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1.
BMC Pulm Med ; 23(1): 258, 2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37452319

RESUMEN

BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.


Asunto(s)
Asma , Neutrófilos , Animales , Ratones , Neutrófilos/metabolismo , Aspergillus fumigatus/metabolismo , Adenosina/metabolismo , Asma/terapia , Citocinas/metabolismo , Inflamación , Quimiocinas/metabolismo , Líquido del Lavado Bronquioalveolar , Extractos Vegetales , Remodelación de las Vías Aéreas (Respiratorias)
2.
Cell Immunol ; 364: 104341, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33798909

RESUMEN

Asthma is a chronic inflammatory disease of the lungs that poses a considerable health and socioeconomic burden. Several risk factors work synergistically to affect the progression of asthma. Lipid metabolism, especially in distinct cells such as T cells, macrophages, granulocytes, and non-immune cells, plays an essential role in the pathogenesis of asthma, as lipids are potent signaling molecules that regulate a multitude of cellular response. In this review, we focused on the metabolic pathways of lipid molecules, especially fatty acids and their derivatives, and summarized their roles in various cells during the pathogenesis of asthma along with the current pharmacological agents targeting lipid metabolism.


Asunto(s)
Asma/metabolismo , Granulocitos/inmunología , Metabolismo de los Lípidos/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Animales , Asma/tratamiento farmacológico , Asma/epidemiología , Ácidos Grasos/metabolismo , Humanos , Inmunidad Celular , Terapia Molecular Dirigida , Factores de Riesgo , Transducción de Señal
3.
Eur Respir J ; 56(5)2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32527738

RESUMEN

INTRODUCTION: Acute lung injury (ALI) is a fatal but undertreated condition with severe neutrophilic inflammation, although little is known about the functions of eosinophils in the pathogenesis of ALI. Our objectives were to investigate the roles and molecular mechanisms of eosinophils in ALI. METHODS: Pulmonary eosinophils were identified by flow cytometry. Mice with abundant or deficient eosinophils were used. Cellularity of eosinophils and neutrophils in bronchoalveolar lavage fluid, inflammatory assessment, and survival rate were determined. Human samples were also used for validating experimental results. RESULTS: Blood eosinophils were increased in surviving patients with acute respiratory distress syndrome (ARDS) independent of corticosteroid usage. There existed homeostatic eosinophils in lung parenchyma in mice and these homeostatic eosinophils, originating from the bone marrow, were predominantly CD101-. More CD101- eosinophils could be recruited earlier than lipopolysaccharide (LPS)-initiated neutrophilic inflammation. Loss of eosinophils augmented LPS-induced pulmonary injury. Homeostatic CD101- eosinophils ameliorated, while allergic CD101+ eosinophils exacerbated, the neutrophilic inflammation induced by LPS. Likewise, CD101 expression in eosinophils from ARDS patients did not differ from healthy subjects. Mechanistically, CD101- eosinophils exhibited higher levels of Alox15 and Protectin D1. Administration of Protectin D1 isomer attenuated the neutrophilic inflammation. CONCLUSIONS: Collectively, our findings identify an uncovered function of native CD101- eosinophils in suppressing neutrophilic lung inflammation and suggest a potential therapeutic target for ALI.


Asunto(s)
Lesión Pulmonar Aguda , Endotoxinas , Lesión Pulmonar Aguda/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar , Eosinófilos , Humanos , Lipopolisacáridos , Pulmón , Ratones
4.
Eur Respir J ; 56(3)2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32366484

RESUMEN

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.


Asunto(s)
Elastina , Enfermedad Pulmonar Obstructiva Crónica , Animales , Autoinmunidad , Modelos Animales de Enfermedad , Humanos , Pulmón , Ratones , Ratones Endogámicos C57BL , Humo/efectos adversos , Fumar/efectos adversos
5.
J Immunol ; 200(8): 2571-2580, 2018 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-29507104

RESUMEN

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD.


