Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.932
Filtrar
1.
J Environ Pathol Toxicol Oncol ; 40(2): 11-21, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822513

RESUMO

Global industrialization not only improved the quality life of millions but also paved the way to solving many health problems. One among them is allergic asthma, which affects approximately 20% of the global population. Poor air quality is the major culprit in allergic asthma, which not only affects the individual's health, but also impairs his or her life quality and that of family members. Asthma is a chronic pulmonary inflammatory disease characterized by excess mucus production, airway hyperresponsiveness, and bronchoconstriction. Inhalation of corticosteroids, leukotriene modifiers, and ß-adrenergic agonists is one treatment prescribed to control the symptoms of asthma, but there is still no effective cure. Phytochemicals such as carotenoids, phenolics, alkaloids, and nitrogen and organosulfur compounds are proven to possess immense pharmacological properties. Betalain is one such phytochemical present in plants of the order Caryophyllales. It is a water-soluble nitrogen-based pigment proven to possess antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, antilipidemic, antidiabetic, and anticancer properties. We examined the curative potential of betalain against allergic asthma in a mouse model. Betalain treatment effectively decreased lung weight and infiltration of inflammatory cells in BAL fluid, and lowered IgE, eotaxin, and cytokine levels in asthma-induced mice. It also improved pulmonary mechanics and decreased oxidative stress and nitric oxide levels. Betalain significantly decreased gene expression of TGF-ß and its downstream signaling Smad proteins. Lung histology confirmed that betalain protected the lung tissue of mice from ovalbumin-induced allergic asthma. Overall, our results show that betalain is a potent antiallergic drug that effectively protects mice from ovalbumin-induced allergic asthma. With further research, it can be prescribed as a treatment for asthma in humans.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Asma/tratamento farmacológico , Betalaínas/uso terapêutico , Proteínas Smad/imunologia , Fator de Crescimento Transformador beta1/imunologia , Alérgenos , Animais , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Betalaínas/farmacologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina E/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos BALB C , Ovalbumina , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
2.
Medicine (Baltimore) ; 100(9): e24772, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655940

RESUMO

BACKGROUND: To explore the association of chronic rhinosinusitis (CRS) with bronchial asthma (BA) as well as its severity. METHODS: A comprehensive database search will be performed from PubMed, Embase, Cochrane Library, and Web of science for related literatures. Heterogeneity test will be used to assess each outcome indicator. If heterogeneity statistics I2 ≥ 50%, the random effects model will be applied; if I2 < 50%, the fixed effects model will be performed. Sensitivity analysis will be performed in all models. STATA 15.0 software (Stata Corporation, College Station, TX) will be used for statistical analysis. Risk ratio (RR) will be used as the effect size for enumeration data. P < .05 is considered statistically significant. CONCLUSION: This study will evaluate the association of CRS with the prevalence of BA as well as its severity. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/GCTM9.


Assuntos
Asma/complicações , Rinite/complicações , Índice de Gravidade de Doença , Sinusite/complicações , Asma/patologia , Brônquios/patologia , Doença Crônica , Estudos de Coortes , Estudos Transversais , Humanos , Metanálise como Assunto , Projetos de Pesquisa , Rinite/patologia , Sinusite/patologia , Revisões Sistemáticas como Assunto
3.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498209

RESUMO

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), RBM thickness (histology), and the bronchial epithelium transcriptome profile (gene expression array) in moderate to severe persistent (n = 21) vs. no persistent (n = 19) airflow limitation asthmatics. RBM thickness was similar in the two studied subgroups. Among the genes associated with increased RBM thickness, the most essential were those engaged in cell activation, proliferation, and growth (e.g., CDK20, TACC2, ORC5, and NEK5) and inhibiting apoptosis (e.g., higher mRNA expression of RFN34, BIRC3, NAA16, and lower of RNF13, MRPL37, CACNA1G). Additionally, RBM thickness correlated with the expression of genes encoding extracellular matrix (ECM) components (LAMA3, USH2A), involved in ECM remodeling (LTBP1), neovascularization (FGD5, HPRT1), nerve functioning (TPH1, PCDHGC4), oxidative stress adaptation (RIT1, HSP90AB1), epigenetic modifications (OLMALINC, DNMT3A), and the innate immune response (STAP1, OAS2). Cluster analysis revealed that genes linked with RBM thickness were also related to thicker bronchial walls in CT. Our study suggests that the pro-fibrotic profile in the airway epithelial cell transcriptome is associated with a thicker RBM, and thus, may contribute to asthma airway remodeling.


