exposed mothers. Offspring born to CS-exposed mothers showed increased levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid compared to offspring from air-exposed mothers. Ex-vivo restimulation of lung cells isolated from HDM-treated offspring born to CS-exposed mothers also resulted in increased IL-4 production. Finally, serum immunoglobulins levels of HDM-specific IgE and HDM-specific IgG1 were significantly increased upon a HDM challenge in offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. In summary, our results reveal a biological plausibility for the epidemiological studies indicating that prenatal and postnatal CS exposure increases the susceptibility of offspring to allergic immune responses., Competing Interests: JG and JB are employees of Danone Nutricia Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Janbazacyabar, van Bergenhenegouwen, Garssen, Leusink-Muis, Ark, van Daal, Folkerts and Braber.)
- Published
- 2021
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18. Human Milk Oligosaccharide 3'-GL Improves Influenza-Specific Vaccination Responsiveness and Immunity after Deoxynivalenol Exposure in Preclinical Models.
- Author
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Toutounchi NS, Braber S, Hogenkamp A, Varasteh S, Cai Y, Wehkamp T, Tims S, Leusink-Muis T, van Ark I, Wiertsema S, Stahl B, Kraneveld AD, Garssen J, Folkerts G, and Van't Land B
- Subjects
- Animals, Caco-2 Cells, Cecum drug effects, Diet, Fatty Acids, Volatile metabolism, Female, Food Contamination, Humans, Intestines drug effects, Mice, Inbred C57BL, Mycotoxins immunology, Spleen drug effects, Th1 Cells metabolism, Vaccines immunology, Mice, Adaptive Immunity drug effects, Influenza, Human immunology, Milk, Human chemistry, Oligosaccharides pharmacology, Trichothecenes immunology, Trisaccharides pharmacology, Vaccination
- Abstract
Deoxynivalenol (DON), a highly prevalent mycotoxin food contaminant, is known to have immunotoxic effects. In the current study, the potential of dietary interventions with specific mixtures of trans-galactosyl-oligosaccharides (TOS) to alleviate these effects were assessed in a murine influenza vaccination model. Vaccine-specific immune responses were measured in C57Bl/6JOlaHsd mice fed diets containing DON, TOS or a combination, starting 2 weeks before the first vaccination. The direct effects of TOS and its main oligosaccharide, 3'-galactosyl-lactose (3'-GL), on DON-induced damage were studied in Caco-2 cells, as an in vitro model of the intestinal epithelial barrier. Exposure to DON significantly reduced vaccine-specific immune responses and the percentages of Tbet
+ Th1 cells and B cells in the spleen. DON significantly altered epithelial structure and integrity in the ileum and reduced the SCFA levels in the cecum. Adding TOS into DON-containing diets significantly improved vaccine-specific immune responses, restored the immune cell balance in the spleen and increased SCFA concentrations in the cecum. Incubating Caco-2 cells with TOS and 3'-GL in vitro further confirmed their protective effects against DON-induced barrier disruption, supporting immune modulation. Overall, dietary intervention with TOS can attenuate the adverse effects of DON on Th1-mediated immune responses and gut homeostasis. These beneficial properties might be linked to the high levels of 3'-GL in TOS.- Published
- 2021
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19. The Effects of Maternal Smoking on Pregnancy and Offspring: Possible Role for EGF?
- Author
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Janbazacyabar H, van Daal M, Leusink-Muis T, van Ark I, Garssen J, Folkerts G, van Bergenhenegouwen J, and Braber S
- Abstract
Cigarette smoke exposure during pregnancy and lactation is associated with adverse pregnancy outcomes. Here, we investigated the effects of maternal smoke exposure on pregnancy and offspring immunity and explored whether, epidermal growth factor (EGF), an important growth-promoting factor in human colostrum and milk, might be a possible missing link in maternal smoke exposure and changes in infants' immune responses. Pregnant BALB/c mice were exposed to either cigarette smoke or air during gestation and lactation, and effects on pulmonary inflammation in dams and immune responses in offspring were examined. Maternal smoke exposure increased airway hyperresponsiveness and accumulation of inflammatory cells in the lungs of pregnant dams compared to non-pregnant dams. The E-cadherin protein expression was reduced in mammary glands of cigarette smoke-exposed pregnant dams. EGF levels were higher in mammary glands and serum of smoke-exposed pregnant dams compared to air-exposed pregnant dams. Offspring from cigarette smoke-exposed dams exhibited elevated levels of IL-17A, MCP-1, IL-22, and IL-13 in anti-CD3 stimulated spleen cell culture supernatants. EGF levels were also increased in serum of offspring from smoke-exposed dams. A positive correlation was observed between serum EGF levels and neutrophil numbers in bronchoalveolar lavage fluid of the dams. Interestingly, IL-17A, MCP-1, IL-22, IL13, and IFN-γ levels in anti-CD3 stimulated spleen cell culture supernatants of male pups also showed a positive correlation with EGF serum levels. In summary, our results reveal that maternal smoke exposure predisposes dams to exacerbated airway inflammation and offspring to exacerbated immune responses and both phenomena are associated with elevated EGF concentrations., Competing Interests: JG and JB are employees of Danone Nutricia Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Janbazacyabar, van Daal, Leusink-Muis, van Ark, Garssen, Folkerts, van Bergenhenegouwen and Braber.)
- Published
- 2021
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20. SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure.
