RESUMEN
Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.
Asunto(s)
Síndrome de Costello/genética , Dermatitis Atópica/genética , Dermatitis Atópica/parasitología , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pyroglyphidae/fisiología , Animales , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Síndrome de Costello/complicaciones , Síndrome de Costello/patología , Citocinas/metabolismo , Dermatitis Atópica/complicaciones , Dermatitis Atópica/patología , Difenilamina/análogos & derivados , Difenilamina/farmacología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Oído/patología , Epidermis/efectos de los fármacos , Epidermis/parasitología , Epidermis/patología , Mediadores de Inflamación/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacología , Prurito/complicaciones , Prurito/patología , Pyroglyphidae/efectos de los fármacosRESUMEN
Nicotine of unprecedented concentrations and purity is being inhaled by those using commercially available electronic nicotine delivery systems (ENDS). The consequences of this route of self-administration on the immunological response to inhaled allergens are not known. In mice, sensitization and inhalation challenge with the common environmental house dust mite (HDM) allergen is an experimental model of this response. When mice were exposed to aerosolized nicotine base (aeroNic) twice daily, 5 days/wk for 8 wk, the HDM-induced recruitment of eosinophils (EOS) was substantially reduced as measured in bronchial alveolar lavage fluid (BALF). Oral nicotine administration had no effect. HDM challenge in the presence of nicotinic receptor subtype α7 (α7)-specific type-1 positive allosteric modulators (PAMs) was alone sufficient to suppress EOS. RNA analysis of alveolar macrophages (AM) collected from BALF after HDM challenge of aeroNic revealed that α7 activation strongly suppresses initiation of Ccl24 (eotaxin 2) transcription. To examine possible cellular signaling mechanisms coupling α7 to Ccl24 transcription, an AM culture model system was used. In AM cultures of freshly collected BALF, Ccl24 transcription was robustly activated by a mixture of IL-4 and IL-10, and this was suppressed by coapplication of type-1 PAMs through a pathway that requires p38MAPK but is independent of Jak2. These results suggest that the EOS response to HDM inhaled allergen is subject to modulation through activation of the α7 receptor and suggest that the allergic response may be substantially modified in ENDS users.
Asunto(s)
Antígenos Dermatofagoides/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Pulmón/efectos de los fármacos , Nicotina/farmacología , Animales , Líquido del Lavado Bronquioalveolar/citología , Eosinófilos/metabolismo , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/metabolismo , Pulmón/metabolismo , Ratones , Ácaros , Nicotina/metabolismo , Pyroglyphidae/efectos de los fármacos , Pyroglyphidae/inmunologíaRESUMEN
Allergic asthma is a common chronic lung inflammatory disease and seriously influences public health. We aim to investigate the effects of formononetin (FMN) and calycosin (CAL), 2 flavonoids in Radix Astragali, on allergic asthma and elucidate possible therapeutic targets. A house dust mite (HDM)-induced allergic asthma mouse model and TNF-α and Poly(I:C) co-stimulated human bronchial epithelial cell line (16HBE) were performed respectively in vivo and in vitro. The role of G protein-coupled estrogen receptor (GPER) was explored by its agonist, antagonist, or GPER small interfering RNA (siGPER). E-cadherin, occludin, and GPER were detected by western blotting, immunohistochemistry, or immunofluorescence. The epithelial barrier integrity was assessed by trans-epithelial electric resistance (TEER). Cytokines were examined by enzyme-linked immunosorbent assay (ELISA). The results showed that flavonoids attenuated pulmonary inflammation and hyperresponsiveness in asthmatic mice. These flavonoids significantly inhibited thymic stromal lymphopoietin (TSLP), increased occludin and restored E-cadherin in vivo and in vitro. The effects of flavonoids on occludin and TSLP were not interfered by ICI182780 (estrogen receptor antagonist), while blocked by G15 (GPER antagonist). Furthermore, compared with PPT (ERα agonist) and DPN (ERß agonist), G1 (GPER agonist) significantly inhibited TSLP, up-regulated occludin, and restored E-cadherin. siGPER and TEER assays suggested that GPER was pivotal for the flavonoids on the epithelial barrier integrity. Finally, G1 attenuated allergic lung inflammation, which could be abolished by G15. Our data demonstrated that 2 flavonoids in Radix Astragali could alleviate allergic asthma by protecting epithelial integrity via regulating GPER, and activating GPER might be a possible therapeutic strategy against allergic inflammation.