Asunto(s)
Muerte Celular/fisiología , Células Epiteliales/metabolismo , Inflamación/metabolismo , Nicotiana/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Humo/efectos adversos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Autofagia/efectos de los fármacos , Autofagia/fisiología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Células Epiteliales/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfisema Pulmonar/metabolismo , Fumar/efectos adversos
6.
Sheng Li Xue Bao ; 72(5): 617-630, 2020 Oct 25.
Artículo en Zh | MEDLINE | ID: mdl-33106832

RESUMEN

Corona virus disease 2019 (COVID-19) is a new type of coronavirus pneumonia, which is caused by infection of a novel coronavirus, SARS-CoV-2. The virus infects lung cells by binding angiotensin-converting enzyme 2 (ACE2) of cell surface, which leads to leukocyte infiltration, increased permeability of blood vessels and alveolar walls, and decreased surfactant in the lung, causing respiratory symptoms. The aggravation of local inflammation causes cytokine storm, resulting in systemic inflammatory response syndrome. In December 2019, a number of new pneumonia cases were reported by Wuhan Municipal Health Commission, after then a novel coronavirus was isolated and identified as SARS-CoV-2. To the date of Sep. 13th, 2020, COVID-19 is affecting 216 countries or regions, causing 28 637 952 cases, 917 417 deaths, and the mortality rate is 3.20%. This review will summarize the structure of SARS-CoV-2 and the pharmaceutical treatment of COVID-19, and their potential relationships.


Asunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Humanos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19
7.
Sheng Li Xue Bao ; 72(5): 575-585, 2020 Oct 25.
Artículo en Zh | MEDLINE | ID: mdl-33106828

RESUMEN

Ferroptosis is a novel form of regulated cell death which is dependent on iron and reactive oxygen species (ROS) and associated with the accumulation of lipid peroxides. It is obviously different from other cell death types in terms of morphology, biochemistry, genetics, etc. Also, it is related to the production of iron catalyzed lipid peroxides which is triggered by non-enzymatic or enzymatic reactions. Ferroptosis has been proved to be involved in hematological diseases, cardio-cerebrovascular diseases, liver and kidney diseases. This paper will review the definition, mechanism, inducers of ferroptosis, as well as the function of ferroptosis in respiratory system. We expect to present a new concept for respiratory research and suggest potential targets for clinical prevention and treatment of respiratory diseases.


Asunto(s)
Ferroptosis , Trastornos Respiratorios , Muerte Celular , Humanos , Hierro , Especies Reactivas de Oxígeno
8.
Acta Pharmacol Sin ; 40(6): 769-780, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30446733

RESUMEN

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Células Endoteliales/metabolismo , Hirudinas/metabolismo , Inflamación/metabolismo , Lipoproteínas/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Coagulación Sanguínea/fisiología , Quimiocinas/metabolismo , Quimiotaxis de Leucocito/fisiología , Hirudinas/genética , Humanos , Inflamación/inducido químicamente , Sanguijuelas/química , Lipopolisacáridos , Lipoproteínas/genética , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Pseudomonas aeruginosa/química , Receptores Proteinasa-Activados/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Trombina/metabolismo , Tromboplastina/metabolismo
9.
Am J Pathol ; 187(2): 280-291, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27912076

RESUMEN

Mucus hypersecretion is an important pathologic feature of chronic obstructive pulmonary disease. Activating transcription factor 3 (ATF3) is an adaptive-response gene that participates in various cellular processes. However, little is known about its role in cigarette smoke (CS)-induced mucus hyperproduction. This study aimed to investigate the role and molecular mechanisms of ATF3 in CS-induced Mucin 5AC (MUC5AC) expression. ATF3 was elevated in lung tissues of mice exposed to CS for 12 weeks. Treatment with CS extract significantly induced ATF3 expression and MUC5AC production in human bronchial epithelial cells, NCI-H292, and mouse tracheal epithelial cells. Interference of ATF3 significantly attenuated CS-induced MUC5AC expression in NCI-H292 and human bronchial epithelial cells. Mouse tracheal epithelial cells isolated from Atf3-/- mice also exhibited less MUC5AC production in response to CS extract treatment. In vivo, the Atf3-/- mice also displayed a significantly reduced mucus production relative to wild-type controls in response to chronic CS exposure. Furthermore, a chromatin immunoprecipitation assay revealed increased ATF3 binding to the MUC5AC promoter after CS treatment, and this transcriptional binding was significantly inhibited by knockdown of JUN, a subunit of activator protein-1. These results demonstrate that ATF3 may be involved in activator protein-1 signaling and transcriptional promotion of CS-induced MUC5AC expression in airway epithelial cells.