Assuntos
Asma/metabolismo , Membrana Basal/metabolismo , Transcriptoma , Adulto , Apoptose , Asma/genética , Asma/patologia , Membrana Basal/patologia , Brônquios/metabolismo , Brônquios/patologia , Feminino , Fibrose , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo
4.
Methods Mol Biol ; 2241: 275-291, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33486743

RESUMO

Eosinophils are an important subtype of leukocytes derived from bone marrow multipotent hematopoietic stem cells and represent about 1% of leukocytes in circulating blood. In homeostatic conditions, eosinophils reside in the intestine to maintain the balance of immune responses by communicating with gut microbes without causing inflammation. However, under the stressed or diseased condition, eosinophils degranulate, releasing their granule-derived cytotoxic proteins that are involved in inflammatory responses. Various eosinophil-associated inflammatory diseases are eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC), together called EGID, asthma, hypereosinophilic syndrome, and eosinophilic pneumonia (EP). Eosinophil degranulation results in the release of their four toxic proteins [major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN)] which promote disease pathogenesis. Pancreatitis is the inflammatory disease of the pancreas that arises due to blockage of the pancreatic duct, trypsinogen mutation, alcohol consumption, and repeated occurrence of pancreatitis leading to chronic pancreatitis (CP); subsequently some CP patients may also develop pancreatic cancer. The presence of eosinophils is now shown in various case reports with acute, recurrent acute, and chronic pancreatitis and pancreatic cancer indicating the role of eosinophils in the pathogenesis of various pancreatic inflammatory disorders. However, the details of eosinophil accumulation during pancreatic diseases are not well explored and need further attention. Overall, the chapter provides the current understanding of reported eosinophils associated with inflammatory diseases like EGID diseases, asthma, and pancreatic disorders, i.e., acute, chronic pancreatitis, and pancreatic cancer. This knowledge will be helpful for future studies to develop novel treatment options for the eosinophils associated diseases. Therefore, more efforts are needed to perform preclinical and clinical studies in this field for the successful development of eosinophil-targeting treatments for a variety of eosinophil-associated diseases.


Assuntos
Eosinofilia/patologia , Eosinófilos/patologia , Eosinófilos/fisiologia , Animais , Asma/patologia , Modelos Animais de Doenças , Enterite , Proteínas Granulares de Eosinófilos , Peroxidase de Eosinófilo , Neurotoxina Derivada de Eosinófilo , Eosinofilia/imunologia , Esofagite Eosinofílica/patologia , Gastrite , Humanos , Síndrome Hipereosinofílica/patologia , Inflamação/imunologia , Camundongos , Modelos Biológicos
6.
Int Immunopharmacol ; 91: 107309, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385710

RESUMO

BACKGROUND: COVID-19 is considered the most critical health pandemic of 21st century. Due to extremely high transmission rate, people are more susceptible to viral infection. COVID-19 patients having chronic type-2 asthma prevails a major risk as it may aggravate the disease and morbidities. OBJECTIVE: The present review mainly focuses on correlating the influence of COVID-19 in type-2 asthmatic patients. Besides, it delineates the treatment measures and drugs that can be used to manage mild, moderate, and severe symptoms of COVID-19 in asthmatic patients, thus preventing any exacerbation. METHODS: An in-depth research was carried out from different peer-reviewed articles till September 2020 from several renowned databases like PubMed, Frontier, MEDLINE, and related websites like WHO, CDC, MOHFW, and the information was analysed and written in a simplified manner. RESULTS: The progressive results were quite conflicting as severe cases of COVID-19 shows an increase in the level of several cytokines that can augment inflammation to the bronchial tracts, worsening the asthma attacks. Contradicting to this, certain findings reveal the decrease in the severity of COVID-19 due to the elevation of T-cells in type-2 asthmatic patients, as prominent reduction of T-cell is seen in most of the COVID-19 positive patients. This helps to counteract the balance of immune responses and hence ameliorate the disease progression. CONCLUSION: Asthmatic patients must remain cautious during the COVID-19 pandemic by maintaining all the precautions to stay safe due to limited research data. Future strategies should include a better understanding of asthmatic exacerbation and its relation to COVID-19.