Asunto(s)
Asma/tratamiento farmacológico , Células Epiteliales/patología , Hipersensibilidad/tratamiento farmacológico , Inflamación/complicaciones , Isoflavonas/uso terapéutico , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Uniones Adherentes/efectos de los fármacos , Uniones Adherentes/metabolismo , Animales , Asma/complicaciones , Asma/parasitología , Astragalus propinquus , Cadherinas/metabolismo , Citocinas/metabolismo , Medicamentos Herbarios Chinos/química , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/parasitología , Isoflavonas/química , Isoflavonas/farmacología , Ratones Endogámicos BALB C , Modelos Biológicos , Ocludina/metabolismo , Neumonía/complicaciones , Neumonía/tratamiento farmacológico , Neumonía/parasitología , Pyroglyphidae/efectos de los fármacos , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Linfopoyetina del Estroma TímicoRESUMEN
Lipoxin A4 (LXA4) is considered a specialised pro-resolving mediator that decreases inflammation: however, pro-inflammatory effects have been described in the airways. Here, we investigated whether LXA4 could influence airway hyperreactivity induced in mouse trachea by house dust mite extract (HDM) or TNFα. Intranasal instillation of HDM caused a serotonin (5-HT) mediated airway hyperreactivity ex vivo (Emax: 78.1 ± 16.2 % versus control 12.8 ± 1.0 %) that was reduced by LXA4 installation one hour prior to HDM (Emax: 49.9 ± 11.4 %). Also, in isolated tracheal segments cultured for four days, HDM induced a hyperreactivity (Emax: 33.2 ± 3.1 % versus control 9.0 ± 0.7 %) that was decreased by LXA4 (Emax: 18.7 ± 1.5 %). One part of the HDM-induced hyperreactivity could be inhibited by the TNFα-inhibitor etanercept. TNFα-induced upregulation of 5-HT responses (Emax: 51.3 ± 1.2 % versus control 13.9 ± 0.5 %) was decreased by 10-1000 nM LXA4. In precontracted tracheal segments, LXA4 had no relaxing effect. Overall, LXA4 was able to decrease airway hyperreactivity induced by both HDM and TNFα, thus having a sub-acute anti-inflammatory effect in airway inflammation.
Asunto(s)
Hiperreactividad Bronquial/tratamiento farmacológico , Lipoxinas/farmacología , Pyroglyphidae/efectos de los fármacos , Tráquea/efectos de los fármacos , Tráquea/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Animales , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos BALB C , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1ß, CCL5, and CXCL10 production, and antiviral interferon-ß and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3+ eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4+CRTH2+ Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Citocinas/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Interleucinas/uso terapéutico , Adulto , Animales , Antiinflamatorios/farmacología , Asma/complicaciones , Asma/genética , Asma/inmunología , Bronquios/patología , Células Cultivadas , Citocinas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Inyecciones Intraperitoneales , Interleucinas/farmacología , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Biológicos , Poli I-C/farmacología , Pyroglyphidae/efectos de los fármacos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/farmacologíaAsunto(s)
Conducto Auditivo Externo/parasitología , Infestaciones por Ácaros/tratamiento farmacológico , Infestaciones por Ácaros/parasitología , Pyroglyphidae/efectos de los fármacos , Administración Tópica , Animales , Antiparasitarios/administración & dosificación , Ácidos Bóricos/administración & dosificación , Peróxido de Hidrógeno/administración & dosificación , Instilación de Medicamentos , Infestaciones por Ácaros/diagnósticoRESUMEN
Blomia tropicalis mite is highly prevalent in tropical and subtropical regions and it is associated with allergic diseases such as rhinitis and asthma. By using an OVA-model of allergic lung disease, we have previously shown that sensitization in the presence of toll like receptors (TLRs) agonists attenuates subsequent OVA-induced allergic responses. Here, we evaluated the effect of CpG-ODN, a specific synthetic TLR-9 agonist, on the development of experimental asthma induced by Blomia tropicalis extract, a relevant source of aeroallergens. Among different protocols of Blomia tropicalis extract sensitization, the subcutaneous sensitization in the presence of alum adjuvant induced the highest Th2 responses, including high IgE levels. Adsorption of CpG to Blomia tropicalis extract/Alum attenuated the airway hyperreactivity, the infiltration of inflammatory cells including eosinophils, and the IL-5 content in BAL. In addition, lung peribronchial inflammatory infiltrate, mucus production and IL-5-producing CD3+ CD4+ T cells were significantly reduced in the Blomia tropicalis extract/Alum+CpG group. Importantly, CpG inhibited total IgE production as well as active systemic or cutaneous anaphylaxis reactions. Inhibition of pulmonary Th2 responses was associated with increased IL-10 production but not with IFN-γ production. Notably, in IL-10-deficient mice, sensitization with OVA/Alum+CpG resulted in intense lung neutrophilia and IFN-γ production, indicating that IL-10 is necessary to inhibit subsequent Th1 immunity. Our work highlights the mechanisms of allergy attenuation by CpG and it indicates the potential use of Alum-based formulation with CpG to treat allergic processes.