RESUMEN
Introduction: Respiratory syncytial virus (RSV) vaccines targeting the fusion glycoprotein (F protein) are highly effective clinically in preventing RSV challenges. The attachment glycoprotein (G protein) is a potentially effective vaccine antigen candidate, as it is important for cell adhesion during infection. However, vaccine-associated enhanced diseases in mice, such as eosinophilic lung inflammation following RSV challenge, are a concern with G protein vaccines. This study aimed to design an effective G protein vaccine with enhanced safety and efficacy by evaluating the efficacy and adverse reactions of vaccines composed of different recombinant G proteins and adjuvants in mice. Methods: Mice were subcutaneously immunized with glycosylated G protein expressed in mammalian cells (mG), non-glycosylated G protein expressed in Escherichia coli (eG), or F protein with or without aluminum salts (alum), CpG oligodeoxynucleotide (CpG ODN), or AddaVax. After vaccination, the levels of G-specific antibody and T-cell responses were measured. The immunized mice were challenged with RSV and examined for the viral load in the lungs and nasal turbinates, lung-infiltrating cells, and lung pathology. Results: mG with any adjuvant was ineffective at inducing G-specific antibodies and had difficulty achieving both protection against RSV challenge and eosinophilia suppression. In particular, mG+CpG ODN induced G-specific T helper 1 (Th1) cells but only a few G-specific antibodies and did not protect against RSV challenge. However, eG+CpG ODN induced high levels of G-specific antibodies and Th1 cells and protected against RSV challenge without inducing pulmonary inflammation. Moreover, the combination vaccine of eG+F+CpG ODN showed greater protection against upper respiratory tract RSV challenge than using each single antigen vaccine alone. Discussion: These results indicate that the efficacy of recombinant G protein vaccines can be enhanced without inducing adverse reactions by using appropriate antigens and adjuvants, and their efficacy is further enhanced in the combination vaccine with F protein. These data provide valuable information for the clinical application of G protein vaccines.
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Eosinofilia , Neumonía , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Vacunas , Ratones , Animales , Anticuerpos Antivirales , Proteínas Virales de Fusión , Adyuvantes Inmunológicos , Proteínas Recombinantes , Eosinofilia/prevención & control , Proteínas de Unión al GTP , Oligodesoxirribonucleótidos , Glicoproteínas , Vacunas Combinadas , MamíferosRESUMEN
Background: The eosinophilic inflammation plays a critical role in myocarditis (Mcd); its underlying mechanism remains to be further elucidated. This study aims to investigate the role of Bcl2-like protein 12 (Bcl2L12) in inducing the defects of apoptosis in eosinophils (Eos) of the heart tissues. Methods: Human explant heart samples were collected. Eosinophilia and myocarditis (Mcd)-like inflammation were induced in the mouse heart by immunizing with murine cardiac α-myosin heavy chain (MyHCα) peptides. Results: Markedly more Eos were observed in heart tissues from patients with Mcd than those from patients with dilated cardiomyopathy. Eos isolated from Mcd hearts showed the signs of apoptosis defects. The Eo counts in the Mcd heart tissues were positively correlated with the Bcl2L12 expression in Eos isolated from the heart tissues. Exposure to interleukin 5 in the culture induced the expression of Bcl2L12 in Eos. Bcl2L12 bound c-Myc, the transcription factor of Fas ligand (FasL), to prevent c-Myc from binding to the FasL promoter, to restrict the FasL gene transcription in Eos. Inhibition of Bcl2L12 prevented the induction of eosinophilia and Mcd-like inflammation in the mouse heart. Conclusions: The Bcl2L12 expression contributes to apoptosis defects in Eos of the Mcd heart. Blocking Bcl2L12 prevents the eosinophilia induction and alleviates Mcd-like inflammation in mice.
