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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209135

RESUMO

Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.


Assuntos
Brônquios , Células Epiteliais , Metformina/farmacologia , Lesões Experimentais por Radiação , Protetores contra Radiação/farmacologia , Animais , Brônquios/metabolismo , Brônquios/patologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Camundongos , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle
2.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204767

RESUMO

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of ß1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2ß1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2ß1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2ß1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.


Assuntos
Asma/metabolismo , Asma/patologia , Progressão da Doença , Integrina alfa2beta1/metabolismo , Pulmão/patologia , Substâncias Protetoras/metabolismo , Adulto , Idoso , Remodelação das Vias Aéreas , Asma/sangue , Asma/imunologia , Membrana Basal/patologia , Brônquios/diagnóstico por imagem , Brônquios/patologia , Brônquios/fisiopatologia , Lavagem Broncoalveolar , Feminino , Humanos , Inflamação/patologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Subunidades Proteicas/metabolismo , Ventilação Pulmonar , Solubilidade , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
3.
Pan Afr Med J ; 38: 298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178217

RESUMO

Introduction: the use of flexible bronchoscopy in developing countries is limited. We report our initial experience and outcome with the use of flexible bronchoscopy at the Tamale Teaching Hospital in Ghana. This is the first reported case series of flexible bronchoscopy in Ghana. Methods: a retrospective review of patients who had flexible bronchoscopy from 2017-2019 was analyzed. Patient demographics and outcomes were summarized using frequency distribution and percentages. Results: we performed flexible bronchoscopies in 33 patients with mean age of 43 years. All patients were symptomatic at the time of presentation with the most common symptoms being chest pain (63.6%), dyspnea (57.6%) and cough (48.5%). The indication for bronchoscopy in most of the cases were suspected malignancy in 16 (48.5%) followed by infection 9 (27.3%), trauma 4 (12.1%) and others 4 (12.1%). We observed abnormal bronchoscopic findings in 25 (75.8%) of the cases with most of the pathologies in the right main bronchus. Twelve patients had toilet bronchoscopy, 6 had biopsy, 5 had no intervention and 4 patients had bronchoalveolar lavage (BAL). Culture and sensitivity results were available for 11 patients, of which 7 patients had negative results. Thirteen (13) malignancies and 11 inflammatory/infectious diseases were diagnosed in this case series. The mean procedure time was 32 minutes with mean hospital stay of 7 days. There was no complication or mortality in our series. Conclusion: flexible bronchoscopy is a safe procedure and indispensable in Ghana where there is an increasing incidence of lung diseases.


Assuntos
Brônquios/patologia , Broncoscopia/métodos , Pneumopatias/diagnóstico , Adolescente , Adulto , Idoso , Biópsia , Lavagem Broncoalveolar/métodos , Feminino , Gana , Hospitalização/estatística & dados numéricos , Hospitais de Ensino , Humanos , Tempo de Internação , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
4.
J Cell Mol Med ; 25(14): 7001-7012, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34137173

RESUMO

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in many deaths throughout the world. It is vital to identify the novel prognostic biomarkers and therapeutic targets to assist with the subsequent diagnosis and treatment plan to mitigate the expansion of COVID-19. Since angiotensin-converting enzyme 2 (ACE2)-positive cells are hosts for COVID-19, we focussed on this cell type to explore the underlying mechanisms of COVID-19. In this study, we identified that ACE2-positive cells from the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 belong to bronchial epithelial cells. Comparing with patients of COVID-19 showing severe symptoms, the antigen processing and presentation pathway was increased and 12 typical genes, HLA-DRB5, HLA-DRB1, CD74, HLA-DRA, HLA-DPA1, HLA-DQA1, HSP90AA1, HSP90AB1, HLA-DPB1, HLA-DQB1, HLA-DQA2, and HLA-DMA, particularly HLA-DPB1, were obviously up-regulated in ACE2-positive bronchial epithelial cells of patients with mild disease. We further discovered SDCBP was positively correlated with above 12 genes particularly with HLA-DPB1 in ACE2-positive bronchial epithelial cells of COVID-19 patients. Moreover, SDCBP may increase the immune infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in different lung carcinoma. Moreover, we found the expression of SDCBP was positively correlated with the expression of antigen processing and presentation genes in post-mortem lung biopsies tissues, which is consistent with previous discoveries. These results suggest that SDCBP has good potential to be further developed as a novel diagnostic and therapeutic target in the treatment of COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Brônquios/patologia , COVID-19/patologia , Células Epiteliais/metabolismo , RNA-Seq , Índice de Gravidade de Doença , Análise de Célula Única , Sinteninas/metabolismo , Apresentação do Antígeno/genética , Líquido da Lavagem Broncoalveolar , COVID-19/genética , COVID-19/metabolismo , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Humanos , Mudanças Depois da Morte , SARS-CoV-2/fisiologia , Regulação para Cima/genética
5.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066693