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/química , Asma/prevención & control , Asma/parasitología , Pyroglyphidae/fisiología , Receptor Toll-Like 9/agonistas , Adyuvantes Inmunológicos/farmacología , Adsorción , Anafilaxia/complicaciones , Anafilaxia/inmunología , Anafilaxia/parasitología , Animales , Asma/complicaciones , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Eosinófilos/patología , Femenino , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/parasitología , Inmunidad/efectos de los fármacos , Inmunización , Interleucina-10/metabolismo , Interleucina-4/biosíntesis , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Ratones Endogámicos C57BL , Neutrófilos/patología , Oligodesoxirribonucleótidos/farmacología , Pyroglyphidae/efectos de los fármacos , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
Interleukin (IL)-37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL-37 against allergic asthma are less well understood. We show here that IL-37 administered intranasally inhibited house dust mite (HDM)-induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2-associated cytokines and chemokines in IL-37-treated mice, IL-37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2-associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL-37. Importantly, compared with IL-37 alone, TSLP coadministration with IL-37 restored HDM-induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2-associated cytokine production. We further found that IL-37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF-κB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16-HBE) cells in vitro. These data highlight the importance of TSLP in IL-37-mediated protective role in asthma. IL-37 might represent a useful innovative and alternative therapy to control TSLP production in the airway.
Asunto(s)
Asma/tratamiento farmacológico , Citocinas/metabolismo , Hipersensibilidad/dietoterapia , Interleucina-1/uso terapéutico , Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Pyroglyphidae/fisiología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Asma/complicaciones , Asma/inmunología , Asma/fisiopatología , Línea Celular , Enfermedad Crónica , Citocinas/administración & dosificación , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/parasitología , Femenino , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Interleucina-1/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Pyroglyphidae/efectos de los fármacos , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by complex symptoms. To treat AD without adverse effects, alternative therapeutic agents are required. The tubers of Helianthus tuberosus L. (Jerusalem artichoke) have been used in folk remedies for diabetes and rheumatism. However, its effect on AD development remains unknown. Therefore, this study examined the inhibitory effect of H. tuberosus (HT) on AD skin symptoms using an NC/Nga mouse model and HaCaT keratinocytes. The effect of HT and associated molecular mechanisms were evaluated in Dermatophagoides farina body (Dfb)-induced AD mice and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes by ELISA, western blot, and histological analysis. Topical HT administration attenuated AD skin symptoms in Dfb-induced AD mice, with a significant reduction in the dermatitis score and production of inflammatory mediators. HT also decreased epidermal thickness and mast cell infiltration. Moreover, HT restored filaggrin expression and inhibited adhesion molecules in the mice. These effects were confirmed in vitro. Furthermore, HT suppressed the activation of NF-κB, Akt, and mitogen-activated protein kinase (MAPK) signaling pathways induced by TNF-α/IFN-γ. These results suggest that HT is a potential therapeutic agent or supplement for skin allergic inflammatory diseases such as AD.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Helianthus/química , Queratinocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Pyroglyphidae/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Proteínas Filagrina , Regulación de la Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Queratinocitos/metabolismo , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Pyroglyphidae/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of "initiator" allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases.