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Apoptosis/efectos de los fármacos , Eosinofilia/prevención & control , Eosinófilos/efectos de los fármacos , Proteínas Musculares/metabolismo , Miocarditis/prevención & control , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Adulto , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Eosinofilia/genética , Eosinofilia/inmunología , Eosinofilia/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Proteína Ligando Fas/metabolismo , Femenino , Humanos , Interleucina-5/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Musculares/genética , Miocarditis/genética , Miocarditis/inmunología , Miocarditis/metabolismo , Cadenas Pesadas de Miosina , Fragmentos de Péptidos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Interferencia de ARN , Transducción de Señal , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys. EXPERIMENTAL APPROACH: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM. KEY RESULTS: In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM. CONCLUSIONS AND IMPLICATIONS: 5-Oxo-ETE may play an important role in allergen-induced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.
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Alérgenos , Antialérgicos/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Dermatitis/prevención & control , Eosinofilia/prevención & control , Eosinófilos/efectos de los fármacos , Receptores Eicosanoides/antagonistas & inhibidores , Piel/efectos de los fármacos , Animales , Antialérgicos/síntesis química , Antialérgicos/farmacocinética , Antígenos Helmínticos/inmunología , Ácidos Araquidónicos , Ascaris suum/inmunología , Células Cultivadas , Dermatitis/inmunología , Dermatitis/metabolismo , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Proteínas de Insectos/inmunología , Macaca fascicularis , Macaca mulatta , Masculino , Proyectos Piloto , Pyroglyphidae/inmunología , Receptores Eicosanoides/metabolismo , Transducción de Señal , Piel/inmunología , Piel/metabolismoRESUMEN
Chronic helminth infection with Schistosoma (S.) mansoni protects against allergic airway inflammation (AAI) in mice and is associated with reduced Th2 responses to inhaled allergens in humans, despite the presence of schistosome-specific Th2 immunity. Schistosome eggs strongly induce type 2 immunity and allow to study the dynamics of Th2 versus regulatory responses in the absence of worms. Treatment with isolated S. mansoni eggs by i.p. injection prior to induction of AAI to ovalbumin (OVA)/alum led to significantly reduced AAI as assessed by less BAL and lung eosinophilia, less cellular influx into lung tissue, less OVA-specific Th2 cytokines in lungs and lung-draining mediastinal lymph nodes and less circulating allergen-specific IgG1 and IgE antibodies. While OVA-specific Th2 responses were inhibited, treatment induced a strong systemic Th2 response to the eggs. The protective effect of S. mansoni eggs was unaltered in µMT mice lacking mature (B2) B cells and unaffected by Treg cell depletion using anti-CD25 blocking antibodies during egg treatment and allergic sensitization. Notably, prophylactic egg treatment resulted in a reduced influx of pro-inflammatory, monocyte-derived dendritic cells into lung tissue of allergic mice following challenge. Altogether, S. mansoni eggs can protect against the development of AAI, despite strong egg-specific Th2 responses.
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Anticuerpos Antiprotozoarios/sangre , Asma/prevención & control , Óvulo/inmunología , Schistosoma mansoni/inmunología , Alérgenos/inmunología , Compuestos de Alumbre/farmacología , Animales , Anticuerpos Antiprotozoarios/inmunología , Asma/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Eosinofilia/prevención & control , Femenino , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inflamación/patología , Subunidad alfa del Receptor de Interleucina-2 , Pulmón/inmunología , Pulmón/parasitología , Pulmón/patología , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Linfocitos T Reguladores/inmunología , Células Th2/inmunologíaRESUMEN
BACKGROUND: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. METHODS: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. RESULTS: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. CONCLUSION: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.