RESUMO

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 µg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.


Assuntos
Fumar Cigarros/efeitos adversos , Neutrófilos/patologia , Piperazinas/uso terapêutico , Animais , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Humanos , Interleucina-8/biossíntese , Pulmão/patologia , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Pneumonia/tratamento farmacológico , Proteínas Quinases/metabolismo
6.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065289

RESUMO

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10-5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.


Assuntos
COVID-19/genética , COVID-19/metabolismo , Predisposição Genética para Doença , Receptores CCR5/genética , Receptores CCR5/metabolismo , Alelos , Brônquios/metabolismo , Brônquios/patologia , Brônquios/virologia , COVID-19/fisiopatologia , Cromossomos Humanos/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
7.
Am J Pathol ; 191(8): 1374-1384, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34033751

RESUMO

Patients with coronavirus disease 2019 (COVID-19) who are critically ill develop vascular complications characterized by thrombosis of small, medium, and large vessels. Dysfunction of the vascular endothelium due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express angiotensin-converting enzyme 2, the receptor that SARS-CoV-2 uses to gain entry into cells, or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated locally by an augmented inflammatory reaction to infected nonendothelial cells, such as the bronchial and alveolar epithelium, and systemically by the excessive immune response to infection. Herein we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.


Assuntos
COVID-19/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , SARS-CoV-2/metabolismo , Trombose/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Brônquios/metabolismo , Brônquios/patologia , COVID-19/complicações , COVID-19/patologia , COVID-19/terapia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/terapia , Endotélio Vascular/patologia , Humanos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Trombose/etiologia , Trombose/patologia , Trombose/terapia
8.
Biomed Pharmacother ; 140: 111701, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34051616

RESUMO

Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17f/f/Cre+ mice compared to control mice. TGF-ß- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-ß and thrombin through an aberrant ADAM17/EGFR signalling pathway.


Assuntos
Proteína ADAM17/genética , Asma/patologia , Brônquios/patologia , Proteína ADAM17/metabolismo , Adulto , Alérgenos , Animais , Asma/genética , Asma/metabolismo , Brônquios/metabolismo , Células Cultivadas , Doença Crônica , Receptores ErbB/genética , Feminino , Fibroblastos/metabolismo , Fibrose , Humanos , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Ovalbumina , Trombina/farmacologia , Fator de Crescimento Transformador beta/farmacologia
9.
Chest ; 159(4): e221-e224, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-34022022

RESUMO

CASE PRESENTATION: A 54-year-old man sought treatment at the ED for a productive cough with green phlegm of approximately 6 months' duration that was accompanied by a 10-pound weight loss, night sweats, and occasional subjective fevers. He had made several prior visits to the ED for the cough and was hospitalized 4 months earlier for similar symptoms, at which time he underwent a bronchoscopy with BAL and was discharged with antibiotics for presumed pneumonia. He did not report any itching, rashes, sinus infections, joint swelling, joint pain, or GI symptoms. His long-term medications included omeprazole and amlodipine. The patient had a past medical history of grade III follicular lymphoma for which he completed six cycles of bendamustine 4 years before presentation and had been in remission since. He was a never smoker, had a recent travel history to the Dominican Republic 8 months before admission, and had no recent sick contacts.