- Author
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Wang L, Pelgrim CE, Swart DH, Krenning G, van der Graaf AC, Kraneveld AD, Leusink-Muis T, van Ark I, Garssen J, Folkerts G, and Braber S
- Subjects
- Animals, Bronchi pathology, Bronchoalveolar Lavage Fluid cytology, Disease Models, Animal, Epithelial Cells drug effects, Epithelial Cells metabolism, Female, Humans, Interleukin-8 biosynthesis, Lung pathology, Mice, Inbred BALB C, Neutrophils drug effects, Oxidative Stress drug effects, Piperazines administration & dosage, Piperazines chemistry, Piperazines pharmacology, Pneumonia drug therapy, Protein Kinases metabolism, Mice, Cigarette Smoking adverse effects, Neutrophils pathology, Piperazines therapeutic use
- Abstract
Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.
- Published
- 2021
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21. A Fermented Milk Matrix Containing Postbiotics Supports Th1- and Th17-Type Immunity In Vitro and Modulates the Influenza-Specific Vaccination Response In Vivo in Association with Altered Serum Galectin Ratios.
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Ayechu-Muruzabal V, Xiao L, Wehkamp T, van Ark I, Hoogendoorn EJ, Leusink-Muis T, Folkerts G, Garssen J, Willemsen LEM, and Van't Land B
- Abstract
During a specific milk fermentation process with Bifidobacterium breve C50 and Streptococcus thermophilus 065 (Lactofidus
TM ), postbiotics with possible immunomodulatory properties are produced. We investigated the effects of this fermentation product (FP) in vitro using a model that allows crosstalk between intestinal epithelial (IEC) and immune cells. IECs were exposed to FP and αCD3/CD28-activated peripheral blood mononuclear cells after which the mediator secretion was measured. Additionally, using a murine influenza vaccination model, immune development was assessed. Mice were fed an AIN93G diet containing FP or lactose as control. Vaccine-specific immunity was measured as delayed-type hypersensitivity (DTH) and correlated to intestinal and systemic immunomodulation levels. In vitro, exposure to FP enhanced IFNγ, TNFα and IL-17A concentrations. Moreover, IEC-derived galectin-3/galectin-9 and galectin-4/galectin-9 ratios were increased. In vivo, dietary intervention with FP increased vaccine-specific DTH responses as compared to the lactose-receiving group. Although no effects on humoral immunity and vaccine-specific T-cell responses were detected, an enhanced systemic serum galectin-3/galectin-9 and galectin-4/galectin-9 ratio correlated with a shift in RORγ (Th17) mRNA expression over regulatory TGFβ1 in the ileum. This was also positively correlated with the increased DTH response. These results indicate that FP can enhance epithelial galectin-3 and -4 over galectin-9 release, and boost adaptive immunity by promoting Th1- and Th17-type cytokines under inflammatory conditions in vitro. Similar variations in galectin and immune balance were observed in the vaccination model, where FP improved the influenza-specific DTH response.- Published
- 2021
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22. Crude Turmeric Extract Improves the Suppressive Effects of Lactobacillus rhamnosus GG on Allergic Inflammation in a Murine Model of House Dust Mite-Induced Asthma.
- Author
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Ghiamati Yazdi F, Zakeri A, van Ark I, Leusink-Muis T, Braber S, Soleimanian-Zad S, and Folkerts G
- Subjects
- Administration, Oral, Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents therapeutic use, Asthma etiology, Asthma immunology, Curcuma, Cytokines metabolism, Disease Models, Animal, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents therapeutic use, Lung drug effects, Lung immunology, Male, Mice, Mice, Inbred BALB C, Models, Immunological, Phytotherapy, Plant Extracts administration & dosage, Prebiotics administration & dosage, Probiotics administration & dosage, Probiotics therapeutic use, Pyroglyphidae immunology, Pyroglyphidae pathogenicity, Respiratory Hypersensitivity drug therapy, Respiratory Hypersensitivity immunology, Th17 Cells drug effects, Th17 Cells immunology, Th2 Cells drug effects, Th2 Cells immunology, Asthma therapy, Lacticaseibacillus rhamnosus immunology, Plant Extracts therapeutic use, Synbiotics administration & dosage
- Abstract
There is a strong correlation between dysregulation of the gastrointestinal microbiota and development of allergic diseases. The most prevalent therapies for relieving asthma symptoms are associated with serious side effects, and therefore novel approaches are needed. Our objective was to elucidate whether oral administration of Lactobacillus rhamnosus GG (LGG) as a probiotic or turmeric powder (TP) as a prebiotic or both as a synbiotic mitigate allergic inflammation including lung function, airway inflammatory cell infiltration, Th2 cytokines/chemokine in a murine model of house dust mite (HDM)-induced asthma. BALB/c mice were intranasally sensitized and challenged with HDM received TP (20 mg/Kg mouse), or/and LGG (10
5 or 107 cfu/ml), or both orally. Interestingly, the synbiotic intervention (HDM-TP-LGG E7) specifically suppress the developement of airway hyperresponsiveness in response to methacholine. Besides, our synbiotic, TP, and LGG strongly down-regulated eosinophilia, IL-5, CCL17, IL-13. In terms of T cell response, CD4+ Th2 cells and CD4+ Th17 population were reduced in the splenocytes of the treatment groups compared to control. The synbiotic group not only elevated CD25+ Foxp3+ Treg frequency compared to asthmatic group, but also increased T reg cells compared to the probiotic group. The synbiotic also indicated the superior effect in suppressing Th2 cells compared to probiotic. Although, TP and LGG alone displayed suppressive effects, this study showed that the combination therapy consisting of TP and LGG (synbiotic) is more effective in some of the parameters than either of the treatments alone. This novel synbiotic, might be considered as a potential food-based drug for translational medicine and can possibly be used along with corticosteroid treatment., (Copyright © 2020 Ghiamati Yazdi, Zakeri, Ark, Leusink-Muis, Braber, Soleimanian-Zad and Folkerts.)- Published
- 2020
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23. The Combination of 2'-Fucosyllactose with Short-Chain Galacto-Oligosaccharides and Long-Chain Fructo-Oligosaccharides that Enhance Influenza Vaccine Responses Is Associated with Mucosal Immune Regulation in Mice.