Assuntos
Asma/patologia , Asma/virologia , /patologia , Animais , Asma/metabolismo , Citocinas , Progressão da Doença , Humanos , Pandemias/prevenção & controle , Fatores de Risco , /patogenicidade
7.
J Cell Mol Med ; 25(4): 2279-2284, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421348

RESUMO

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Obesidade/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Asma/imunologia , Asma/patologia , Peso Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Linfócito CD4 , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Inflamação , Interleucina-4/antagonistas & inibidores , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Obesidade/imunologia , Obesidade/patologia , Ovalbumina/administração & dosagem , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
10.
11.
Methods Mol Biol ; 2223: 101-114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226590

RESUMO

Mouse models of allergic asthma have been utilized to establish the role of T helper type 2 (Th2) cells in driving lung inflammation, airway hyperresponsiveness, and obstruction. Here, we present the allergic asthma models, in which mice are hypersensitized to ovalbumin (OVA) and house dust mite (HDM). These models mimic the major characteristics of human asthma including the eosinophilic inflammation and hyperactivity of the airway, overproduction of Th2 cytokines in the lung, and elevated total and allergen-specific immunoglobulin E (IgE) in serum.


Assuntos
Asma/imunologia , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Ovalbumina/administração & dosagem , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Células Th2/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Alérgenos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Biomarcadores/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Expressão Gênica , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pyroglyphidae/química , Testes de Função Respiratória , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Células Th2/imunologia , Células Th2/patologia
12.
Methods Mol Biol ; 2223: 217-236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226598

RESUMO

Cellular inflammation, with elevated levels of Th1/Th2 cytokines, airway mucus hypersecretion, and thickening of the airway smooth muscle, are characteristic features of the allergic lung. Assessment of pathophysiological changes in allergic lungs serves as an important tool to determine disease progression and understand the underlying mechanisms of pathogenesis. This can be achieved by evaluating the lung tissue for inflammation and airway structural changes along with the measurement of important pro-inflammatory mediators such as Th1/Th2 cytokines and eotaxins. This chapter describes procedures to histologically evaluate inflammatory and pathological changes observed during allergic airway inflammation using lung tissue from mice.


Assuntos
Alérgenos/administração & dosagem , Asma/imunologia , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Coloração e Rotulagem/métodos , Equilíbrio Th1-Th2 , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Progressão da Doença , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Microtomia/métodos , Muco/imunologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Inclusão em Parafina/métodos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
13.
Methods Mol Biol ; 2223: 237-266, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226599

RESUMO

Eosinophils are rare white blood cells that are recruited from circulation to accumulate in the lung in mouse models of allergic respiratory inflammation. In hematoxylin-eosin (HE) stained lungs, eosinophils may be difficult to detect despite their bright eosin staining in the secondary granules. For this reason, antibody-mediated detection of eosinophils is preferable for specific and clearer identification of these cells. Moreover, eosinophils may degranulate, releasing their granule proteins into surrounding tissue, and remnants of cytolysed cells cannot be detected by HE staining. The methods here demonstrate the use of eosinophil-specific anti-mouse antibodies to detect eosinophil granule proteins in formalin-fixed cells both in situ in paraffin-embedded lungs, as well as in cytospin preparations from the lung. These antibody staining techniques enable either colorimetric or fluorescence imaging of eosinophils or their granule proteins with the potential for additional antibodies to be added for detection of multiple molecules.


Assuntos
Asma/imunologia , Eosinófilos/imunologia , Imuno-Histoquímica/métodos , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Coloração e Rotulagem/métodos , Alérgenos/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Biomarcadores/metabolismo , Proteína Básica Maior de Eosinófilos/imunologia , Proteína Básica Maior de Eosinófilos/metabolismo , Peroxidase de Eosinófilo/imunologia , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/patologia , Formaldeído/química , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microtomia/métodos , Inclusão em Parafina/métodos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Fixação de Tecidos/métodos
14.
Methods Mol Biol ; 2223: 295-335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226602