Assuntos
Brônquios/patologia , Bronquiolite/diagnóstico , Tosse/diagnóstico , Eosinofilia/diagnóstico , Infecções Respiratórias/diagnóstico , Biópsia , Bronquiolite/complicações , Broncoscopia , Doença Crônica , Tosse/etiologia , Diagnóstico Diferencial , Eosinofilia/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/etiologia , Tomografia Computadorizada por Raios X
10.
Arch Biochem Biophys ; 706: 108897, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34004182

RESUMO

Diseases such as asthma are exacerbated by inflammation, cigarette smoke and even nicotine delivery devices such as e-cigarettes. However, there is currently little information on how nicotine affects airways, particularly in humans, and changes in the context of inflammation or asthma. Here, a longstanding assumption is that airway smooth muscle (ASM) that is key to bronchoconstriction has muscarinic receptors while nicotinic receptors (nAChRs) are only on airway neurons. In this study, we tested the hypothesis that human ASM expresses α7nAChR and explored its profile in inflammation and asthma using ASM of non-asthmatics vs. mild-moderate asthmatics. mRNA and western analysis showed the α7 subunit is most expressed in ASM cells and further increased in asthmatics and smokers, or by exposure to nicotine, cigarette smoke or pro-inflammatory cytokines TNFα and IL-13. In these effects, signaling pathways relevant to asthma such as NFκB, AP-1 and CREB are involved. These novel data demonstrate the expression of α7nAChR in human ASM and suggest their potential role in asthma pathophysiology in the context of nicotine exposure.


Assuntos
Asma/genética , Broncoconstrição/efeitos dos fármacos , Misturas Complexas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Nicotina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/metabolismo , Asma/patologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Fumar Cigarros/efeitos adversos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-13/farmacologia , Masculino , Pessoa de Meia-Idade , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Cultura Primária de Células , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Índice de Gravidade de Doença , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
11.
Medicine (Baltimore) ; 100(21): e26149, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032770

RESUMO

RATIONALE: Lung pleomorphic carcinoma (LPC) is generally resistant to chemotherapy or radiotherapy. However, a combination of immune checkpoint inhibitors and radiotherapy has a remarkable efficacy against LPC. PATIENT CONCERNS AND DIAGNOSES: Here, we report the case of a 50-year old man diagnosed with progressive LPC. The tumor invaded the carina and predominantly obstructed the right main bronchus; therefore, a combination of palliative chemoradiotherapy and atezolizumab was initiated. However the trachea was gradually obstructed. INTERVENTION AND OUTCOME: Argon plasma coagulation (APC) was performed to prevent tumor invasion. After three APC sessions, the tumor showed a necrotic change and was easily excised using biopsy forceps. LESSONS: A combination of chemoradiotherapy, atezolizumab, and APC showed a good efficacy, and the patient had a good response to atezolizumab maintenance therapy. Multidisciplinary treatments, such as a combination of immune checkpoint inhibitors and APC, could have synergistic efficacy in lung cancer.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fotocoagulação a Laser , Lasers de Gás/uso terapêutico , Neoplasias Pulmonares/terapia , Brônquios/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Necrose , Traqueia/patologia , Resultado do Tratamento
12.
Exp Mol Pathol ; 120: 104641, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33901418

RESUMO

Several mechanisms have been suggested to explain the adverse effects of air pollutants on airway cells. One such explanation is the presence of high concentrations of oxidants and pro-oxidants in environmental pollutants. All animal and plant cells have developed several mechanisms to prevent damage by oxidative molecules. Among these, the peroxiredoxins (PRDXs) are of interest due to a high reactivity with reactive oxygen species (ROS) through the functioning of the thioredoxin/thioredoxin reductase system. This study aimed to verify the gene expression patterns of the PRDX family in bronchial epithelial airway cells (BEAS-2B) cells exposed to diesel exhaust particles (DEPs) at a concentration of 15 µg/mL for 1 or 2 h because this it is a major component of particulate matter in the atmosphere. There was a significant decrease in mRNA fold changes of PRDX2 (0.43 ± 0.34; *p = 0.0220), PRDX5 (0.43 ± 0.34; *p = 0.0220), and PRDX6 (0.33 ± 0.25; *p = 0.0069) after 1 h of exposure to DEPs. The reduction in mRNA levels may consequently lead to a decrease in the levels of PRDX proteins, increasing oxidative stress in bronchial epithelial cells BEAS-2B and thus, negatively affecting cellular functions.