- Author
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Xiao L, Engen PA, Leusink-Muis T, van Ark I, Stahl B, Overbeek SA, Garssen J, Naqib A, Green SJ, Keshavarzian A, Folkerts G, and Van't Land B
- Subjects
- Animals, B-Lymphocytes, Cecum metabolism, Cecum microbiology, Colon metabolism, Colon microbiology, Feces microbiology, Female, Fructose pharmacology, Fructose therapeutic use, Galactose pharmacology, Galactose therapeutic use, Humans, Immunoglobulin G blood, Immunologic Factors pharmacology, Immunologic Factors therapeutic use, Influenza, Human immunology, Mice, Inbred C57BL, Mucous Membrane immunology, Oligosaccharides pharmacology, Th1 Cells, Trisaccharides pharmacology, Vaccination, Influenza Vaccines, Influenza, Human prevention & control, Milk, Human chemistry, Mucous Membrane drug effects, Oligosaccharides therapeutic use, Prebiotics, Trisaccharides therapeutic use
- Abstract
Background: A critical role for host-microbe interactions and establishment of vaccine responses has been postulated. Human milk oligosaccharides, of which 2'-fucosyllactose (2'FL) is the most prevalent, are known to alter host-associated microbial communities and play a critical role in the immunologic development of breastfed infants., Objectives: Dietary supplementation with a combination of 2'FL and prebiotic short-chain (sc) galacto-oligosaccharides (GOS) and long-chain (lc) fructo-oligosaccharides (FOS) was employed to examine human milk oligosaccharide effects on immune responsiveness, within a murine influenza vaccination model., Methods: Female mice (6 wk old, C57Bl/6JOlaHsd) were fed either control diet (CON) or scGOS/lcFOS/2'FL-containing diet (GF2F) for 45 d. After starting dietary intervention (day 14), mice received a primary influenza vaccination (day 0) followed by a booster vaccination (day 21), after which ear challenges were conducted to measure vaccine-specific delayed type hypersensitivity (DTH). Serum immunoglobulin (Ig) levels, fecal and cecal microbial community structure, short-chain fatty acids, host intestinal gene expression and cellular responses in the mesenteric lymph nodes (MLNs) were also measured., Results: Relative to CON, mice fed the GF2F diet had increased influenza vaccine-specific DTH responses (79.3%; P < 0.01), higher levels of both IgG1 (3.2-fold; P < 0.05) and IgG2a (1.2-fold; P < 0.05) in serum, and greater percentages of activated B cells (0.3%; P < 0.05), regulatory T cells (1.64%; P < 0.05), and T-helper 1 cells (2.2%; P < 0.05) in their MLNs. GF2F-fed mice had elevated cecal butyric (P < 0.05) and propionic (P < 0.05) acid levels relative to CON, which correlated to DTH responses (R2 = 0.22; P = 0.05 and R2 = 0.39; P < 0.01, respectively). Specific fecal microbial taxa altered in GF2F diet fed mice relative to CON were significantly correlated with the DTH response and IgG2a level increases., Conclusions: Dietary GF2F improved influenza vaccine-specific T-helper 1 responses and B cell activation in MLNs and enhanced systemic IgG1 and IgG2a concentrations in mice. These immunologic changes are correlated with microbial community structure and metabolites., (Copyright © American Society for Nutrition 2019.)
- Published
- 2019
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24. LAIR-1 Limits Neutrophilic Airway Inflammation.