Asunto(s)
Factor de Transcripción Activador 3/metabolismo , Mucina 5AC/biosíntesis , Mucosa Respiratoria/patología , Fumar/efectos adversos , Factor de Transcripción AP-1/metabolismo , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Mucosa Respiratoria/metabolismo
10.
Crit Care ; 22(1): 301, 2018 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-30442203

RESUMEN

BACKGROUND: Aerosolized antibiotics have been proposed as a novel and promising treatment option for the treatment of ventilator-associated pneumonia (VAP). However, the optimum aerosolized antibiotics for VAP remain uncertain. METHODS: We included studies from two systematic reviews and searched PubMed, EMBASE, and Cochrane databases for other studies. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis. RESULTS: Eight observational and eight randomized studies were identified for this analysis. By pairwise meta-analysis using intravenous antibiotics as the reference, patients treated with aerosolized antibiotics were associated with significantly higher rates of clinical recovery (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.09-1.34; P = 0.001) and microbiological eradication (RR 1.42, 95% CI 1.22-1.650; P < 0.0001). There were no significant differences in the risks of mortality (RR 0.88, 95% CI 0.74-1.04; P = 0.127) or nephrotoxicity (RR 1.00, 95% CI 0.72-1.39; P = 0.995). Using network meta-analysis, clinical recovery benefits were seen only with aerosolized tobramycin and colistin (especially tobramycin), and microbiological eradication benefits were seen only with colistin. Aerosolized tobramycin was also associated with significantly lower mortality when compared with aerosolized amikacin and colistin and intravenous antibiotics. The assessment of rank probabilities indicated aerosolized tobramycin presented the greatest likelihood of having benefits for clinical recovery and mortality, and aerosolized colistin presented the best benefits for microbiological eradication. CONCLUSIONS: Aerosolized antibiotics appear to be a useful treatment for VAP with respect to clinical recovery and microbiological eradication, and do not increase mortality or nephrotoxicity risks. Our network meta-analysis in patients with VAP suggests that clinical recovery benefits are associated with aerosolized tobramycin and colistin (especially tobramycin), microbiological eradication with aerosolized colistin, and survival with aerosolized tobramycin, mostly based on observational studies. Due to the low levels of evidence, definitive recommendations cannot be made before additional, large randomized studies are carried out.


Asunto(s)
Administración por Inhalación , Antibacterianos/administración & dosificación , Neumonía Asociada al Ventilador/tratamiento farmacológico , Antibacterianos/uso terapéutico , Teorema de Bayes , Humanos , Metaanálisis en Red , Resultado del Tratamiento
11.
Med Sci Monit ; 24: 1524-1532, 2018 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-29536984

RESUMEN

BACKGROUND WeChat is a convenient and popular social medium, and it seems to be an appropriate platform for education and management of patients. This study sought to identify usefulness in clinical control of cough-variant asthma (CVA). MATERIAL AND METHODS A randomized controlled trial was conducted among 80 CVA patients. After being assigned to either the traditional group (TG) or the WeChat group (WG), they received the same inhalation therapy, but patients in WG received additional education and instruction via our public account on the WeChat application. Questionnaires on asthma and chronic cough, data on pulmonary function, blood-related items, follow-up adherence, and Emergency Department (ED) visits were collected at the initial visit and at 3 months. RESULTS A total of 67 participants completed the trial for analysis. FEV1/predicted and FEV1/FVC were significantly increased in WG (p<0.001; p=0.012) after 3 months. PD20-FEV1 was increased in both groups compared with baseline, but more pronounced in WG (p=0.004). ACQ-7 scores were improved in both groups (p=0.024; p<0.001). Participants allocated to WG experienced a greater improvement in AQLQ and LCQ scores, and between-group differences were significant at 3 months (p=0.040; p=0.001). Furthermore, we observed decreases in blood eosinophil count and FeNO in WG (p=0.048; p=0.014), and WG presented better follow-up compliance (p=0.034). CONCLUSIONS Using WeChat as part of treatment and management of CVA can help patients learn about their disease and medications, as well as improve disease control and therapy outcomes.


