Chemokines and their receptors as potential targets for the treatment of asthma

Palmqvist, C; Wardlaw, Andrew J.; Bradding, Peter

doi:10.1038/sj.bjp.0707263

Cited by 116 publications

(118 citation statements)

References 127 publications

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“…The immu nomodulatory NPs (SiO 2 plain and SiO 2 PEG), but not the counterpart NPs (SiO 2 P and SiO 2 NH 2 ), increased the inflammatory milieu in the pulmonary tissue, with upregulation of Th2 cytokines, as well as sensitization induced chemokines, the latter responsible for chemoat traction of granulocytes (MIP-1/CCL3 and MIP-2/CxCL2, KC/CXCL1), lymphocytes (Tarc/CCL17, MIP-3/CCL20, and MDC/CCL22), and macrophages (MCP-1/CCL2). 40 These data support the concept of recruitment of inflam matory cells observed in the BALF of OVAsensitized mice by immunomodulatory NPs only. Furthermore, our gene expression analysis showed that only SiO 2 plain and SiO 2 PEG NPs could lead to increased marker of eosinophils acti vation (Ear11) 41 and alternative activation of macrophages, with no modulation of markers of classical activation of macrophages (Arg1/Retnla versus Nos2/CxCL9).…”

supporting

confidence: 76%

Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

Marzaioli¹,

Aguilar-Pimentel²,

Weichenmeier³

et al. 2014

IJN

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Background Silica (SiO 2 ) nanoparticles (NPs) are widely used in diverse industrial and biomedical applications. Their applicability depends on surface modifications, which can limit potential health problems. Objective To assess the potential impact of SiO 2 NP exposure and NPs chemical modifications in allergic airway inflammation. Methods Mice were sensitized by five repetitive intraperitoneal injections of ovalbumin/aluminum hydroxide (1 μg) over 42 days, then intratracheally instilled with plain or modified SiO 2 NPs (50 μg/mouse), and subsequently aerosol challenged for 20 minutes with ovalbumin. One or 5 days later, allergic inflammation was evaluated by cell differentiation of bronchoalveolar lavage fluid, lung function and gene expression and histopathology, as well as electron and confocal microscopy of pulmonary tissue. Results Plain SiO 2 NPs induced proinflammatory and immunomodulatory effects in vivo, highlighted by enhanced infiltration of inflammatory cells in the bronchoalveolar lavage fluid, induction of a pulmonary T helper type 2 (Th2) cytokine pattern, differentiation of type 2 macrophages, and by morphological changes in the lung of sensitized mice. These effects were dramatically attenuated using surface-functionalized NPs with amino and phosphate groups, but not with polyethylene glycol. The role of macrophages in taking up SiO 2 NPs was confirmed by flow cytometry, confocal microscopy, and gene expression analysis. Conclusion Our data suggest that amino and phosphate surface modifications, but not polyethylene glycol (PEG), mitigate the proinflammatory and immunomodulatory effect of SiO 2 NPs in allergic airway inflammation, paving the way for new strategies in the production of nanomaterials with lower health impact for humans.

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supporting

confidence: 76%

Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

Marzaioli¹,

Aguilar-Pimentel²,

Weichenmeier³

et al. 2014

IJN

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“…Immunoreactive PGE 2 in the supernatants of overnight-cultured monocytes was determined as described previously (34) using [5,6,8,11,12,14, H(N)]PGE 2 as tracer and synthetic PGE 2 as standard. Charcoal was used to separate the free and Ab-bound fractions.…”

Section: Radioimmunoassaymentioning

confidence: 99%

“…A wide range of agonists can stimulate the accumulation of eosinophils, in particular those of the CC chemokine family, which are acting through the chemokine receptor CCR3 (8). In addition, activated complement factors such as C5a, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, and platelet-activating factor are also potent chemoattractants for eosinophils (9 -11).…”

mentioning

confidence: 99%

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Sturm

Schratl

Schuligoi

et al. 2008

The Journal of Immunology

108

110

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The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E2 exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE2 potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD2, and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE2 on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE2, inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE2 on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.

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“…CCL2 is produced by a wide variety of cells, including monocyte/macrophages, lymphocytes, fibroblasts, endothelial and epithelial cells, neutrophils, mast cells and dendritic cells, all of which are involved in airway remodelling and can contribute to recruitment of CCL2-sensitive cells (monocytes, T cells, dendritic cells and neutrophils) both to and within the airways of the lungs. 41 CCL2 mediates airway hyperactivity in normal and allergic mice and directly induces in vitro pulmonary mast cell degranulation. 42 Several human studies demonstrate the upregulation of CCL2 during asthmatic responses, 43,44 and CCL2 protein expression in bronchial tissue is significantly higher in subjects with asthma than in control subjects.…”

Section: Discussionmentioning

confidence: 99%

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case–control and a family study in Tunisia

et al. 2008

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Asthma is a complex genetic disorder characterized by chronic airway inflammation. We hypothesized that genetic polymorphisms in chemokines and their receptors alter leukocyte mobilization and may thus influence the risk and severity of childhood asthma. Distributions of the chemokine CCL2-2578G, CCL2-927C, CCR2-V64I, CX3CR1-V249I and CX3CR1-T280M receptor polymorphisms were examined in a case-control study of 121 children with asthma and 226 age-matched healthy controls and then replicated in a family study of 99 simplex families (297 individuals). The case-control study revealed that the CCL2-2578G allele was less frequent in children with than in those without asthma (P ¼ 0.0012). No association with asthma was found for the CCL2-927, CCR2 or CX3CR1 polymorphisms. The finding in the family study that the CCL2-2578G allele was transmitted less often by heterozygous parents to their children with asthma (P ¼ 0.0016) confirms the association of CCL2-2578G with asthma risk. Biochemical studies indicated that plasma CCL2 concentrations were higher in both patients (P ¼ 0.0214) and controls (P ¼ 0.001) carrying the G allele than in subjects with other polymorphisms. Both case-control and family-based studies suggest a protective effect of allele CCL2-2578G in Tunisian asthmatic children.

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Chemokines and their receptors as potential targets for the treatment of asthma

Cited by 116 publications

References 127 publications

Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case–control and a family study in Tunisia

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