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Kumawat K, Geerdink RJ, Hennus MP, Roda MA, van Ark I, Leusink-Muis T, Folkerts G, van Oort-Jansen A, Mazharian A, Watson SP, Coenjaerts FE, Bont L, and Meyaard L
- Subjects
- Animals, Bronchiolitis, Viral immunology, Bronchiolitis, Viral pathology, Chemokine CXCL1 immunology, Lung immunology, Lung pathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Pneumonia pathology, Receptors, Immunologic genetics, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections pathology, Respiratory Syncytial Virus, Human immunology, Smoke adverse effects, Nicotiana toxicity, Cell Movement immunology, Neutrophil Infiltration immunology, Neutrophils immunology, Pneumonia immunology, Receptors, Immunologic immunology
- Abstract
Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation induces immune pathology. The mechanisms by which neutrophils are regulated to prevent injury and preserve tissue homeostasis are not completely understood. We recently identified the collagen receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1 as a functional inhibitory receptor on airway-infiltrated neutrophils in viral bronchiolitis patients. In the current study, we sought to examine the role of LAIR-1 in regulating airway neutrophil responses in vivo . LAIR-1-deficient ( Lair1
-/- ) and wild-type mice were infected with respiratory syncytial virus (RSV) or exposed to cigarette smoke as commonly accepted models of neutrophil-driven lung inflammation. Mice were monitored for cellular airway influx, weight loss, cytokine production, and viral loads. After RSV infection, Lair1-/- mice show enhanced airway inflammation accompanied by increased neutrophil and lymphocyte recruitment to the airways, without effects on viral loads or cytokine production. LAIR-1-Fc administration in wild type mice, which blocks ligand induced LAIR-1 activation, augmented airway inflammation recapitulating the observations in Lair1-/- mice. Likewise, in the smoke-exposure model, LAIR-1 deficiency enhanced neutrophil recruitment to the airways and worsened disease severity. Intranasal CXCL1-mediated neutrophil recruitment to the airways was enhanced in mice lacking LAIR-1, supporting an intrinsic function of LAIR-1 on neutrophils. In conclusion, the immune inhibitory receptor LAIR-1 suppresses neutrophil tissue migration and acts as a negative regulator of neutrophil-driven airway inflammation during lung diseases. Following our recent observations in humans, this study provides crucial in-vivo evidence that LAIR-1 is a promising target for pharmacological intervention in such pathologies.- Published
- 2019
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25. The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma.
- Author
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Verheijden KAT, Braber S, Leusink-Muis T, Jeurink PV, Thijssen S, Kraneveld AD, Garssen J, Folkerts G, and Willemsen LEM
- Subjects
- Animals, Antigens, Dermatophagoides immunology, Cell Degranulation, Combined Modality Therapy, Cytokines metabolism, Dietary Supplements, Disease Models, Animal, Humans, Mice, Mice, Inbred BALB C, Pyroglyphidae immunology, Th1-Th2 Balance, Anti-Inflammatory Agents therapeutic use, Asthma therapy, Budesonide therapeutic use, Hypersensitivity therapy, Lung pathology, Mast Cells immunology, Oligosaccharides administration & dosage, Th2 Cells immunology
- Abstract
Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective. Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice. Methods: BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined. Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3
+ CD4+ Th2 and CD4+ RORγt+ Th17 cells in the lungs of the allergic mice. Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation.- Published
- 2018
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26. Human Milk Oligosaccharide 2'-Fucosyllactose Improves Innate and Adaptive Immunity in an Influenza-Specific Murine Vaccination Model.
- Author
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Xiao L, Leusink-Muis T, Kettelarij N, van Ark I, Blijenberg B, Hesen NA, Stahl B, Overbeek SA, Garssen J, Folkerts G, and Van't Land B
- Subjects
- Adaptive Immunity, Animals, Antibodies blood, Disease Models, Animal, Female, Humans, Immunity, Innate, Mice, Mice, Inbred C57BL, Milk, Vaccination, Hypersensitivity, Delayed immunology, Influenza A virus immunology, Influenza Vaccines immunology, Influenza, Human immunology, Oligosaccharides immunology, Ovalbumin immunology, Trisaccharides immunology
- Abstract
Background: Human milk is uniquely suited to provide optimal nutrition and immune protection to infants. Human milk oligosaccharides are structural complex and diverse consisting of short chain and long chain oligosaccharides typically present in a 9:1 ratio. 2'-Fucosyllactose (2'FL) is one of the most prominent short chain oligosaccharides and is associated with anti-infective capacity of human milk., Aim: To determine the effect of 2'FL on vaccination responsiveness (both innate and adaptive) in a murine influenza vaccination model and elucidate mechanisms involved., Methods: A dose range of 0.25-5% (w/w) dietary 2'FL was provided to 6-week-old female C57Bl/6JOlaHsd mice 2 weeks prior primary and booster vaccination until the end of the experiment. Intradermal (i.d.) challenge was performed to measure the vaccine-specific delayed-type hypersensitivity (DTH). Antigen-specific antibody levels in serum as well as immune cell populations within several organs were evaluated using ELISA and flow cytometry, respectively. In an ex vivo restimulation assay, spleen cells were cocultured with influenza-loaded bone marrow-derived dendritic cells (BMDCs) to study the effects of 2'FL on vaccine-specific CD4+ and CD8+ T-cell proliferation and cytokine secretions. Furthermore, the direct immune regulatory effects of 2'FL were confirmed using in vitro BMDCs T-cell cocultures., Results: Dietary 2'FL significantly ( p < 0.05) enhanced vaccine specific DTH responses accompanied by increased serum levels of vaccine-specific immunoglobulin (Ig) G1 and IgG2a in a dose-dependent manner. Consistently, increased activation marker (CD27) expression on splenic B-cells was detected in mice receiving 2'FL as compared to control mice. Moreover, proliferation of vaccine-specific CD4+ and CD8+ T-cells, as well as interferon-γ production after ex vivo restimulation were significantly increased in spleen cells of mice receiving 2'FL as compared to control mice, which were in line with changes detected within dendritic cell populations. Finally, we confirmed a direct effect of 2'FL on the maturation status and antigen presenting capacity of BMDCs., Conclusion: Dietary intervention with 2'FL improves both humoral and cellular immune responses to vaccination in mice, which might be attributed in part to the direct effects of 2'FL on immune cell differentiation.