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Antiinflamatorios/farmacología , Ácidos Araquidónicos/farmacología , Asma/prevención & control , Eosinofilia/prevención & control , Inflamación/fisiopatología , Pulmón/fisiopatología , Animales , Asma/inmunología , Asma/fisiopatología , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/fisiopatología , Inflamación/inmunología , Pulmón/inmunología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Seed kernel of the plant Ceasalpinia bonducella Linn (Caesalpiniacaeae) are used for the treatment of asthma in folk medicine and ancient books. AIM OF STUDY: To assess the pharmacological efficacy of the plant in asthma and to confine and describe the synthetic constituents from the seeds that are in charge of the action. MATERIAL AND METHODS: The viability of petroleum ether, ethanol extract and ethyl acetate fraction from ethanol extract of C. bonducella seeds were screened for the treatment of asthma by various methods viz. effect of test drug on clonidine and haloperidol induced catalepsy, milk-induced leukocytosis and eosinophilia, mast cell stabilizing activity in mice and studies on smooth muscle preparation of guinea pig ileum (in-vitro). Column chromatography of active extract was done to pinpoint the active compound followed by structure elucidation by FTIR, GCMS and NMR spectroscopic methods. RESULTS: Ethyl acetate fraction from ethanol extract of C. bonducella seeds exhibited antihistaminic activity at the dose of 50 and 100â¯mg/kg, inhibited clonidine-induced catalepsy but not haloperidol-induced catalepsy. Ethyl acetate fraction from ethanol extract significantly inhibited increased leukocyte and eosinophil count due to milk allergen and showed maximum protection against mast cell degranulation by clonidine. The results of guinea pig ileum indicated that the compound 2 methyl, 1 hexadecanol isolated from ethyl acetate fraction of ethanol extract relaxed significantly the ileum muscle strips pre-contracted by which suggests the involvement of ß2-agonists on the relaxation of the tissue. All the results are dose dependent. Active ethyl acetate fraction from ethanol extract showed presence of anti-asthmatic compound, 2-methyl, 1-hexadecanol. CONCLUSION: The ethyl acetate fraction from ethanol extract of seeds of the plant C. bonducella can inhibit parameters linked to asthma disease.
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Antialérgicos/farmacología , Antiasmáticos/farmacología , Caesalpinia , Antagonistas de los Receptores Histamínicos/farmacología , Extractos Vegetales/farmacología , Semillas , Acetatos/química , Animales , Antialérgicos/aislamiento & purificación , Antialérgicos/toxicidad , Antiasmáticos/aislamiento & purificación , Antiasmáticos/toxicidad , Caesalpinia/química , Caesalpinia/toxicidad , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Degranulación de la Célula/efectos de los fármacos , Clonidina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eosinofilia/inducido químicamente , Eosinofilia/prevención & control , Femenino , Cobayas , Haloperidol , Antagonistas de los Receptores Histamínicos/aislamiento & purificación , Antagonistas de los Receptores Histamínicos/toxicidad , Íleon/efectos de los fármacos , Íleon/metabolismo , Dosificación Letal Mediana , Leucocitosis/inducido químicamente , Leucocitosis/prevención & control , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Leche , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Plantas Medicinales , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Semillas/química , Semillas/toxicidad , Solventes/química , Factores de TiempoRESUMEN
Mucus hypersecretion and eosinophil infiltration are important characteristics of eosinophilic inflammation in upper airways, such as allergic rhinitis and chronic rhinosinusitis with nasal polyp. EGFR transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. However, the roles of EGFR in eosinophilic inflammation in upper airways are still unknown. The purpose of the study is to elucidate the effects of the EGFR inhibitor AG1478 on eosinophilic airway inflammation. AG1478 significantly inhibited thrombin-induced GM-CSF secretion from nasal epithelial cells and thrombin-induced secretion of eotaxin-1 and RANTES from nasal fibroblasts. Intranasal instillation of AG1478 inhibited OVA-induced goblet cell metaplasia, mucus production and eosinophil/neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478. These results indicate that EGFR transactivation plays an important role in eosinophilic airway inflammation. Intranasal instillation of an EGFR inhibitor may be a new therapeutic approach for the treatment of intractable eosinophilic inflammation in upper airways.