Asunto(s)
Antígenos Dermatofagoides/inmunología , Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Inmunidad Innata/inmunología , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/química , Alérgenos/inmunología , Alérgenos/metabolismo , Animales , Antígenos Dermatofagoides/metabolismo , Humanos , Inmunidad Innata/efectos de los fármacos , Inhibidores de Proteasas/metabolismo , Pyroglyphidae/efectos de los fármacos , Pyroglyphidae/inmunología , Pyroglyphidae/metabolismoRESUMEN
Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
Asunto(s)
Asma/tratamiento farmacológico , Cloroquina/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Quinina/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Gusto , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Alérgenos/inmunología , Animales , Asma/inmunología , Asma/fisiopatología , Asma/prevención & control , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Quimiotaxis/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Hipersensibilidad/prevención & control , Inmunización , Inflamación/complicaciones , Inflamación/patología , Pulmón/inmunología , Pulmón/parasitología , Pulmón/patología , Pulmón/fisiopatología , Metaloproteinasas de la Matriz/metabolismo , Ratones Endogámicos BALB C , Moco/metabolismo , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Neutrófilos/efectos de los fármacos , Pyroglyphidae/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
the aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient (Tnfsf10-/-) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10-/- mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID50). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID50 HDM-challenged Tnfsf10-/- mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10-/- mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-ß. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.
Asunto(s)
Inflamación/patología , Inflamación/virología , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/patología , Infecciones por Picornaviridae/virología , Rhinovirus/fisiología , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Animales , Antivirales/farmacología , Hiperreactividad Bronquial/patología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células HeLa , Humanos , Hipersensibilidad/metabolismo , Hipersensibilidad/parasitología , Hipersensibilidad/patología , Mediadores de Inflamación/metabolismo , Interferón Tipo I/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Masculino , Ratones Endogámicos BALB C , Fosfoproteínas Fosfatasas/metabolismo , Proteínas/genética , Proteínas/metabolismo , Pyroglyphidae/efectos de los fármacos , Pyroglyphidae/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rhinovirus/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/deficiencia , Ubiquitina-Proteína Ligasas , Replicación Viral/efectos de los fármacosRESUMEN
Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is thought to contribute to increased asthma incidence associated with smoking. Here, we explored the effects of acute acrolein exposure on innate airway responses to two common airborne allergens, house dust mite and Alternaria alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h) dramatically inhibited innate airway responses to subsequent allergen challenge, demonstrated by attenuated release of the epithelial-derived cytokines IL-33, IL-25, and IL-1α. Acrolein and other anti-inflammatory thiol-reactive electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited allergen-induced production of these cytokines from human or murine airway epithelial cells in vitro. Based on our previous observations indicating the importance of Ca2+-dependent signaling, activation of the NADPH oxidase DUOX1, and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of these cytokines, we explored the impact of acrolein on these pathways. Acrolein and other thiol-reactive electrophiles were found to dramatically prevent allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of inhibiting EGFR tyrosine kinase activity via modification of C797. Biotin-labeling strategies indicated increased cysteine modification and carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in vitro and in vivo, suggesting that direct alkylation of these proteins on accessible cysteine residues may be responsible for their inhibition. Collectively, our findings indicate a novel anti-inflammatory mechanism of CS-derived acrolein and other thiol-reactive electrophiles, by directly inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne allergens.
Asunto(s)
Acroleína/farmacología , Alérgenos/efectos adversos , Bronquios/patología , Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , NADPH Oxidasas/antagonistas & inhibidores , Compuestos de Sulfhidrilo/farmacología , Acroleína/química , Administración por Inhalación , Animales , Calcio/metabolismo , Cisteína/metabolismo , Oxidasas Duales , Activación Enzimática/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Inmunidad Innata/efectos de los fármacos , Interleucina-33/metabolismo , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Carbonilación Proteica/efectos de los fármacos , Pyroglyphidae/efectos de los fármacos , Pyroglyphidae/fisiología , Compuestos de Sulfhidrilo/química , Familia-src Quinasas/metabolismoRESUMEN
Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation contribute to pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and although Langerhans cells expressing the nonclassical major histocompatibility complex (MHC) family member CD1a are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. We observed that house dust mite (HDM) allergen generates neolipid antigens presented by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth in individuals with atopic dermatitis and showed rapid effector function, consistent with antigen-driven maturation. In HDM-challenged human skin, we observed phospholipase A2 (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2, and such cells infiltrated the skin after allergen challenge. Moreover, we observed that the skin barrier protein filaggrin, insufficiency of which is associated with atopic skin disease, inhibited PLA2 activity and decreased CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity suggest that nonpeptide stimulants of T cells act as haptens that modify peptides or proteins; however, our results show that HDM proteins may also generate neolipid antigens that directly activate T cells. These data define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.