Asunto(s)
Asma/prevención & control , Tos/prevención & control , Medios de Comunicación Sociales , Adulto , Asma/sangre , Asma/fisiopatología , Recuento de Células Sanguíneas , Tos/sangre , Tos/fisiopatología , Servicio de Urgencia en Hospital , Espiración , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Hospitalización , Humanos , Inmunoglobulina E/metabolismo , Masculino , Óxido Nítrico/metabolismo , Cooperación del Paciente , Calidad de Vida , Encuestas y Cuestionarios
12.
J Allergy Clin Immunol ; 140(2): 418-430, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28043871

RESUMEN

BACKGROUND: Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. OBJECTIVE: We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma. METHODS: Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. RESULTS: Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17 cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis ex vivo from patients with severe asthma. CONCLUSION: Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.


Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Compuestos de Bifenilo/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Nitrofenoles/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Alérgenos/inmunología , Compuestos de Alumbre , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Asma/inmunología , Asma/metabolismo , Compuestos de Bifenilo/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Líquido del Lavado Bronquioalveolar/citología , Dexametasona/farmacología , Dexametasona/uso terapéutico , Resistencia a Medicamentos/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Adyuvante de Freund/inmunología , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Nitrofenoles/farmacología , Ovalbúmina/inmunología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/farmacología
13.
Am J Physiol Lung Cell Mol Physiol ; 313(2): L207-L217, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28473329

RESUMEN

Pulmonary epithelial cells form the first line of defense of human airways against foreign irritants and also represent as the primary injury target of these pathogenic assaults. Autophagy is a revolutionary conserved ubiquitous process by which cytoplasmic materials are delivered to lysosomes for degradation when facing environmental and/or developmental changes, and emerging evidence suggests that autophagy plays pivotal but controversial roles in pulmonary epithelial injury. Here we review recent studies focusing on the roles of autophagy in regulating airway epithelial injury induced by various stimuli. Articles eligible for this purpose are divided into two groups according to the eventual roles of autophagy, either protective or deleterious. From the evidence summarized in this review, we draw several conclusions as follows: 1) in all cases when autophagy is decreased from its basal level, autophagy is protective; 2) when autophagy is deleterious, it is generally upregulated by stimulation; and 3) a plausible conclusion is that the endosomal/exosomal pathways may be associated with the deleterious function of autophagy in airway epithelial injury, although this needs to be clarified in future investigations.


Asunto(s)
Autofagia/fisiología , Células Epiteliales/patología , Lesión Pulmonar/patología , Animales , Células Epiteliales/metabolismo , Humanos , Lesión Pulmonar/metabolismo , Lisosomas/metabolismo , Lisosomas/patología , Transducción de Señal/fisiología
14.
Biochem Biophys Res Commun ; 490(2): 147-154, 2017 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-28602698

RESUMEN

Early growth response factor 1 (Egr-1) is a zinc finger transcription factor which responses rapidly to a variety of extracellular stimuli. Previous studies have suggested that Egr-1 exerts pathological functions in chronic obstructive pulmonary disease (COPD) by regulation of cigarette smoking-induced autophagy, cell death, and inflammation. However, little is known about the role of Egr-1 in regulation of mucus production in airway epithelium. In this study, we observed that cigarette smoke extract (CSE) induced a successive expression of Egr-1 and MUC5AC in human bronchial epithelial (HBE) cells. Knockdown of Egr-1 markedly attenuated CSE-induced MUC5AC production, and chromatin immunoprecipitation revealed that Egr-1 transcriptionally bound to MUC5AC promoter upon CSE stimulation. Concurrently, CSE increased the expression of c-Jun and c-Fos, two subunits of activator protein 1 (AP-1) which also critically regulates CSE-induced MUC5AC in HBE cells. CSE also induced a physical interaction of Egr-1 and AP-1, and knockdown of Egr-1 significantly decreased CSE-induced expression of c-Fos and c-Jun. Furthermore, knockdown of c-Fos remarkably attenuated the CSE-induced Egr-1 binding to MUC5AC promoter. These data taken together demonstrate that Egr-1 is essential for CSE-induced MUC5AC production in HBE cells likely through interaction with and modulation of AP-1, and re-emphasize targeting Egr-1 as a novel therapeutic strategy for COPD.