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Eosinófilos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Inflamación/prevención & control , Quinazolinas/farmacología , Mucosa Respiratoria/efectos de los fármacos , Tirfostinos/farmacología , Administración Intranasal , Animales , Células Cultivadas , Quimiocina CCL11/metabolismo , Quimiocina CCL5/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Eosinofilia/metabolismo , Eosinofilia/prevención & control , Eosinófilos/metabolismo , Eosinófilos/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Inflamación/metabolismo , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/patología , Infiltración Neutrófila/efectos de los fármacos , Quinazolinas/administración & dosificación , Ratas , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Trombina/farmacología , Tirfostinos/administración & dosificaciónRESUMEN
BACKGROUND: Periostin is a recently discovered biomarker for eosinophilic inflammation. Chronic rhinosinusitis with nasal polyps is a T-helper 2-skewed chronic inflammatory airway disease. Medical treatments aim to relieve symptoms and maintain clinical control by interfering with the inflammatory cascade. The effect on nasal and serum periostin levels is however yet unknown. We aimed to evaluate the effect of omalizumab, mepolizumab, methylprednisolone and doxycycline on nasal and systemic periostin expression. METHODS: This study is based on 3 previously published trials. Nasal and systemic periostin were assessed in CRSwNP patients, randomly assigned to receive doxycycline (n=14), methylprednisolone (n=14), mepolizumab (n=20) or omalizumab (n=15). There was a control group for each treatment scheme. Doxycycline (200 mg on the first day, followed by 100 mg once daily) and methylprednisolone (32-8 mg once daily) were administered during 20 days; mepolizumab was injected at baseline and at 4 weeks. Omalizumab was injected every 2 or 4 weeks, following the official drug leaflet. RESULTS: Methylprednisolone and omalizumab significantly reduced serum periostin levels at 4 and 8 weeks, respectively, after the start of the treatment. The effect of methylprednisolone was transient. Nasal periostin levels decreased significantly after 8 weeks of treatment with mepolizumab. The periostin expression is in accordance with the previously reported effect on the eosinophilic inflammation and clinical outcome. CONCLUSION: All treatment options distinctly influence periostin expression, reflecting the interference with the local or systemic eosinophilic inflammatory cascade.
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Moléculas de Adhesión Celular/metabolismo , Pólipos Nasales/complicaciones , Rinitis/tratamiento farmacológico , Sinusitis/tratamiento farmacológico , Administración Oral , Antialérgicos/uso terapéutico , Antibacterianos/uso terapéutico , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/análisis , Enfermedad Crónica , Doxiciclina/uso terapéutico , Eosinofilia/prevención & control , Femenino , Humanos , Inflamación/prevención & control , Inyecciones , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Omalizumab/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Rinitis/etiología , Sinusitis/etiología , Resultado del TratamientoAsunto(s)
Factores Inmunológicos/uso terapéutico , Lenalidomida/uso terapéutico , Linfoma de Efusión Primaria/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Anciano de 80 o más Años , ADN Viral/sangre , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/prevención & control , Monitoreo de Drogas , Eosinofilia/inducido químicamente , Eosinofilia/prevención & control , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/inmunología , Tumores del Estroma Gastrointestinal/patología , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/metabolismo , Humanos , Factores Inmunológicos/efectos adversos , Lenalidomida/efectos adversos , Linfoma de Efusión Primaria/diagnóstico por imagen , Linfoma de Efusión Primaria/inmunología , Linfoma de Efusión Primaria/virología , Masculino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/inmunología , Neoplasias Primarias Secundarias/virología , Radiografía Torácica , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