Asunto(s)
Antígenos CD1/metabolismo , Fosfolipasas A2 Grupo IV/metabolismo , Proteínas de Filamentos Intermediarios/farmacología , Pyroglyphidae/enzimología , Adolescente , Adulto , Anciano , Animales , Separación Celular , Citocinas/metabolismo , Dermatitis Atópica/sangre , Dermatitis Atópica/inmunología , Proteínas Filagrina , Humanos , Células K562 , Persona de Mediana Edad , Pyroglyphidae/efectos de los fármacos , Piel/inmunología , Piel/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Adulto JovenRESUMEN
The present study was conducted at Elkom Elakhdar village, Shebin El-Kom, Menoufia Governorate along 2012 year seasons, to calculate and identify the species composition and the occurrence frequency of the extracted dust mites collected from three building ages at rural houses, as well as to determine the toxicity limits of different concentrations of three plant essential oils against two species of the family Pyroglyphidae the main causal of allergy to humans. The obtained results revealed that there were eleven mite species belong to five families (Pyroglyphidae, Chortoglyphidae, Glycyphagidae, Acaridae and Cheyletidae). Of the total collected mites (5276) the highest dominant percentage species was the dust mites: Dermatophagoides farinae (66.1%), followed by D. pteronyssinus (23.3%), while the percentages of the rest species: Chortoglyphus arcuatus, Lepidoglyphus destructor, Glycyphagus domesticus, Gohieria fusca, Tyrophagusputrescentiae, Caloglyphus sp, Cheyletus malaccensis, Blomia sp. and Acarus siro were ranged between 0.16-2.0%. Regarding to the effect of temperature degrees on mite population, high degrees more than 25 degrees C at summer season, decreased the numbers of D. farinae and D. pteronyssinus. Toxicological tests of the three plant essential oils against adult stages of D. farinae and D. pteronyssinus showed that lemon grass oil gave the highest toxicity effect, in comparison with geranium and thyme oils, where mortality percentages were approximately around 100% at 800 ppm concentration on both species. The LC50 of lemon grass were 228.992 and 293.615 ppm against the two species, respectively. From the results of the research, it could be recommend that it is preferable to apply control operation during summer season where the mite population density is the least, moreover, the botanical oil extracts effectively controlled the parasitic dust mites, D. farinae and D. pteronyssinus and can be used in the biological control programs, as well as, it can play effective role in the integrated management programs.