- Published
- 2018
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27. Human milk oligosaccharides protect against the development of autoimmune diabetes in NOD-mice.
- Author
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Xiao L, Van't Land B, Engen PA, Naqib A, Green SJ, Nato A, Leusink-Muis T, Garssen J, Keshavarzian A, Stahl B, and Folkerts G
- Subjects
- Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Feces microbiology, Female, Gastrointestinal Microbiome drug effects, Humans, Immune System metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Microbiota immunology, Milk, Human physiology, Oligosaccharides metabolism, Pancreas metabolism, Protective Agents pharmacology, Diabetes Mellitus, Type 1 prevention & control, Milk, Human metabolism, Oligosaccharides pharmacology
- Abstract
Development of Type 1 diabetes (T1D) is influenced by non-genetic factors, such as optimal microbiome development during early life that "programs" the immune system. Exclusive and prolonged breastfeeding is an independent protective factor against the development of T1D, likely via bioactive components. Human Milk Oligosaccharides (HMOS) are microbiota modulators, known to regulate immune responses directly. Here we show that early life provision (only for a period of six weeks) of 1% authentic HMOS (consisting of both long-chain, as well as short-chain structures), delayed and suppressed T1D development in non-obese diabetic mice and reduced development of severe pancreatic insulitis in later life. These protective effects were associated with i) beneficial alterations in fecal microbiota composition, ii) anti-inflammatory microbiota-generating metabolite (i.e. short chain fatty acids (SCFAs)) changes in fecal, as well as cecum content, and iii) induction of anti-diabetogenic cytokine profiles. Moreover, in vitro HMOS combined with SCFAs induced development of tolerogenic dendritic cells (tDCs), priming of functional regulatory T cells, which support the protective effects detected in vivo. In conclusion, HMOS present in human milk are therefore thought to be vital in the protection of children at risk for T1D, supporting immune and gut microbiota development in early life.
- Published
- 2018
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28. Regulatory T Cell Depletion Abolishes the Protective Effect of Dietary Galacto-Oligosaccharides on Eosinophilic Airway Inflammation in House Dust Mite-Induced Asthma in Mice.
- Author
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Verheijden KA, Braber S, Leusink-Muis T, Thijssen S, Boon L, Kraneveld AD, Garssen J, Folkerts G, and Willemsen LE
- Abstract
Background: In a murine model for house dust mite (HDM)-induced asthma, dietary galacto-oligosaccharides have been shown to suppress allergic symptoms. Previously, CD25+ regulatory T cells (Tregs) induced by nondigestible oligosaccharides were found to protect against allergy development., Objective: The aim of the current study was to examine the effect of anti-CD25-induced Treg depletion in a murine HDM-induced asthma model and to study the contribution of Tregs in the protective effect of dietary intervention with galacto-oligosaccharides., Methods: Male BALB/c mice (aged 6-8 wk) were intranasally sensitized and challenged with phosphate-buffered saline (PBS) or HDM. Two weeks before sensitization and throughout the whole experiment, mice were fed a control or 1% w/w galacto-oligosaccharide diet. Tregs were depleted by anti-mouse CD25 antibody (intraperitoneally injected). On day 14, T helper cell subtypes in lung and spleen were analyzed and cytokines were measured. Leukocyte subtypes were analyzed in the bronchoalveolar lavage fluid, and interleukin (IL)-33 and chemokines were measured in lung homogenate supernatants., Results: Anti-CD25 treatment depleted CD25+ Forkhead box P3+ Tregs in the lung and spleen of control and HDM-allergic mice (P < 0.0001) by >70% while increasing the percentage of activated T helper cells (P < 0.05) and type 2 T helper cells (P < 0.05). This was associated with increased IL-10, IL-4, and IL-13 concentrations in supernatants of ex vivo restimulated lung cells (P < 0.01). Bronchoalveolar lavage fluid leukocyte numbers and percentages of eosinophils and lymphocytes were greater in HDM-allergic mice compared with PBS mice (P < 0.01) but remained unaffected by the anti-CD25 treatment. Galacto-oligosaccharides decreased airway eosinophilia compared with HDM-allergic mice fed the control diet (from 47.8% ± 6.7% to 26.6% ± 8.5%, P < 0.01). This protective effect was lost in anti-CD25-treated mice (P < 0.05). In lung homogenates of HDM-allergic mice, IL-33 was increased compared with PBS mice (from 2.8 ± 0.3 to 5.4 ± 0.6 ng protein/mg, P < 0.01). Galacto-oligosaccharides abrogated the increase in IL-33 compared with HDM-allergic mice fed the control diet (3.0 ± 0.6 ng protein/mg, P < 0.05), which was abolished by the anti-CD25 treatment (P < 0.01)., Conclusions: Treg depletion enhances pulmonary type 2 T helper cell frequency and cytokine release in HDM-induced asthma in mice. Galacto-oligosaccharides decreased airway eosinophilia and IL-33 concentrations in the lung, which was abrogated by Treg depletion. This indicates that galacto-oligosaccharides have a beneficial effect in the prevention of HDM-induced allergic asthma by supporting pulmonary Treg function., (© 2016 American Society for Nutrition.)
- Published
- 2015
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29. Dietary galacto-oligosaccharides prevent airway eosinophilia and hyperresponsiveness in a murine house dust mite-induced asthma model.