RESUMO

Allergic asthma is characterized by airway hyperresponsiveness, remodeling, and reversible airway obstruction. This is associated with an eosinophilic inflammation of the airways, caused by inhaled allergens such as house dust mite or grass pollen. The inhaled allergens trigger a type-2 inflammatory response with the involvement of innate lymphoid cells (ILC2) and Th2 cells, resulting in high immunoglobulin E (IgE) antibody production by B cells and mucus production by airway epithelial cells. As a consequence of the IgE production, subsequent allergen reexposure results in a classic allergic response with distinct early and late phases, both resulting in bronchoconstriction and shortness of breath. Allergen-specific immunotherapy (AIT) is the only treatment that is capable of modifying the immunological process underlying allergic responses including allergic asthma. Both subcutaneous AIT (SCIT) as well as sublingual AIT (SLIT) have shown clinical efficacy in long-term suppression of the allergic response. Although AIT treatments are very successful for rhinitis, application in asthma is hampered by variable efficacy, long duration of treatment, and risk of severe side effects. A more profound understanding of the mechanisms by which AIT induces tolerance to allergens in sensitized individuals is needed to be able to improve its efficacy. Mouse models have been very valuable in preclinical research for characterizing the mechanisms of desensitization in AIT and evaluating novel approaches to improve its efficacy. Here, we present a rapid and reproducible mouse model for allergen-specific immunotherapy. In this model, mice are sensitized with two injections of allergen adsorbed to aluminum hydroxide, followed by subcutaneous injections (SCIT) or sublingual administrations (SLIT) of allergen extracts as an immunotherapy treatment. Finally, mice are challenged by intranasal allergen administrations. We will also describe the protocols as well as the most important readout parameters for the measurements of invasive lung function, serum immunoglobulin levels, isolation of bronchoalveolar lavage fluid (BALF), and preparation of cytospin slides. Moreover, we describe how to perform ex vivo restimulation of lung single-cell suspensions with allergens, flow cytometry for identification of relevant immune cell populations, and ELISAs and Luminex assays for assessment of the cytokine concentrations in BALF and lung tissue.


Assuntos
Alérgenos/administração & dosagem , Asma/terapia , Modelos Animais de Doenças , Pólen/imunologia , Pyroglyphidae/imunologia , Imunoterapia Sublingual/métodos , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Alérgenos/imunologia , Hidróxido de Alumínio/administração & dosagem , Animais , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Misturas Complexas/administração & dosagem , Misturas Complexas/imunologia , Citocinas/genética , Citocinas/imunologia , Orelha , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Injeções Subcutâneas , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/patologia , Pólen/química , Pyroglyphidae/química , Análise de Célula Única/métodos
15.
Life Sci ; 267: 118912, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338503

RESUMO

AIM: To explore the different consequences of acute and chronic exposure to chlorine gas (Cl2) on the functional and histological parameters of health mice. MAIN METHODS: Firstly, male BALB/c mice were acute exposed to 3.3 or 33.3 or 70.5 mg/m3 Cl2. We analyzed the lung function, the inflammatory cells in the bronchoalveolar lavage, cell influx in the peribrochoalveolar space and mucus production. In a second phase, mice were chronic exposed to 70.5 mg/m3 Cl2. Besides the first phase analyses, we also evaluated the epithelial cells thickness, collagen deposition in the airways, immunohistochemistry stain for IL-1ß, iNOS, IL-17 and ROCK-2 and the levels of IL-5, IL-13, IL-17, IL-1ß and TNF-α in lung homogenate. KEY FINDINGS: Acute exposure to chlorine impaired the lung function, increased the number of inflammatory cells in the BALF and in the airways, also increased the mucus production. Furthermore, when chlorine was exposed chronically, increased the airway remodeling with collagen deposition and epithelial cells thickness, positive cells for IL-1ß, iNOS, IL-17 in the airways and in the alveolar walls and ROCK-2 in the alveolar walls, lung inflammation with increased levels of IL-5, IL-13, IL-1ß and TNF-α in the lung homogenate, and also, induced the acid mucus production by the nasal epithelium. SIGNIFICANCE: Acute and chronic exposure to low dose of chlorine gas worsens lung function, induces oxidative stress activation and mucus production and contributes to augmenting inflammation in health mice.


Assuntos
Cloro/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Cloro/metabolismo , Inflamação/patologia , Exposição por Inalação , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
16.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L393-L404, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33325803

RESUMO

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. nonfungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils, and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α, and IL-1ß), neutrophil survival factors (granulocyte colony-stimulating factor), and neutrophil-targeting chemokines (CCL3 and CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5 and IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ and CXCL9) and survival factors (macrophage colony-stimulating factor). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T-cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a nonclassical immunoregulatory mechanism.


Assuntos
Asma/imunologia , Quimiocina CX3CL1/imunologia , Fungos/imunologia , Pulmão/imunologia , Animais , Asma/genética , Asma/microbiologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Quimiocina CX3CL1/genética , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout
17.
Life Sci ; 266: 118884, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310038