Assuntos
Brônquios/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Material Particulado/efeitos adversos , Peroxirredoxinas/metabolismo , Emissões de Veículos/análise , Brônquios/efeitos dos fármacos , Brônquios/patologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Peroxirredoxinas/genética
13.
Toxicol Lett ; 347: 1-11, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33878386

RESUMO

The fluorescent properties of cadmium telluride (CdTe) containing quantum dots (QDs) have led to novel products and applications in the ink and pigment industry. The toxic effects of the emissions associated to the use of printing ink containing CdTe QDs might differ from those of conventional formulations which do not integrate nanoparticles, as CdTe QDs might be emitted. Within this work, the airborne emissions of a water-soluble fluorescent ink containing polyethylene glycol (PEG)-coated CdTe QDs of 3-5 nm diameter have been characterized and studied under controlled conditions during household inkjet printing in a scenario simulating the use phase. Subsequently, the cytotoxicological potential of atomized CdTe QDs ink in an acute exposure regimen simulating an accidental, worse-case scenario has been evaluated in vitro at the air-liquid interface (ALI) using the pulmonary cell line BEAS-2B. Endpoints screened included cell viability, oxidative stress and inflammatory effects. We have observed that CdTe QDs ink at 54.7 ng/mL decreased cell viability by 25.6 % when compared with clean air after 1h of exposure; a concentration about 65 times higher was needed to observe a similar effect in submerged conditions. However, we did not observe oxidative stress or inflammatory effects. The present study integrates the development of scenarios simulating the use phase of nano-additivated inks and the direct cell exposure for in vitro effects assessment, thus implementing a life-cycle oriented approach in the assessment of the toxicity of CdTe QDs.


Assuntos
Brônquios/efeitos dos fármacos , Compostos de Cádmio/toxicidade , Células Epiteliais/efeitos dos fármacos , Tinta , Impressão/instrumentação , Pontos Quânticos/toxicidade , Telúrio/toxicidade , Aerossóis , Brônquios/metabolismo , Brônquios/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fluorescência , Humanos , Mediadores da Inflamação/metabolismo , Exposição por Inalação , Estresse Oxidativo/efeitos dos fármacos , Medição de Risco
14.
J Allergy Clin Immunol ; 147(6): 2083-2097.e6, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33852936

RESUMO

BACKGROUND: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. OBJECTIVE: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related coronavirus, SARS-CoV-1, and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells on exposure to SARS-CoV-2 in terms of complement component 3 (C3)-mediated effects. METHODS: For this, we used highly differentiated primary human 3-dimensional tissue models infected with SARS-CoV-2 patient isolates. On infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms, and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses, and transepithelial electrical resistance measurements. RESULTS: Here, we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2-infected 3-dimensional cultures secreted significantly higher levels of C3a and the proinflammatory cytokines IL-6, monocyte chemoattractant protein 1, IL-1α, and RANTES. CONCLUSIONS: Crucially, we illustrate here for the first time that targeting the anaphylotoxin receptors C3a receptor and C5a receptor in nonimmune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19.


Assuntos
Brônquios/imunologia , COVID-19/imunologia , Ativação do Complemento , Células Epiteliais/imunologia , Receptor da Anafilatoxina C5a/imunologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Brônquios/patologia , Brônquios/virologia , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Complemento C3/imunologia , Citocinas/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia
15.
PLoS Biol ; 19(3): e3001143, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33730024

RESUMO

There are currently limited Food and Drug Administration (FDA)-approved drugs and vaccines for the treatment or prevention of Coronavirus Disease 2019 (COVID-19). Enhanced understanding of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and pathogenesis is critical for the development of therapeutics. To provide insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2, we performed single-cell (sc) RNA sequencing (RNA-seq) of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface (ALI) cultures over a time course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target at the onset of infection, which we confirmed by electron and immunofluorescence microscopy. Over the course of infection, the cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III interferons (IFNs) and interleukin (IL)-6 but not IL-1. This results in expression of interferon-stimulated genes (ISGs) in both infected and bystander cells. This provides a detailed characterization of genes, cell types, and cell state changes associated with SARS-CoV-2 infection in the human airway.