- Author
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Verheijden KA, Willemsen LE, Braber S, Leusink-Muis T, Delsing DJ, Garssen J, Kraneveld AD, and Folkerts G
- Subjects
- Animals, Asthma immunology, Asthma metabolism, Asthma physiopathology, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity physiopathology, Bronchoalveolar Lavage Fluid immunology, Bronchodilator Agents pharmacology, Budesonide pharmacology, Cytokines immunology, Cytokines metabolism, Disease Models, Animal, Male, Mice, Inbred BALB C, Pulmonary Eosinophilia immunology, Pulmonary Eosinophilia metabolism, Pulmonary Eosinophilia physiopathology, Th2 Cells immunology, Th2 Cells metabolism, Asthma diet therapy, Bronchial Hyperreactivity prevention & control, Bronchoconstriction drug effects, Dietary Carbohydrates administration & dosage, Galactosides administration & dosage, Lung drug effects, Lung immunology, Lung metabolism, Lung physiopathology, Oligosaccharides administration & dosage, Prebiotics administration & dosage, Pulmonary Eosinophilia prevention & control, Pyroglyphidae
- Abstract
Background: Allergic asthma is strongly associated with the exposure to house dust mite (HDM) and is characterized by eosinophilic pulmonary inflammation and airway hyperresponsiveness (AHR). Recently, there is an increased interest in using dietary oligosaccharides, also known as prebiotics, as a novel strategy to prevent the development of, or reduce, symptoms of allergy., Aim: We investigated the preventive capacity of dietary galacto-oligosaccharides (GOS) compared to an intra-airway therapeutic treatment with budesonide on the development of HDM-induced allergic asthma in mice., Methods: BALB/c mice were intranasally sensitized with 1 μg HDM on day 0 followed by daily intranasal challenge with PBS or 10 μg HDM on days 7 to 11. Two weeks prior to the first sensitization and throughout the experiment mice were fed a control diet or a diet containing 1% GOS. Reference mice were oropharyngeally instilled with budesonide (500 μg/kg) on days 7, 9, 11, and 13, while being fed the control diet. On day 14, AHR was measured by nebulizing increasing doses of methacholine into the airways. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lungs were collected., Results: Sensitization and challenge with HDM resulted in AHR. In contrast to budesonide, dietary intervention with 1% GOS prevented the development of AHR. HDM sensitization and challenge resulted in a significant increase in BALF leukocytes numbers, which was suppressed by budesonide treatment and dietary intervention with 1% GOS. Moreover, HDM sensitization and challenge resulted in significantly enhanced concentrations of IL-6, CCL17, IL-33, CCL5 and IL-13 in lung tissue. Both dietary intervention with 1% GOS or budesonide treatment significantly decreased the HDM-induced increased concentrations of CCL5 and IL-13 in lung tissue, while budesonide also reduced the HDM-enhanced concentrations of IL-6 and CCL17 in lung tissue., Conclusion: Not only did dietary intervention with 1% GOS during sensitization and challenge prevent the induction of airway eosinophilia and Th2-related cytokine and chemokine concentrations in the lung equally effective as budesonide treatment, it also prevented AHR development in HDM-allergic mice. GOS might be useful for the prevention and/or treatment of symptoms in asthmatic disease.
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- 2015
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30. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles.
- Author
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van Noort JM, Bsibsi M, Nacken PJ, Gerritsen WH, Amor S, Holtman IR, Boddeke E, van Ark I, Leusink-Muis T, Folkerts G, Hennink WE, and Amidi M
- Subjects
- Animals, Anti-Inflammatory Agents immunology, Anti-Inflammatory Agents therapeutic use, Cell Line, Drug Carriers chemistry, Heat-Shock Proteins, Small administration & dosage, Heat-Shock Proteins, Small immunology, Heat-Shock Proteins, Small therapeutic use, Humans, Lactic Acid chemistry, Lipopolysaccharide Receptors immunology, Lung immunology, Macrophages immunology, Male, Mice, Mice, Inbred BALB C, Pneumonia immunology, Polyglycolic Acid chemistry, Polylactic Acid-Polyglycolic Acid Copolymer, Toll-Like Receptor 1 immunology, Toll-Like Receptor 2 immunology, alpha-Crystallin B Chain immunology, alpha-Crystallin B Chain therapeutic use, Anti-Inflammatory Agents administration & dosage, Lung drug effects, Macrophages drug effects, Pneumonia complications, Pneumonia drug therapy, Pulmonary Disease, Chronic Obstructive complications, alpha-Crystallin B Chain administration & dosage
- Abstract
As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via endosomal/phagosomal CD14 and Toll-like receptors 1 and 2. Humans, however, possess natural antibodies against HSPB5 that block receptor binding. To protect it from these antibodies, we encapsulated HSPB5 in porous PLGA microparticles. We document here size, morphology, protein loading and release characteristics of such microparticles. Apart from effectively protecting HSPB5 from neutralization, PLGA microparticles also strongly promoted macrophage targeting of HSPB via phagocytosis. As a result, HSPB5 in porous PLGA microparticles was more than 100-fold more effective in activating macrophages than free soluble protein. Yet, the immune-regulatory nature of the macrophage response, as documented here by microarray transcript profiling, remained the same. In mice developing cigarette smoke-induced COPD, HSPB5-loaded PLGA microparticles were selectively taken up by alveolar macrophages upon intratracheal administration, and significantly suppressed lung infiltration by lymphocytes and neutrophils. In contrast, 30-fold higher doses of free soluble HSPB5 remained ineffective. Our data indicate that porous HSPB5-PLGA microparticles hold considerable promise as an anti-inflammatory biomaterial for humans., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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31. Specific modulation of calmodulin activity induces a dramatic production of superoxide by alveolar macrophages.