RESUMO

AIMS: Growing evidence indicates insufficient autophagy is crucial to airway remodeling in asthma. However, it is uncertain whether p62, an autophagy major regulator, mediates the airway remodeling process. This study aimed to evaluate the role and underlying mechanism of p62 in airway remodeling in asthma. MATERIALS AND METHODS: Airway remodeling was confirmed via histopathology. Western blotting and RT-PCR were used to detect the expression of autophagic and glycolytic proteins, as well as glycolytic genes. Glycolysis was measured by glucose consumption and lactate production. Cell proliferation was analyzed by CCK8 assays while and the scratch test and transwell method were used for cell migration. KEY FINDINGS: We found that insufficient autophagic flux and increased p62 expression existed in chronic asthma mice. Additionally, knockdown of p62 inhibited asthmatic human bronchial smooth muscle cells (BSMCs) proliferation and migration in vitro. To elucidate the underlying mechanism of p62-mediated autophagy flux in directing BSMCs function, we demonstrated that knockdown of p62 decreased the glucose consumption and lactate production in BSMCs, whereas p62 overexpression had the opposite effect. Furthermore, we showed that p62 regulated glycolysis in BSMCs by the mTOR/c-Myc/hexokinase 2 (HK2) pathway. SIGNIFICANCE: Our findings suggest that p62 is involved in BSMCs proliferation and migration via the mTOR/c-Myc/HK2-mediated glycolysis, thereby providing a new target for airway remodeling treatment.


Assuntos
Remodelação das Vias Aéreas , Asma/patologia , Autofagia , Reprogramação Celular , Modelos Animais de Doenças , Miócitos de Músculo Liso/patologia , Proteína Sequestossoma-1/metabolismo , Animais , Asma/induzido quimicamente , Asma/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Glicólise , Hexoquinase/genética , Hexoquinase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/metabolismo , Ovalbumina/toxicidade , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Sequestossoma-1/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
18.
PLoS One ; 15(12): e0243826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370308

RESUMO

PURPOSE: Recent studies suggest that occupational inhalant exposures trigger exacerbations of asthma and chronic obstructive pulmonary disease, but findings are conflicting. METHODS: We included 7,768 individuals with self-reported asthma (n = 3,215) and/or spirometric airflow limitation (forced expiratory volume in 1 second (FEV1)/ forced expiratory volume (FVC) <0.70) (n = 5,275) who participated in The Copenhagen City Heart Study or The Copenhagen General Population Study from 2001-2016. Occupational exposure was assigned by linking job codes with job exposure matrices, and exacerbations were defined by register data on oral corticosteroid treatment, emergency care unit assessment or hospital admission. Associations between occupational inhalant exposure each year of follow-up and exacerbation were assessed by Cox regression with time varying exposure and age as the underlying time scale. RESULTS: Participants were followed for a median of 4.6 years (interquartile range, IQR 5.4), during which 870 exacerbations occurred. Exacerbations were not associated with any of the selected exposures (high molecular weight sensitizers, low molecular weight sensitizers, irritants or low and high levels of mineral dust, biological dust, gases & fumes or the composite variable vapours, gases, dusts or fumes). Hazards ratios ranged from 0.8 (95% confidence interval: 0.7;1.0) to 1.2 (95% confidence interval: 0.9;1.7). CONCLUSION: Exacerbations of obstructive airway disease were not associated with occupational inhalant exposures assigned by a job exposure matrix. Further studies with alternative exposure assessment are warranted.


Assuntos
Asma/epidemiologia , Asma/patologia , Progressão da Doença , Exposição Ocupacional/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Feminino , Humanos , Exposição por Inalação , Masculino , Pessoa de Meia-Idade
20.
PLoS One ; 15(10): e0239561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33091038

RESUMO

Pulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arteries in severe equine asthma, its distribution throughout the lungs, and its reversibility following long-term antigen avoidance strategies and inhaled corticosteroid administration. Using histomorphometry, the total wall area of pulmonary arteries from different regions of the lungs of asthmatic horses and controls was measured. The smooth muscle mass of pulmonary arteries was also estimated on lung sections stained for α-smooth muscle actin. Reversibility of vascular changes in asthmatic horses was assessed after 1 year of antigen avoidance alone or treatment with inhaled fluticasone. Pulmonary arteries showed increased wall area in apical and caudodorsal lung regions of asthmatic horses in both exacerbation and remission. The pulmonary arteries smooth muscle mass was similarly increased. Both treatments reversed the increase in wall area. However, a trend for normalization of the vascular smooth muscle mass was observed only after treatment with antigen avoidance, but not with fluticasone. In conclusion, severe equine asthma is associated with remodeling of the pulmonary arteries consisting in an increased smooth muscle mass. The resulting narrowing of the artery lumen could enhance hypoxic vasoconstriction, contributing to pulmonary hypertension. In our study population, the antigen avoidance strategy appeared more promising than inhaled corticosteroids in controlling vascular remodeling. However, further studies are needed to support the reversibility of vascular smooth muscle mass remodeling after asthma treatment.


Assuntos
Asma/patologia , Asma/fisiopatologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Remodelação Vascular , Animais , Cavalos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...