Assuntos
Brônquios/patologia , COVID-19/diagnóstico , Expressão Gênica , SARS-CoV-2/isolamento & purificação , Análise de Célula Única/métodos , Adulto , Brônquios/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Células Cultivadas , Epitélio/patologia , Epitélio/virologia , Humanos , Imunidade Inata , Estudos Longitudinais , SARS-CoV-2/genética , Transcriptoma , Tropismo Viral
16.
PLoS Biol ; 19(3): e3001006, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33760807

RESUMO

Since entering the human population, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; the causative agent of Coronavirus Disease 2019 [COVID-19]) has spread worldwide, causing >100 million infections and >2 million deaths. While large-scale sequencing efforts have identified numerous genetic variants in SARS-CoV-2 during its circulation, it remains largely unclear whether many of these changes impact adaptation, replication, or transmission of the virus. Here, we characterized 14 different low-passage replication-competent human SARS-CoV-2 isolates representing all major European clades observed during the first pandemic wave in early 2020. By integrating viral sequencing data from patient material, virus stocks, and passaging experiments, together with kinetic virus replication data from nonhuman Vero-CCL81 cells and primary differentiated human bronchial epithelial cells (BEpCs), we observed several SARS-CoV-2 features that associate with distinct phenotypes. Notably, naturally occurring variants in Orf3a (Q57H) and nsp2 (T85I) were associated with poor replication in Vero-CCL81 cells but not in BEpCs, while SARS-CoV-2 isolates expressing the Spike D614G variant generally exhibited enhanced replication abilities in BEpCs. Strikingly, low-passage Vero-derived stock preparation of 3 SARS-CoV-2 isolates selected for substitutions at positions 5/6 of E and were highly attenuated in BEpCs, revealing a key cell-specific function to this region. Rare isolate-specific deletions were also observed in the Spike furin cleavage site during Vero-CCL81 passage, but these were rapidly selected against in BEpCs, underscoring the importance of this site for SARS-CoV-2 replication in primary human cells. Overall, our study uncovers sequence features in SARS-CoV-2 variants that determine cell-specific replication and highlights the need to monitor SARS-CoV-2 stocks carefully when phenotyping newly emerging variants or potential variants of concern.


Assuntos
SARS-CoV-2/fisiologia , Replicação Viral/fisiologia , Substituição de Aminoácidos , Animais , Sequência de Bases , Brônquios/patologia , COVID-19/diagnóstico , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/patologia , Células Epiteliais/virologia , Furina/metabolismo , Interações Hospedeiro-Patógeno , Humanos , SARS-CoV-2/isolamento & purificação , Células Vero
17.
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
18.
J Cell Physiol ; 236(9): 6597-6606, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33624300

RESUMO

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) binds to the angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. Akt inhibitor triciribine (TCBN) has demonstrated promising results in promoting recovery from advanced-stage acute lung injury in preclinical studies. In the current study, we tested the direct effect of TCBN on ACE2 expression in human bronchial (H441) and lung alveolar (A549) epithelial cells. Treatment with TCBN resulted in the downregulation of both messenger RNA and protein levels of ACE2 in A549 cells. Since HMGB1 plays a vital role in the inflammatory response in COVID-19, and because hyperglycemia has been linked to increased COVID-19 infections, we determined if HMGB1 and hyperglycemia have any effect on ACE2 expression in lung epithelial cells and whether TCBN has any effect on reversing HMGB1- and hyperglycemia-induced ACE2 expression. We observed increased ACE2 expression with both HMGB1 and hyperglycemia treatment in A549 as well as H441 cells, which were blunted by TCBN treatment. Our findings from this study, combined with our previous reports on the potential benefits of TCBN in the treatment of acute lung injury, generate reasonable optimism on the potential utility of TCBN in the therapeutic management of patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/tratamento farmacológico , Proteína HMGB1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células A549 , Brônquios/metabolismo , Brônquios/patologia , Brônquios/virologia , COVID-19/genética , COVID-19/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , RNA Viral/genética , Ribonucleosídeos/administração & dosagem , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade
19.
Medicine (Baltimore) ; 100(3): e24028, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546000