Hemodialysis-associated eosinophilia (HAE) is believed to be associated with allergic reactions to dialyzer materials. This study aimed to investigate the use of Polyflux membranes to improve HAE. Thirty-one patients suffering from HAE were included. Patients were dialyzed with polysulfone membranes when they developed HAE. After that, patients were dialyzed with Polyflux membranes three times every week, 4 h every time without changing the dialysis parameters and medication. Levels of peripheral eosinophils, hsCRP, IgE, C3a, IL-5 and peripheral CD4+ lymphocytes and CD8+ lymphocytes were assessed before Polyflux treatment, and at 4th, 8th and 12th weeks of treatment. Any symptoms including chest tightness and skin itching were observed during the study period. After 12 weeks of Polyflux membrane dialysis and compared with polysulfone membrane dialysis, levels of peripheral eosinophils were significantly decreased (1.26 ± 0.61 vs. 0.71 ± 0.29 × 10(9)/L, p < 0.001); serum IL-5 levels were significantly decreased (24.43 ± 10.21 vs. 9.11 ± 4.21 pg/mL, p < 0.001); and chest tightness and skin itching were significantly improved (45.2% vs. 19.4%, p = 0.028). After 12 weeks, there was no significant change in serum levels of hsCRP (2.00 ± 0.94 vs. 1.81 ± 0.79 mg/L, p = 0.352), IgE (104.61 ± 98.79 vs. 114.95 ± 101.07 IU/mL, p = 0.422) and C3a (121.61 ± 34.04 vs. 120.29 ± 32.81 µg/L, p = 0.316), and in peripheral levels of CD4+ (589 ± 181 vs. 569 ± 171 cells/mm(3), p = 0.672) and CD8+ (443 ± 123 vs. 414 ± 140 cells/mm(3), p = 0.395) cells. Eosinophil count was correlated with serum IL-5 levels (r = 0.873, p < 0.001). Changing to a Polyflux membrane may alleviate HAE and reduce serum IL-5 levels. Therefore, this could be a strategy to manage HAE in the clinical practice.
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Eosinofilia/prevención & control , Membranas Artificiales , Diálisis Renal/efectos adversos , Anciano , Proteína C-Reactiva/metabolismo , Complemento C3a/metabolismo , Eosinofilia/sangre , Eosinofilia/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Interleucina-5/metabolismo , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Diálisis Renal/instrumentaciónRESUMEN
OBJECTIVE: Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. APPROACH AND RESULTS: We demonstrate that CD25(+) ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr(-/-)rag1(-/-) mice. To investigate the role of ILCs in atherosclerosis, ldlr(-/-)rag1(-/-) mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or IL-2/anti-IL-2 complexes that expand CD25(+) ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2-treated mice. These IL-2-treated mice had reduced very low-density lipoprotein cholesterol and increased triglycerides compared with controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila, and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2 complex-induced eosinophilia but did not change lesion size. CONCLUSIONS: This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in very low-density lipoprotein cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis.
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Anticuerpos/farmacología , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Proliferación Celular/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-2/farmacología , Linfocitos/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/inmunología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteína B-100 , Apolipoproteínas B/sangre , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Biomarcadores/sangre , VLDL-Colesterol/sangre , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/metabolismo , Eosinofilia/prevención & control , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Interleucina-5/antagonistas & inhibidores , Interleucina-5/sangre , Interleucina-5/inmunología , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/deficiencia , Receptores de LDL/genética , Triglicéridos/sangreRESUMEN
Puerarin is an isoflavonoid isolated from the root of the plant Pueraria lobata and has been used as a prescribed drug in China for the treatment of many diseases in the clinical practice. The present study aimed to determine the protective effects and the underlying mechanisms of puerarin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2 mg/kg), and puerarin (10 mg/kg, 20 mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Th1/Th2 cytokines were measured by enzyme-linked immunosorbent assay, eotaxin-3 was evaluated by western blotting. Our study demonstrated that, compared with model group, puerarin inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γ level in bronchoalveolar lavage fluid; histological studies demonstrated that puerarin substantially inhibited OVA-induced eosinophilia in lung tissue compared with model group. Western blotting studies demonstrated that puerarin substantially inhibited eotaxin-3 compared with model group. Our findings support puerarin can prevent some signs of allergic asthma in the mouse model.