Asunto(s)
Cymbopogon , Geranium , Vivienda , Aceites Volátiles/farmacología , Control de Plagas/métodos , Aceites de Plantas/farmacología , Pyroglyphidae/efectos de los fármacos , Población Rural , Thymus (Planta) , Animales , Relación Dosis-Respuesta a Droga , Egipto , Humanos , Densidad de Población , Pyroglyphidae/clasificación , Pyroglyphidae/crecimiento & desarrollo , Estaciones del Año , TemperaturaRESUMEN
BACKGROUND: Eczema is an inflammatory skin disease that tends to involve skin creases, such as the folds of the elbows or knees; it is an intensely itchy skin condition, which can relapse and remit over time. As many as a third of people with eczema who have a positive test for allergy to house dust mite have reported worsening of eczema or respiratory symptoms when exposed to dust. OBJECTIVES: To assess the effects of all house dust mite reduction and avoidance measures for the treatment of eczema. SEARCH METHODS: We searched the following databases up to 14 August 2014: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 8), MEDLINE (from 1946), Embase (from 1974), LILACS (from 1982), and the GREAT database. We also searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant studies. We handsearched abstracts from international eczema and allergy meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any of the house dust mite reduction and avoidance measures for the treatment of eczema, which included participants of any age diagnosed by a clinician with eczema as defined by the World Allergy Organization. We included all non-pharmacological and pharmacological interventions that sought to reduce or avoid exposure to house dust mite and their allergenic faeces. The comparators were any active treatment, no treatment, placebo, or standard care only. DATA COLLECTION AND ANALYSIS: Two authors independently checked the titles and abstracts identified, and there were no disagreements. We contacted authors of included studies for additional information. We assessed the risk of bias using Cochrane methodology. MAIN RESULTS: We included seven studies of 324 adults and children with eczema. Overall, the included studies had a high risk of bias. Four of the seven trials tested interventions with multiple components, and three tested a single intervention. Two of the seven trials included only children, four included children and adults, and one included only adults. Interventions to reduce or avoid exposure to house dust mite included covers for mattresses and bedding, increased or high-quality vacuuming of carpets and mattresses, and sprays that kill house dust mites.Four studies assessed our first primary outcome of 'Clinician-assessed eczema severity using a named scale'. Of these, one study (n = 20) did not show any significant short-term benefit from allergen impermeable polyurethane mattress encasings and acaricide spray versus allergen permeable cotton mattress encasings and placebo acaricide spray. One study (n = 60) found a modest statistically significant benefit in the Six Area, Six Sign Atopic Dermatitis (SASSAD) scale over six months (mean difference of 4.2 (95% confidence interval 1.7 to 6.7), P = 0.008) in favour of a mite impermeable bedding system combined with benzyltannate spray and high-filtration vacuuming versus mite permeable cotton encasings, water with a trace of alcohol spray, and a low-filtration vacuum cleaner. The third study (n = 41) did not compare the change in severity of eczema between the two treatment groups. The fourth study (n = 86) reported no evidence of a difference between the treatment groups.With regard to the secondary outcomes 'Participant- or caregiver-assessed global eczema severity score' and the 'Amount and frequency of topical treatment required', one study (n = 20) assessed these outcomes with similar results being reported for these outcomes in both groups. Four studies (n = 159) assessed 'Sensitivity to house dust mite allergen using a marker'; there was no clear evidence of a difference in sensitivity levels reported between treatments in any of the four trials.None of the seven included studies assessed our second primary outcome 'Participant- or caregiver-assessed eczema-related quality of life using a named instrument' or the secondary outcome of 'Adverse effects'.We were unable to combine any of our results because of variability in the interventions and paucity of data. AUTHORS' CONCLUSIONS: We were unable to determine clear implications to inform clinical practice from the very low-quality evidence currently available. The modest treatment responses reported were in people with atopic eczema, specifically with sensitivity to one or more aeroallergens. Thus, their use in the eczema population as a whole is unknown. High-quality long-term trials of single, easy-to-administer house dust mite reduction or avoidance measures are worth pursuing.
Asunto(s)
Polvo/prevención & control , Eccema/prevención & control , Exposición a Riesgos Ambientales/prevención & control , Tareas del Hogar/métodos , Pyroglyphidae , Acaricidas , Adolescente , Adulto , Animales , Ropa de Cama y Ropa Blanca , Niño , Preescolar , Eccema/etiología , Codo , Humanos , Rodilla , Persona de Mediana Edad , Pyroglyphidae/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/prevención & control , Adulto JovenRESUMEN
BACKGROUND: The search for more eco-friendly acaricides has prompted testing of medicinal plants from botanical sources. OBJECTIVE: To evaluate the eradication of house dust mites (HDM), Dermatophagoides pteronyssinus, by direct contact using the essential clove oil (Eugenia caryophyllus). METHODS: A pilot study was initiated to determine the killing power of clove oil. Synthetic fibers were immersed in 2% clove oil for 30 min, dried in a hot air oven at 60°C for 2 hrs after which 0.5 gm of HDMs were exposed to these coated fibers placed in the Siriraj Chamber (SC). Two additional long-term methods were employed. Ten mites were placed in the SC and 10 µl of clove oil was pipetted or sprayed onto them. These latter two procedures were each carried out for 3 consecutive days at 0, 1, 3 and 6 months. The solutions antimicrobial and antifungal properties were evaluated by exposing common bacteria and fungi to sterile filter disks impregnated with the mixture, and after overnight incubation, the disc diffusion method on nutrient agar was used. Ethyl alcohol served as the placebo. 99% and 81%, respectively, while the placebo mortality was <5%. The zone of inhibition indicated significant clearance for all the bacteria and fungi indicating greater biocidal activity when compared to the controls. RESULTS: SEMs revealed dead mites on the fibers. The effectiveness of pipetting and spraying was 99% and 81%, respectively, while the placebo mortality was <5%. The zone of inhibition indicated significant clearance for all the bacteria and fungi indicating greater biocidal activity when compared to the controls. CONCLUSIONS: Clove oil is a promising agent for killing dust mites with a potential use in dust-mite laden mattresses. Spraying diminishes in efficiency after 3 months.