RESUMO

RATIONALE: Bronchial involvement alone is a rare initial manifestation of granulomatosis with polyangiitis (GPA). Herein, we report a case of refractory GPA with obstructive pneumonia caused by bronchial involvement. PATIENT CONCERNS: A 65-year-old man complained of a 2-week cough and fever. DIAGNOSES: Considering the presence of opacities and multiple consolidations in both lungs due to obstruction or stenosis on the bronchus, which did not respond to antibiotics, and proteinase-3-antineutrophil cytoplasmic autoantibody positivity, he was diagnosed with GPA. Positron emission tomography- computed tomography scan revealed no abnormal findings in the upper respiratory tract. INTERVENTIONS: He was treated with prednisolone (PSL, 50 mg/d) and intravenous cyclophosphamide. OUTCOMES: His general and respiratory symptoms improved. However, 8 weeks after PSL treatment at 20 mg/d, he developed a relapse of vasculitis along with sinusitis and hypertrophic pachymeningitis. Hence, PSL treatment was resumed to 50 mg/d, and weekly administration of rituximab was initiated. Consequently, the symptoms gradually mitigated. LESSONS: GPA with bronchial involvement is often intractable and requires careful follow-up, which should include upper respiratory tract and hypertrophic pachymeningitis assessment.


Assuntos
Obstrução das Vias Respiratórias/etiologia , Granulomatose com Poliangiite/complicações , Meningite/etiologia , Pneumonia/etiologia , Idoso , Brônquios/patologia , Progressão da Doença , Humanos , Hipertrofia , Masculino
20.
Medicine (Baltimore) ; 100(6): e24606, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578566

RESUMO

ABSTRACT: Although Candida species can cause invasive fungal diseases, such as disseminated infection and pneumonia, they rarely cause tracheobronchitis, which is often fatal.To identify the clinical characteristics of Candida tracheobronchitis, we retrospectively evaluated 8 patients who had pathologically proven Candida tracheobronchitis.Their median age was 64 (range: 51-70) years and 5 were females. Three patients had solid cancers and 5 had hematological malignancies. We classified tracheobronchitis into localized and diffuse types. Of the 8 patients, 5 had localized and 3 had diffuse tracheobronchitis. While all patients with diffuse tracheobronchitis had predisposing risk factors for invasive fungal disease, such as prolonged corticosteroid use, recent use of nucleoside analogues, or recent neutropenia (<500/m3), only 2 of the 5 with localized tracheobronchitis had predisposing risk factors. Four of the 5 patients with localized tracheobronchitis had loco-regional bronchial mucosal damage (e.g., radiation or photodynamic therapy). Although all 8 patients ultimately died, some improved with or without antifungal treatment. Two of the 5 patients (1 with localized and the other with diffuse tracheobronchitis) who received antifungal agents improved after treatment, and 1 patient with localized tracheobronchitis who did not receive antifungal treatment improved spontaneously. Two of the 3 patients with diffuse tracheobronchitis did not respond to antifungal treatment.Candida tracheobronchitis can present as both localized and diffuse types. While the former was influenced more by loco-regional mucosal damage, the latter was influenced more by the patient's immune status. The treatment outcomes were especially poor in patients with diffuse tracheobronchitis.


Assuntos
Brônquios/patologia , Bronquite/microbiologia , Candidíase Invasiva/patologia , Traqueíte/microbiologia , Idoso , Bronquite/tratamento farmacológico , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Traqueíte/tratamento farmacológico
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