Asunto(s)
Asma/prevención & control , Quimiocinas CC/antagonistas & inhibidores , Inflamación/prevención & control , Isoflavonas/farmacología , Sistema Respiratorio/efectos de los fármacos , Animales , Asma/inducido químicamente , Asma/metabolismo , Western Blotting , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Quimiocina CCL26 , Quimiocinas CC/metabolismo , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Eosinofilia/inducido químicamente , Eosinofilia/metabolismo , Eosinofilia/prevención & control , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Fitoterapia/métodos , Pueraria/química , Distribución Aleatoria , Sistema Respiratorio/metabolismo , Sistema Respiratorio/patología , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
Over 20 species of Angiostrongylus have been described from around the world, but only Angiostrongylus cantonensis has been confirmed to cause central nervous system disease in humans. A neurotropic parasite that matures in the pulmonary arteries of rats, A. cantonensis is the most common cause of eosinophilic meningitis in southern Asia and the Pacific and Caribbean islands. The parasite can also cause encephalitis/encephalomyelitis and rarely ocular angiostrongyliasis. The present paper reviews the life cycle, epidemiology, pathogenesis, clinical features, diagnosis, treatment, prevention and prognosis of A. cantonesis infection. Emphasis is given on the spectrum of central nervous system manifestations and disease pathogenesis.
Asunto(s)
Angiostrongylus cantonensis/fisiología , Encefalomielitis/epidemiología , Eosinofilia/epidemiología , Encefalitis Infecciosa/epidemiología , Estadios del Ciclo de Vida , Meningitis/epidemiología , Infecciones por Strongylida/epidemiología , Animales , Asia/epidemiología , Encefalomielitis/prevención & control , Encefalomielitis/terapia , Eosinofilia/prevención & control , Eosinofilia/terapia , Humanos , Encefalitis Infecciosa/prevención & control , Encefalitis Infecciosa/terapia , Larva/fisiología , Meningitis/prevención & control , Meningitis/terapia , Infecciones por Strongylida/prevención & control , Infecciones por Strongylida/terapiaRESUMEN
A 53-year-old female with idiopathic hypereosinophilic syndrome underwent recurrent tricuspid valve replacement for Löffler's endocarditis. We review the literature on tricuspid valve surgery in patients with this uncommon disorder.
Asunto(s)
Bioprótesis , Implantación de Prótesis de Válvulas Cardíacas/métodos , Síndrome Hipereosinofílico/complicaciones , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/cirugía , Válvula Tricúspide/cirugía , Eosinofilia/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa , Complicaciones Posoperatorias/prevención & control , Trombosis/prevención & control , Resultado del TratamientoRESUMEN
Astragaloside IV is the chief ingredient of Radix Astragali, which has been used in the Traditional Chinese Medicine as a major component of many polyherbal formulations for the repair and regeneration of injured organ and tissues. We tested the anti-asthmatic effects of AST IV and the possible mechanisms. BALB/c mice that were sensitized and challenged to ovalbumin (OVA) were treated with AST IV (40mg/kg and 20mg/kg) 1h before they were challenged with OVA. Our study demonstrated that AST IV inhibited OVA-induced increases in eosinophil count; interleukin (IL)-4 level were recovered in bronchoalveolar lavage fluid increased IFN-γ and IL-10 levels in bronchoalveolar lavage fluid. Histological studies demonstrated that AST IV substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry studies demonstrated that AST IV substantially increased CD4(+)CD25(+)Foxp3 T cells (Treg). Furthermore quantitative real-time (qPCR) studies demonstrated that AST IV substantially enhanced Foxp3 mRNA expression in lung tissue. These findings suggest that AST IV may effectively ameliorate the progression of airway inflammation and could be used as a therapy for patients with allergic inflammation.
Asunto(s)
Asma/inmunología , Citocinas/inmunología , Inflamación/inmunología , Saponinas/inmunología , Linfocitos T Reguladores/inmunología , Triterpenos/inmunología , Animales , Antiasmáticos/inmunología , Antiasmáticos/farmacología , Antiinflamatorios/inmunología , Antiinflamatorios/farmacología , Asma/inducido químicamente , Asma/prevención & control , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/prevención & control , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Eosinofilia/inducido químicamente , Eosinofilia/inmunología , Eosinofilia/prevención & control , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Inflamación/prevención & control , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ovalbúmina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Saponinas/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Triterpenos/farmacologíaRESUMEN
Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA). Airway inflammation was assessed based on inflammatory cell recruitment, measurement of lung Th1-Th2 cytokines, chemokines, eicosanoids, and other proinflammatory mediators as well as airway hyperresponsiveness (AHR). CRA-challenged mice fed a HFD exhibited significantly decreased allergen-induced airway eosinophilia along with reduced lung IL-5, IL-13, LTC4, CCL11, and CCL2 levels as well as reduced mucus secretion and smooth muscle mass compared to ND fed mice. However, allergen-challenged HFD fed mice demonstrated significantly increased PAI-1 and reduced PGE2 levels in the lung relative to corresponding ND fed mice. Interestingly, saline-exposed HFD fed mice demonstrated elevated baseline levels of TGF-ß1, arginase-1, hypoxia-inducible factor-1α, and lung collagen expression associated with decreased lung function compared to corresponding ND fed mice. These studies indicate that a HFD inhibits airway eosinophilia while altering levels of PAI-1 and PGE2 in response to CRA in mice. Further, a HFD can lead to the development of lung fibrosis even in the absence of allergen exposure which could be due to innate elevated levels of specific profibrotic factors, potentially affecting lung function during asthma.
Asunto(s)
Alérgenos/efectos adversos , Dieta Alta en Grasa/efectos adversos , Eosinofilia/prevención & control , Fibrosis Pulmonar/etiología , Enfermedades Respiratorias/prevención & control , Animales , Arginasa/metabolismo , Asma/etiología , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Quimiocinas/metabolismo , Cucarachas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eicosanoides/metabolismo , Eosinofilia/inmunología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/inmunología , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patología , Enfermedades Respiratorias/inmunología , Factores de Riesgo , Serpina E2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The aim of the study was to investigate the anti-asthmatic effects of apigenin and the possible mechanisms. Asthma model was established by ovalbumin-induced asthma. A total of 50 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg) and apigenin (5 mg/kg, 10 mg/kg). Airway resistance (Raw) was measured, histological studies were evaluated by hematoxylin and eosin (HE) staining, OVA-specific serum and BALF IgE levels and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), Th17 cells were evaluated by flow cytometry (FCM), and protein level of RORγt was measured by western blotting. Our study demonstrated that apigenin inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-6, TNF- and IL-17A levels were recovered. Histological studies demonstrated that apigenin substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue. Flow cytometry studies demonstrated that apigenin substantially inhibited Th17 cells. Western blotting studies demonstrated that apigenin substantially inhibited RORγt protein level. These findings suggest that apigenin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.
Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Antiasmáticos/uso terapéutico , Apigenina/uso terapéutico , Asma/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Células Th17/metabolismo , Animales , Antiasmáticos/farmacología , Apigenina/farmacología , Asma/inducido químicamente , Asma/metabolismo , Citocinas/metabolismo , Eosinofilia/metabolismo , Eosinofilia/prevención & control , Eosinófilos/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ovalbúmina , Extractos Vegetales/farmacologíaRESUMEN
Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Modelos Animales de Enfermedad , Eosinofilia/prevención & control , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Pirazoles/farmacología , Animales , Citocinas/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB CRESUMEN
Successive extracts of whole plant of Actiniopteris radiata screened for its therapeutic potential as an antiallergic and antistress agent in asthma using specific in vivo animal models. Only ethanol extract (AREE) at a higher dose of 100 mg/kg i.p significantly (p < 0.05) decreased milk induced eosinophilia by 16.20 ± 2.235 when compared with control group while even lower doses of 50 mg/kg, i.p exhibited significant inhibition (P < 0.05) of leukocytosis induced by milk in mice. Other extracts like petroleum ether, ethyl acetate and methanol unable to exhibit that significant potential. Results obtained thus validate the traditional claim of the Actiniopteris radiata utilization in different aspect of asthma due to presence of various polar secondary metabolites in ethanol extract.