- Author
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Broeke RT, Leusink-Muis T, Hilberdink R, Van Ark I, van den Worm E, Villain M, De Clerck F, Blalock JE, Nijkamp FP, and Folkerts G
- Subjects
- Animals, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, Calcium metabolism, Calcium Channel Agonists metabolism, Calmodulin antagonists & inhibitors, Carrier Proteins antagonists & inhibitors, Enzyme Inhibitors pharmacology, Guinea Pigs, Intercellular Signaling Peptides and Proteins, Macrophages, Alveolar drug effects, Male, Onium Compounds pharmacology, Peptides antagonists & inhibitors, Sulfonamides pharmacology, Superoxide Dismutase pharmacology, Calmodulin metabolism, Carrier Proteins pharmacology, Macrophages, Alveolar metabolism, Peptides pharmacology, Superoxides metabolism
- Abstract
Airway inflammation is a characteristic feature in airway diseases such as asthma and chronic obstructive pulmonary disease. Oxidative stress, caused by the excessive production of reactive oxygen species by inflammatory cells like macrophages, eosinophils and neutrophils, is thought to be important in the complex pathogenesis of such airway diseases. The calcium-sensing regulatory protein calmodulin (CaM) binds and regulates different target enzymes and proteins, including calcium channels. In the present study, we investigated whether CaM, via the modulation of calcium channel function, influences [Ca(2+)](i) in pulmonary inflammatory cells, and consequently, modulates the production of reactive oxygen species by these cells. This was tested with a peptide termed calcium-like peptide 2 (CALP2), which was previously shown to regulate such channels. Specifically, radical production by purified broncho-alveolar lavage cells from guinea-pigs in response to CALP2 was measured. CALP2 was a strong activator of alveolar macrophages. In contrast, CALP2 was only a mild activator of neutrophils and did not induce radical production by eosinophils. The CALP2-induced radical production was mainly intracellular, and was completely blocked by the NADPH-oxidase inhibitor DPI, the superoxide inhibitor SOD and the CaM antagonist W7. Furthermore, the calcium channel blocker lanthanum partly inhibited the cellular activation by CALP2. We conclude that alveolar macrophages, but not neutrophils or eosinophils, can produce extremely high amounts of reactive oxygen species when stimulated via the calcium/CaM pathway. These results may contribute to new therapeutic strategies against oxidative stress in airway diseases.
- Published
- 2004
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32. Ca2+ sensors modulate asthmatic symptoms in an allergic model for asthma.
- Author
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Ten Broeke R, Brandhorst MC, Leusink-Muis T, Villain M, De Clerck F, Blalock JE, Nijkamp FP, and Folkerts G
- Subjects
- Animals, Asthma immunology, Asthma physiopathology, Bronchoconstriction drug effects, Carrier Proteins pharmacology, Cell Count, Cell Degranulation drug effects, Disease Models, Animal, Guinea Pigs, In Vitro Techniques, Intercellular Signaling Peptides and Proteins, Male, Mast Cells drug effects, Mast Cells physiology, Oligopeptides pharmacology, Ovalbumin immunology, Peptides pharmacology, Pulmonary Alveoli drug effects, Pulmonary Alveoli immunology, Pulmonary Alveoli pathology, Reactive Oxygen Species metabolism, Asthma prevention & control, Calcium metabolism, Calmodulin metabolism
- Abstract
We previously described two novel peptides, Ca2+-like peptide (CALP) 1 and CALP2, which interact with Ca2+-binding EF hand motifs, and therefore have the characteristics to define the role of the Ca2+-sensing regulatory protein calmodulin in asthma. In the present study, the effects of the calcium-like peptides were investigated in an animal model for allergic asthma. For that purpose, sensitized guinea pigs were intratracheally pretreated with CALP1 or CALP2. Thirty minutes later, the animals were challenged with aerosolized ovalbumin. Acute bronchoconstriction was measured as well as characteristic features of asthma 6 and 24 hours (h) after challenge. Neither CALP1 nor CALP2 prevented the anaphylactic response elicited by ovalbumin challenge. However, CALP1 pretreatment attenuated the influx of inflammatory cells in the lungs 6 h after challenge. Furthermore, radical production by these cells was diminished both 6 and 24 h after challenge. Moreover, CALP1 completely inhibited airway hyperresponsiveness in vitro 24 h after challenge. We conclude that CALP1, as a selective calmodulin agonist, inhibits the development of asthmatic features probably via the attenuation of mast cell degranulation and radical production. Specific modulation of calmodulin activity might therefore be a potential new target for the treatment of allergic asthma.
- Published
- 2003
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33. Respiratory allergy and pulmonary irritation to trimellitic anhydride in Brown Norway rats.