Asunto(s)
Acaricidas/farmacología , Aceite de Clavo/farmacología , Dermatophagoides pteronyssinus/efectos de los fármacos , Aceites Volátiles/farmacología , Pyroglyphidae/efectos de los fármacos , Animales , Antibacterianos/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Proyectos Piloto , Plantas Medicinales , SyzygiumRESUMEN
Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+) DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Hipersensibilidad/inmunología , Hipersensibilidad/parasitología , Interleucinas/metabolismo , Pulmón/inmunología , Pulmón/parasitología , Pyroglyphidae/inmunología , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/patología , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Inmunidad/efectos de los fármacos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Interleucina-1alfa/metabolismo , Interleucina-33 , Pulmón/patología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Endogámicos BALB C , Modelos Inmunológicos , Pyroglyphidae/efectos de los fármacos , Factores de TiempoRESUMEN
The acaricidal activities of Artemisia aucheri oil and (1S)-(-)-verbenone structural analogues were evaluated using a fumigant method against Dermatophagoides farinae , Dermatophagoides pteronyssinus , and Tyrophagus putrescentiae and then compared to those of benzyl benzoate. On the basis of the LD50 values against D. farinae , (1S)-(-)-verbenone (1.38 µg/cm(2)) was about 7.4 times more active than benzyl benzoate (10.15 µg/cm(2)), followed by (+)-trans-myrtanol (2.27 µg/cm(2)), (-)-trans-myrtanol (2.30 µg/cm(2)), and A. aucheri oil (8.75 µg/cm(2)). (1S)-(-)-Verbenone (1.25 µg/cm(2)) was approximately 7.8 times more effective against D. pteronyssinus than benzyl benzoate (9.80 µg/cm(2)), followed by (+)-trans-myrtanol (2.18 µg/cm(2)), (-)-trans-myrtanol (2.22 µg/cm(2)), and A. aucheri oil (8.46 µg/cm(2)). In the case of T. putrescentiae , (1S)-(-)-verbenone (3.75 µg/cm(2)) was roughly 3.5 times more toxic than benzyl benzoate (13.25 µg/cm(2)), followed by (+)-trans-myrtanol (12.57 µg/cm(2)), (-)-trans-myrtanol (12.95 µg/cm(2)), and A. aucheri oil (11.55 µg/cm(2)). These results indicate that A. aucheri oil and (1S)-(-)-verbenone structural analogues may be effective natural agents to control house dust and storage mites.
Asunto(s)
Acaricidas/farmacología , Acaridae/efectos de los fármacos , Asteraceae/química , Extractos Vegetales/farmacología , Aceites de Plantas/farmacología , Pyroglyphidae/efectos de los fármacos , Terpenos/farmacología , Acaricidas/química , Acaricidas/aislamiento & purificación , Animales , Monoterpenos Bicíclicos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Aceites de Plantas/química , Aceites de Plantas/aislamiento & purificación , Terpenos/química , Terpenos/aislamiento & purificaciónRESUMEN
BACKGROUND: The Ca(2+)-activated K(+) channel K(Ca)3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca)3.1 modifies experimental asthma in sheep. METHODOLOGY AND PRINCIPAL FINDINGS: Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of the K(Ca)3.1-channel, or vehicle alone (0.5% methylcellulose) twice daily (orally). Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; nâ=â10, Pâ=â0.0147). The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; nâ=â10, Pâ=â0.0288). Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; nâ=â10, Pâ=â0.0340). Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling. CONCLUSIONS: These findings suggest that K(Ca)3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of K(Ca)3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans.