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1.
Int J Cosmet Sci ; 46(3): 468-477, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38326978

RESUMEN

BACKGROUND: Atopic dermatitis has a marked economic impact and affects the quality of life. A cosmetic compound with an innovative strategy is proposed here as a small chemical neutraligand, GPN279 (previously identified as a theophylline derivative), that binds and potently neutralizes the TARC/CCL17 chemokine, activating the Th2 cell-expressed CCR4 receptor. OBJECTIVE: Our objective was to evaluate the safety and activity of topically applied GPN279 in mild-to-moderate atopic dermatitis patients in a randomized, double-blind, placebo-controlled, parallel group trial. Such cosmetic active ingredient targeting dry skin with an atopic tendency would open a parallel strategy to the pharmaceutical approach, in particular for mild to moderate subjects, as an alternative to reduce the evolution towards severe forms of atopy. METHODS: This 4-week trial included adults with mild-to-moderate atopic dermatitis, according to the SCORAD index. Patients were randomized into two groups treated by topical applications of either an emulsion containing 0.44% GPN279 in placebo on skin lesions or the placebo (4.56% glycerin). Clinical activity was evaluated with the SCORAD as the primary objective. As secondary objectives, POEM, erythema, skin moisturization, its barrier function (TEWL) and safety were evaluated. RESULTS: Twenty-one patients in each group completed the study. SCORAD was significantly improved in the GPN279 group vs. placebo. GPN279 also significantly improved POEM, induced a rapid and significant decrease of erythema, and improved skin moisture. GPN279 and placebo were well tolerated throughout the study. CONCLUSION: A cosmetic cream comprising the CCL17 neutraligand GPN279 improved the skin barrier and physiology criteria in patients with mild-to-moderate atopic dermatitis.


GÉNÉRALITÉS: La dermatite atopique a un impact économique marqué et affecte la qualité de vie. Un composé cosmétique dote d'une stratégie innovante est proposé ici sous la forme d'un petit neutraligand chimique, le GPN279 (précédemment identifié comme un dérivé de la théophylline), qui se lie et neutralise puissamment la chimiokine TARC/CCL17, activant le récepteur CCR4 exprimé par les cellules Th2. OBJECTIF: Notre objectif était d'évaluer l'innocuité et l'activité du GPN279 appliqué localement chez des patients atteints de dermatite atopique légère à modérée dans un essai randomisé, en double aveugle contre placebo et en groupes parallèles. Un tel actif cosmétique ciblant les peaux sèches à tendance atopique ouvrirait une stratégie parallèle à l'approche pharmaceutique, notamment pour les sujets atteints de forme légère à modérée, comme alternative visant à réduire l'évolution vers des formes sévères d'atopie. MÉTHODES: Cet essai de 4 semaines incluait des adultes atteints de dermatite atopique légère à modérée, selon l'indice SCORAD. Les patients ont été randomisés en deux groupes traités par application topique sur les lésions cutanées soit d'une émulsion contenant 0,44% de GPN279 dans un placebo, soit du placebo seul (4,56% de glycérine). L'activité clinique a été évaluée selon l'indice SCORAD comme objectif principal. Les objectifs secondaires évaluaient le POEM, l'érythème, l'hydratation de la peau, sa fonction barrière (TEWL) et la sécurité. RÉSULTATS: Vingt et un patients de chaque groupe ont terminé l'étude. L'indice SCORAD a été significativement amélioré dans le groupe GPN279 par rapport au placebo. Le GPN279 a également amélioré de manière significative le POEM, a induit une diminution rapide et significative de l'érythème et amélioré l'hydratation de la peau. Le GPN279 et le placebo ont été bien tolérés tout au long de l'étude. CONCLUSION: Une crème cosmétique contenant le neutraligand CCL17 GPN279 améliore la barrière cutanée et les critères physiologiques chez les patients atteints de dermatite atopique légère à modérée.


Asunto(s)
Administración Tópica , Quimiocina CCL17 , Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Adulto , Femenino , Masculino , Persona de Mediana Edad , Adulto Joven , Cosméticos/administración & dosificación , Placebos/administración & dosificación
2.
J Cardiovasc Pharmacol ; 78(6): 792-801, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34882111

RESUMEN

ABSTRACT: Left-ventricular hypertrophy, characterized by cardiomyocyte hypertrophy, interstitial cell proliferation, and immune cell infiltration, is a high risk factor for heart failure and death. Chemokines interacting with G protein-coupled chemokine receptors probably play a role in left-ventricular hypertrophy development by promoting recruitment of activated leukocytes and modulating left-ventricular remodeling. Using the minimally invasive model of transverse aortic constriction in mice, we demonstrated that a variety of chemokine and chemokine receptor messenger Ribonucleic Acid are overexpressed in the early and late phase of hypertrophy progression. Among the chemokine receptors, Cx3cr1 and Ccr2 were most strongly overexpressed and were significantly upregulated at 3, 7, and 14 days after transverse aortic constriction. Ligands of CX3CR1 (Cx3cl1) and CCR2 (Ccl2, Ccl7, Ccl12) were significantly overexpressed in the left ventricle at the early stages after mechanical pressure overload. Pharmacological inhibition of CX3CR1 signaling using the antagonist AZD8797 led to a significant reduction of hypertrophy, whereas inhibition of CCR2 with the RS504393 antagonist did not show any effect. Furthermore, AZD8797 treatment reduced the expression of the hypertrophic marker genes Nppa and Nppb as well as the profibrotic genes Tgfb1 and Col1a1 at 14 days after transverse aortic constriction. These findings strongly suggest the involvement of the CX3CR1/CX3CL1 pathway in the pathogenesis of left-ventricular hypertrophy.


Asunto(s)
Receptor 1 de Quimiocinas CX3C/antagonistas & inhibidores , Hipertrofia Ventricular Izquierda/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Pirimidinas/farmacología , Tiazoles/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Aorta/fisiopatología , Aorta/cirugía , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Cadena alfa 1 del Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Constricción , Modelos Animales de Enfermedad , Fibrosis , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Transducción de Señal , Factores de Tiempo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo
3.
Molecules ; 26(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33450992

RESUMEN

Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.


Asunto(s)
Diseño de Fármacos , Guanidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Células Cultivadas , Guanidinas/síntesis química , Guanidinas/química , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo
4.
Biochim Biophys Acta Mol Cell Res ; 1864(6): 1018-1027, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28109792

RESUMEN

Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca2+ release from the InsP3 receptors.


Asunto(s)
Bisacodilo/farmacología , Neoplasias Encefálicas/patología , Señalización del Calcio , Glioblastoma/patología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Glioblastoma/metabolismo , Humanos , Células Madre Neoplásicas/metabolismo
5.
Eur Respir J ; 51(5)2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29773606

RESUMEN

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numbers of animals employed, thereby enhancing the ethical standards and translational capacity of experimental research.The task force statement addresses general issues of experimental research (ethics, species, sex, age, ex vivo and in vitro models, gene editing). The statement also includes research recommendations on modelling asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung infections, acute lung injury and pulmonary hypertension.The task force stressed the importance of using multiple models to strengthen validity of results, the need to increase the availability of human tissues and the importance of standard operating procedures and data quality.


Asunto(s)
Experimentación Animal/ética , Investigación Biomédica/normas , Modelos Animales de Enfermedad , Trastornos Respiratorios , Comités Consultivos , Animales , Europa (Continente) , Humanos , Sociedades Médicas
7.
Neuroimmunomodulation ; 24(6): 331-340, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29680839

RESUMEN

OBJECTIVE: The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation. METHODS: A 21-day ovalbumin (OVA)-induced allergic-airway TH2 inflammation model in BALB/c mice was used. Four groups were sensitized with OVA adsorbed on alum and challenged either with OVA or saline for 4 days. Mice were treated intranasally with chalcone 4 (300 nmol/kg body weight) or solvent 2 h before each OVA or saline challenge; 24 h after the last challenge, CD11c+F4/80- DCs were counted in the bronchoalveolar lavage. Jugular-nodose ganglion complex (JNC) sections were sampled, and for immunofluorescence staining, cryocut sections were prepared. MHC II+F4/80- DCs as well as calcitonin gene-related peptide (CGRP)- and substance P (SP)-positive neuronal cell bodies were analyzed. RESULTS: In OVA-challenged mice, chalcone 4 caused a significantly decreased DC/neuron ratio in the JNC from 51.7% in solvent-treated to 32.6% in chalcone 4-treated mice. In parallel, chalcone 4 also decreased the DC population in BALF from 11.5 × 103 cells in solvent to 4.5 × 103 cells in chalcone 4-treated mice. By contrast, chalcone 4 had no effect on the expression of the neuropeptides CGRP and SP in JNC. CONCLUSION: This study reported the CXCL12 neutraligand chalcone 4 to affect DC infiltration into the airways and airway ganglia as well as to decrease airway eosinophilic inflammation and, therefore, validated CXCL12 as a new target in allergic disease models of asthma.


Asunto(s)
Asma/inmunología , Movimiento Celular/inmunología , Chalcona/farmacología , Quimiocina CXCL12/farmacología , Células Dendríticas/inmunología , Ganglio Nudoso/inmunología , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Chalcona/uso terapéutico , Quimiocina CXCL12/uso terapéutico , Células Dendríticas/efectos de los fármacos , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Ganglio Nudoso/citología , Ganglio Nudoso/efectos de los fármacos , Ovalbúmina/toxicidad
8.
Neuroimmunomodulation ; 23(5-6): 261-270, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28030866

RESUMEN

OBJECTIVES: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. METHODS: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. RESULTS: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. CONCLUSIONS: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR.


Asunto(s)
Mastocitos/metabolismo , Mucosa Nasal/inervación , Fibras Nerviosas/metabolismo , Receptores de Neuropéptido/metabolismo , Rinitis Alérgica/patología , Adolescente , Adulto , Quimasas/metabolismo , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mucosa Nasal/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-2/metabolismo , Receptores de Neuropéptido/genética , Sustancia P/metabolismo , Factores de Transcripción/metabolismo , Triptasas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Adulto Joven
9.
J Immunol ; 192(4): 1847-54, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24453258

RESUMEN

Mast cells (MCs) are found in large numbers in lungs of patients with pulmonary fibrosis. However, the functions of MCs in lung fibrosis remain largely unknown. We assessed the role of MCs and MC protease 4 (MCPT4), the mouse counterpart of human MC chymase, in a mouse model of bleomycin (BLM)-induced lung injury. We found that levels of inflammation in the bronchoalveolar lavage and the lung, as well as levels of lung fibrosis, were reduced 7 d after intranasal delivery of BLM MC-deficient Kit(W-sh/W-sh) mice compared with wild-type (WT) mice. Confirming the implication of MCs in these processes, we report that the levels of inflammation and fibrosis observed in Kit(W-sh/W-sh) mice can be restored to those observed in WT mice after the adoptive transfer of bone marrow-derived cultured MCs into Kit(W-sh/W-sh) mice. Additionally, we show that levels of inflammation and fibrosis are also reduced in MC chymase MCPT4-deficient mice as compared with WT mice at day 7, suggesting a role for MC-derived MCPT4 in these processes. Our results support the conclusion that MCs can contribute to the initial lung injury induced by BLM through release of the MCPT4 chymase.


Asunto(s)
Quimasas/metabolismo , Mastocitos/inmunología , Neumonía/inmunología , Fibrosis Pulmonar/inmunología , Serina Endopeptidasas/metabolismo , Traslado Adoptivo , Animales , Bleomicina , Células de la Médula Ósea/inmunología , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Pulmón/inmunología , Pulmón/patología , Mastocitos/metabolismo , Mastocitos/trasplante , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/inducido químicamente , Serina Endopeptidasas/genética
10.
Respir Res ; 16: 77, 2015 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-26112287

RESUMEN

BACKGROUND: Potential involvement of the CCR10/CCL28 axis was recently reported in murine models of allergic asthma. If confirmed, blockade of the CCR10 receptor would represent an alternative to current asthma therapies. We evaluated the effect of a novel Protein Epitope Mimetic CCR10 antagonist, POL7085, in a murine model of allergic eosinophilic airway inflammation. METHODS: Mice were sensitized and challenged to ovalbumin. POL7085, a CCR10 antagonist (7.5 and 15 mg/kg), dexamethasone (1 mg/kg) or vehicle were administered intranasally once daily 1h before each allergen challenge. On day 21, airway hyperresponsiveness, bronchoalveolar lavage inflammatory cells and Th2 cytokines, and lung tissue mucus and collagen were measured. RESULTS: Allergen challenge induced airway hyperresponsiveness in vehicle-treated animals as measured by whole body barometric plethysmography, and eosinophilia in bronchoalveolar lavage. POL7085 dose-dependently and significantly decreased airway hyperresponsiveness (34 ± 16 %) and eosinophil numbers in bronchoalveolar lavage (66 ± 6 %). In addition, the highest dose of POL7085 used significantly inhibited lung IL-4 (85 ± 4 %), IL-5 (87 ± 2 %) and IL-13 (190 ± 19 %) levels, and lung collagen (43 ± 11 %). CONCLUSIONS: The Protein Epitope Mimetic CCR10 antagonist, POL7085, significantly and dose-dependently decreased allergen-induced airway hyperresponsiveness and airway inflammation after once daily local treatment. Our data give strong support for further investigations with CCR10 antagonists in asthmatic disease.


Asunto(s)
Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Epítopos/uso terapéutico , Eosinofilia Pulmonar/prevención & control , Receptores CCR10/antagonistas & inhibidores , Animales , Asma/patología , Hiperreactividad Bronquial/patología , Relación Dosis-Respuesta a Droga , Epítopos/química , Epítopos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Eosinofilia Pulmonar/patología , Receptores CCR10/química
11.
J Biol Chem ; 288(17): 11865-76, 2013 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-23449983

RESUMEN

The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair, in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue and should not diffuse in the systemic circulation, where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile-chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin-sensitized and challenged mice in vivo when administered directly to the airways by the intranasal route, but not when administered systemically by the intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands although the target protein is widely distributed in the organism.


Asunto(s)
Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Chalconas/farmacología , Quimiocina CXCL12/antagonistas & inhibidores , Animales , Antiasmáticos/química , Asma/metabolismo , Asma/patología , Chalconas/química , Quimiocina CXCL12/metabolismo , Evaluación Preclínica de Medicamentos , Eosinófilos/metabolismo , Eosinófilos/patología , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Receptores CXCR4/metabolismo
12.
Magn Reson Med ; 71(1): 35-43, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23412987

RESUMEN

PURPOSE: Using the metabolomics by NMR high-resolution magic angle spinning spectroscopy, we assessed the lung metabolome of various animal species in order to identify the animal model that could be substituted to human lung in studies on fresh lung biopsies. METHODS: The experiments were conducted on intact lung biopsy samples of pig, rat, mouse, and human using a Bruker Advance III 500 spectrometer. Thirty-five to 39 metabolites were identified and 23 metabolites were quantified. Principal component analysis, partial least-squares discriminant analysis, and analysis of variance tests were performed in order to compare the metabolic profiles of each animal lung biopsies to those of the human lung. RESULTS: The metabolic composition between human and pig lung was similar. However, human lung was distinguishable from mouse and rat regarding: Trimethylamine N-oxide and betaïne which were present in rodents but not in human lung, carnitine, and glycerophosphocholine which were present in mouse but not in human lung. Conversely, succinic acid was undetected in rat lung. Furthermore, fatty acids concentration was significantly higher in rodent lungs compared to human lung. CONCLUSION: Using the metabolomics by NMR high-resolution magic angle spinning spectroscopy on lung biopsy, samples allowed to highlight that pig lung seems to be close to human lung as regarding its metabolite composition with more similarities than dissimilarities.


Asunto(s)
Pulmón/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Metaboloma/fisiología , Ratones/metabolismo , Ratas/metabolismo , Porcinos/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Biopsia , Femenino , Humanos , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Especificidad de la Especie
13.
J Immunol ; 188(7): 3478-87, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22393156

RESUMEN

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-κB and its subsequent recruitment onto the IκBα promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.


Asunto(s)
Antiasmáticos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Compuestos de Amonio Cuaternario/uso terapéutico , Receptores de Glucocorticoides/efectos de los fármacos , Acetatos , Animales , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Citocinas/biosíntesis , Citocinas/genética , Dexametasona/farmacología , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Fosfatasa 1 de Especificidad Dual/biosíntesis , Fosfatasa 1 de Especificidad Dual/genética , Inducción Enzimática/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Células Caliciformes/patología , Inflamación , Leucocitos/inmunología , Pulmón/inmunología , Pulmón/patología , Mastocitos/inmunología , Metaplasia , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/toxicidad , Compuestos de Amonio Cuaternario/farmacología , Receptores de Glucocorticoides/fisiología , Factor de Transcripción STAT6/metabolismo , Activación Transcripcional/efectos de los fármacos , Tiramina/análogos & derivados
14.
Transpl Int ; 26(10): 1027-37, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23895147

RESUMEN

The aim of this study was to assess the functional preservation of the lung graft with anterograde lung perfusion in a model of donation after cardiac death. Thirty minutes after cardiac arrest, in situ anterograde selective pulmonary cold perfusion was started in six swine. The alveolo-capillary membrane was challenged at 3, 6, and 8 h with measurements of the mean pulmonary arterial pressure (mPAP), the pulmonary vascular resistance (PVR), the PaO2 /FiO2 ratio, the transpulmonary oxygen output (tpVO2 ), and the transpulmonary CO2 clearance (tpCO2 ). Mitochondrial homeostasis was investigated by measuring maximal oxidative capacity (Vmax ) and the coupling of phosphorylation to oxidation (ACR, acceptor control ratio) in lung biopsies. Inflammation and induction of primary immune response were assessed by measurement of tumor necrosis factor alpha (TNFα), interleukine-6 (IL-6) and receptor for advanced glycation endproducts (RAGE) in bronchoalveolar lavage fluid. Data were compared using repeated measures Anova. Pulmonary hemodynamics (mPAP: P = 0.69; PVR: P = 0.46), oxygenation (PaO2 /FiO2 : P = 0.56; tpVO2 : P = 0.46), CO2 diffusion (tpCO2 : P = 0.24), mitochondrial homeostasis (Vmax : P = 0.42; ACR: P = 0.8), and RAGE concentrations (P = 0.24) did not significantly change up to 8 h after cardiac arrest. TNFα and IL-6 were undetectable. Unaffected pulmonary hemodynamics, sustained oxygen and carbon dioxide diffusion, preserved mitochondrial homeostasis, and lack of inflammation suggest a long-lasting functional preservation of the graft with selective anterograde in situ pulmonary perfusion.


Asunto(s)
Isquemia Fría , Muerte , Trasplante de Pulmón/métodos , Pulmón/patología , Preservación de Órganos/métodos , Animales , Presión Arterial , Biopsia , Hemodinámica , Homeostasis , Inmunidad Innata , Inflamación , Interleucina-6/metabolismo , Mitocondrias/patología , Modelos Animales , Oxígeno/química , Oxígeno/metabolismo , Perfusión , Fosforilación , Intercambio Gaseoso Pulmonar , Porcinos , Factores de Tiempo , Recolección de Tejidos y Órganos/métodos , Factor de Necrosis Tumoral alfa/metabolismo , Resistencia Vascular
15.
Front Med (Lausanne) ; 10: 1126697, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36968829

RESUMEN

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD. Methods: To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression. Results: Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD. Conclusion: Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.

16.
Magn Reson Med ; 68(4): 1026-38, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22161974

RESUMEN

Standards are needed to control the quality of the lungs from nonheart-beating donors as potential grafts. This was here assessed using the metabolomics 1H high-resolution magic angle spinning NMR spectroscopy. Selective perfusion of the porcine bilung block was set up 30 min after cardiac arrest with cold Perfadex®. Lung alterations were analyzed at 3, 6, and 8 h of cold ischemia as compared to baseline and to nonperfused lung. Metabolomics analysis of lung biopsies allowed identification of 35 metabolites. Levels of the majority of the metabolites increased over time at 4°C without perfusion, indicating cellular degradation, whereas levels of glutathione decreased. When lung was perfused at 4°C, levels of the majority of the metabolites remained stable, including levels of glutathione. Levels of uracil by contrast showed a reverse profile, as its signal increased over time in the absence of perfusion while being totally absent in perfused samples. Our results showed glutathione and uracil as potential biomarkers for the quality of the lung. The metabolomics 1H high-resolution magic angle spinning NMR spectroscopy can be efficiently applied for the assessment of the quality of the lung as an original technique characterized by a rapid assessment of intact biopsy samples without extraction and can be implemented in hospital environment.


Asunto(s)
Trasplante de Pulmón , Pulmón/fisiología , Espectroscopía de Resonancia Magnética/métodos , Metaboloma/fisiología , Proteoma/análisis , Supervivencia Tisular/fisiología , Animales , Protones , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Marcadores de Spin , Porcinos
17.
Proc Natl Acad Sci U S A ; 106(5): 1536-41, 2009 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-19188585

RESUMEN

Atopic dermatitis (AD) is often the initial step in the "atopic march," given that more than half of AD patients with moderate to severe AD develop asthma later in life. Both AD and asthma share a similar "atopy" phenotype that includes T helper type 2 inflammation with eosinophilia and hyper-IgE immunoglobulinemia, but the molecular mechanisms underlying the "atopic march" remain elusive. In the present study, we show that induced expression of thymic stromal lymphopoietin (TSLP) in mouse epidermal keratinocytes upon topical application of MC903 (a low calcemic analogue of vitamin D3) not only triggers AD as we previously reported but also aggravates experimental allergic asthma induced by ovalbumin sensitization and challenge. Our study, which provides a mouse model to study human "atopic march," indicates that keratinocyte-produced TSLP may represent an important factor in the link of atopic dermatitis to asthma.


Asunto(s)
Asma/patología , Citocinas/fisiología , Queratinocitos/metabolismo , Piel/patología , Células del Estroma/patología , Timo/patología , Animales , Asma/inmunología , Asma/metabolismo , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Queratinocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Piel/inmunología , Piel/metabolismo , Células del Estroma/inmunología , Timo/inmunología , Linfopoyetina del Estroma Tímico
18.
Am J Respir Cell Mol Biol ; 45(1): 81-7, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20855652

RESUMEN

Cathepsin S (Cat S) is predominantly expressed in antigen-presenting cells and is up-regulated in several preclinical models of antigen-induced inflammation, suggesting a role in the allergic response. Prophylactic dosing of an irreversible Cat S inhibitor has been shown to attenuate pulmonary eosinophilia in mice, supporting the hypothesis that Cat S inhibition before the initiation of airway inflammation is beneficial in airway disease. In addition, Cat S has been shown to play a role in more distal events in the allergic response. To determine where Cat S inhibition may affect the allergic response, we used complementary genetic and pharmacological approaches to investigate the role of Cat S in the early and downstream allergic events in a murine model of antigen-induced lung inflammation. Cat S knockout mice did not develop ovalbumin-induced pulmonary inflammation, consistent with a role for Cat S in the development of the allergic response. Alternatively, wild-type mice were treated with a reversible, highly selective Cat S inhibitor in prophylactic and therapeutic dosing paradigms and assessed for changes in airway inflammation. Although both treatment paradigms resulted in potent Cat S inhibition, only prophylactic Cat S inhibitor dosing blocked lung inflammation, consistent with our findings in Cat S knockout mice. The findings indicate that although Cat S is up-regulated in allergic models, it does not appear to play a significant role in the downstream effector inflammatory phase in this model; however, our results demonstrate that Cat S inhibition in a prophylactic paradigm would ameliorate airway inflammation.


Asunto(s)
Asma/prevención & control , Catepsinas/genética , Catepsinas/farmacología , Animales , Asma/genética , Asma/metabolismo , Catepsinas/biosíntesis , Modelos Animales de Enfermedad , Evaluación de Medicamentos , Humanos , Ratones , Ratones Noqueados , Ovalbúmina/efectos adversos , Ovalbúmina/farmacología , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/prevención & control , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
19.
Methods Mol Biol ; 2241: 75-87, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33486729

RESUMEN

Murine models of asthma are developed to better understand the mechanisms of asthma including eosinophil recruitment in the airways with the aim of evaluating new therapeutic strategies. They are intended to model the typical features of human disease, in particular airway inflammation, hyperresponsiveness (AHR), and remodeling. The phenotype of inflammatory cells recovered from the bronchoalveolar lavage fluid (BAL) is studied with innovative flow cytometry techniques while airway obstruction is measured using the forced oscillation technique, and airway responsiveness approached by barometric plethysmography in awake and unconstrained animals. We here describe models of asthma of house dust mite (HDM) as a clinically relevant allergen: a short study design (8 days) model of hypereosinophilic asthma and a chronic (31 days) asthma model, both suitable to evaluate the potential of new drug candidates to prevent allergic asthma.


Asunto(s)
Desarrollo de Medicamentos/métodos , Eosinófilos/citología , Pyroglyphidae/inmunología , Alérgenos/inmunología , Animales , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Citocinas , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Hipersensibilidad/inmunología , Recuento de Leucocitos , Pulmón/citología , Ratones , Ratones Endogámicos/inmunología , Ratones Transgénicos , Trastornos Respiratorios/inmunología , Hipersensibilidad Respiratoria/inmunología , Células Th2/inmunología
20.
Cells ; 10(9)2021 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-34572117

RESUMEN

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.


Asunto(s)
Asma/complicaciones , Hipersensibilidad/complicaciones , Inflamación/prevención & control , Pulmón/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Pyroglyphidae/patogenicidad , Animales , Asma/patología , Autofagia , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Femenino , Hipersensibilidad/patología , Inmunoglobulina E/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Pyroglyphidae/química , Proteína Sequestosoma-1/metabolismo
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