- Author
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Arts JH, Bloksma N, Leusink-Muis T, and Kuper CF
- Subjects
- Animals, Body Weight drug effects, Bronchoalveolar Lavage Fluid chemistry, Female, Immunization, Immunoglobulin E blood, Lung pathology, Organ Size drug effects, Rats, Rats, Inbred BN, Respiration drug effects, Respiratory Function Tests, Allergens toxicity, Lung drug effects, Phthalic Anhydrides toxicity
- Abstract
Occupational exposure to low-molecular-weight (LMW) allergens such as acid anhydrides can result in occupational asthma, an allergic disease characterized by episodic airway obstruction, airways inflammation, and non specific airways hyperresponsiveness. Since LMW irritants can provoke rather similar effects and since most, if not all, LMW allergens have irritant properties, this study addressed the distinction between allergenic and irritant effects of the respiratory allergen trimellitic anhydride (TMA). BN rats were sensitized by dermal application of TMA or vehicle alone and 3 weeks later were challenged by inhalation of a slightly irritating concentration of TMA or the vehicle. Lung function was measured before, during, and shortly after challenge. One day after challenge, in vivo and in vitro nonspecific airways hyperresponsiveness to methacholine was measured, and bronchoalveolar lavage was performed to measure total protein, lactate dehydrogenase, N-acetyl-glucosaminidase, and total and differential leukocyte numbers in the fluid. In addition, IgE measurements and histopathological examinations of the respiratory tract were carried out. TMA challenge of sensitized, but not sham-sensitized, BN rats reduced breathing frequency during challenge, elevated total and TMA-specific serum IgE levels, and caused a typical allergic asthma-associated airway pathology, as observed earlier. Vehicle challenge did not cause these effects, irrespective of sensitization. Hyperresponsiveness to methacholine was only seen in TMA-sensitized and -challenged rats. These rats also showed increased levels of the biochemical parameters and increased numbers of eosinophils and neutrophils in the lung lavage fluid; TMA challenge of sham-sensitized rats caused similar but markedly less pronounced effects. During TMA challenge of sham-sensitized rats, a breathing pattern typical of irritation was noticed but a clearly distinct pattern was seen upon TMA challenge of sensitized rats. In conclusion, TMA challenge of sensitized rats caused sensitization-dependent asthma-like early changes in breathing pattern that clearly could be distinguished from irritant-induced changes and non-specific airways hyperresponsiveness 24 h after challenge. Sensitization-dependent functional changes were accompanied by inflammatory changes characteristic of asthma and biochemical evidence of airway damage.
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- 2003
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34. Increased expression and decreased activity of cytochrome P450 1A1 in a murine model of toluene diisocyanate-induced asthma.
- Author
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Haag M, Leusink-Muis T, Le Bouquin R, Nijkamp FP, Lugnier A, Frossard N, Folkerts G, and Pons F
- Subjects
- Animals, Asthma enzymology, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1A1 metabolism, Male, Methylcholanthrene, Mice, Mice, Inbred BALB C, Microsomes, Liver enzymology, RNA, Messenger analysis, Asthma chemically induced, Cytochrome P-450 CYP1A1 drug effects, Toluene 2,4-Diisocyanate toxicity
- Abstract
In the lung, cytochromes P450 (CYP) may be affected by inhaled pollutants. In a previous study, we showed that acute inhalation of toluene diisocyanate (TDI), a low molecular weight chemical known to cause occupational asthma, decreased CYP2B1 expression in rat lung. In the present work, we investigated the effect of TDI in a murine model of TDI-induced asthma. Mice were skin-sensitized with TDI on 2 consecutive days and challenged intranasally 8 days later. Lung expression and activity of CYP were assessed 24 h after the challenge. A significant increase in Cyp1a1 protein expression was detected by western blotting in lung from mice sensitized and challenged with TDI, whereas no modification of expression of other CYP, namely Cyp2b, Cyp2e1 and Cyp3a was observed. Increase in Cyp1a1 protein was associated with an increase in Cyp1a1 mRNA, as assessed by polymerase chain reaction after reverse transcription of total lung RNA. However, a decreased Cyp1a1 activity, as measured by O-deethylation of ethoxyresorufin was observed in lung from TDI-sensitized and challenged mice, suggesting that TDI may inhibit Cyp1a1 function. In agreement with this hypothesis, in vitro experiments conducted on liver microsomes overexpressing Cyp1a1 after treatment of mice with 3-methylcholanthrene showed that TDI markedly inhibited in a concentration-dependent manner Cyp1a1 activity. In conclusion, expression of Cyp1a1, known to exhibit rather negative functions in the lung, is increased in mice sensitized and challenged with TDI. However, this effect is associated with a decreased enzyme activity, which might limit the toxicological consequences of increased Cyp1a1 expression.
- Published
- 2002
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35. Calcium sensors as new therapeutic targets for airway hyperresponsiveness and asthma.
- Author
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Ten Broeke R, Folkerts G, Leusink-Muis T, Van der Linde HJ, Villain M, Manion MK, De Clerck F, Blalock JE, and Nijkamp FP
- Subjects
- Acetylcholine pharmacology, Animals, Bradykinin pharmacology, Calcium Channels physiology, Epithelium physiology, Guinea Pigs, Histamine administration & dosage, Histamine pharmacology, Intercellular Signaling Peptides and Proteins, Muscle Contraction drug effects, Nitric Oxide metabolism, Trachea drug effects, Trachea physiology, Asthma drug therapy, Calcium physiology, Carrier Proteins pharmacology, Oligopeptides pharmacology, Peptides
- Published
- 2001
- Full Text
- View/download PDF
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