Asunto(s)
Bronquios/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Células Epiteliales/metabolismo , Mucina 5AC/genética , Fumar , Bronquios/patología , Células Cultivadas , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/aislamiento & purificación , Células Epiteliales/patología , Humanos , Mucina 5AC/metabolismo
17.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1042-52, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27036871

RESUMEN

Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases.


Asunto(s)
Autofagia/efectos de los fármacos , Mucina 5AC/genética , Mucosa Respiratoria/metabolismo , Fumar/metabolismo , Animales , Células Cultivadas , Receptores ErbB/metabolismo , Expresión Génica , Células Caliciformes , Humanos , Pulmón/metabolismo , Pulmón/patología , Ratones Noqueados , Mucina 5AC/metabolismo , Moco/metabolismo , Naftiridinas/farmacología , Mucosa Respiratoria/patología , Transducción de Señal , Nicotiana/química , Factor de Transcripción AP-1/metabolismo
18.
Mediators Inflamm ; 2016: 6943135, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27478309

RESUMEN

Asthma is one of the most common chronic inflammatory disorders, associated with reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. This disease has a significant impact on individuals, their families, and society. Standardized therapeutics such as inhaled corticosteroid in combination with long acting ß2 agonist have been applied for asthma control; however, complementary and alternative medicines, especially herbal medicines, are still widely used all over the world. A growing body of literature suggests that various herbals or related products might be effective in inhibiting asthmatic inflammation. In this review, we summarize recent advances about the mechanistic studies of herbal medicines on allergic airway inflammation in animal models and their potential application into clinic for asthma control.


Asunto(s)
Asma/tratamiento farmacológico , Medicina de Hierbas/métodos , Inflamación/tratamiento farmacológico , Animales , Humanos
19.
Am J Respir Cell Mol Biol ; 52(4): 459-70, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25180833

RESUMEN

IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5-transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.


Asunto(s)
Antiinflamatorios/farmacología , Asma/inmunología , Diferenciación Celular/efectos de los fármacos , Eosinófilos/fisiología , Interleucina-17/farmacología , Animales , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Células de la Médula Ósea/fisiología , Supervivencia Celular , Células Cultivadas , Evaluación Preclínica de Medicamentos , Eosinófilos/efectos de los fármacos , Femenino , Interleucina-17/uso terapéutico , Ratones Endogámicos C57BL , Ratones Transgénicos
20.
Respirology ; 20(7): 1055-65, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26053964

RESUMEN

BACKGROUND AND OBJECTIVE: The mammalian target of rapamycin (mTOR) signalling pathway regulates immune responses, and promotes cell growth and differentiation. Inhibition of mTOR with rapamycin modulates allergic asthma, while the underlying molecular mechanisms remain elusive. Here, we demonstrate that rapamycin, effectively inhibits eosinophil differentiation, contributing to its overall protective role in allergic airway inflammation. METHODS: Rapamycin was administered in a mouse model of ovalbumin-induced allergic airway inflammation, and the eosinophil differentiation was analysed in vivo and in vitro. RESULTS: Rapamycin significantly attenuated allergic airway inflammation and markedly decreased the amount of eosinophils in local airways, peripheral blood and bone marrow, independently of levels of interleukin-5 (IL-5). In vitro colony forming unit assay and liquid culture demonstrated that rapamycin directly inhibited IL-5-induced eosinophil differentiation. In addition, rapamycin reduced the production of IL-6 and IL-13 by eosinophils. Rapamycin was also capable of reducing the eosinophil levels in IL-5 transgenic NJ.1638 mice, again regardless of the constitutive high levels of IL-5. Interestingly, rapamycin inhibition of eosinophil differentiation in turn resulted in an accumulation of eosinophil lineage-committed progenitors in bone marrow. CONCLUSIONS: Altogether these results clearly demonstrate a direct inhibitory role of rapamycin in eosinophil differentiation and function, and reemphasize the importance of rapamycin and possibly, mTOR, in allergic airway disease.


Asunto(s)
Asma , Diferenciación Celular , Eosinófilos , Inflamación , Sirolimus/farmacología , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Hipersensibilidad/inmunología , Inmunosupresores/farmacología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interleucinas/inmunología , Recuento de Leucocitos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovalbúmina/farmacología , Inhibidores de Serina Proteinasa/farmacología , Transducción de Señal , Serina-Treonina Quinasas TOR/inmunología
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