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1.
Int J Mol Med ; 46(4): 1266-1273, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945352

RESUMO

The outbreak of the 2019 coronavirus disease (named, COVID­19), caused by the novel SARS­CoV­2 virus, represents a worldwide severe threat to public health. It is of the utmost importance to characterize the immune responses against the SARS­CoV­2 and the mechanisms of hyperinflammation, in order to design better therapeutic strategies for COVID­19. In the present study, a transcriptomic analysis was performed to profile the immune signatures in lung and the bronchoalveolar lavage fluid samples from COVID­19 patients and controls. Our data concordantly revealed increased humoral responses to infection. The elucidation of the host responses to SARS­CoV­2 infection may further improve our understanding of COVID­19 pathogenesis and suggest better therapeutic strategies.


Assuntos
Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Ativação Linfocitária , Pneumonia Viral/imunologia , Transcriptoma , Linfócitos B/metabolismo , Betacoronavirus/fisiologia , Líquido da Lavagem Broncoalveolar , Infecções por Coronavirus/genética , Bases de Dados Factuais , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Pandemias , Pneumonia Viral/genética
2.
Int J Mol Sci ; 21(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872332

RESUMO

Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.


Assuntos
Apoptose/efeitos dos fármacos , Betacoronavirus/fisiologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Citocinas/imunologia , Dronabinol/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Idoso , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Enterotoxinas/efeitos adversos , Feminino , Humanos , Pulmão/imunologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , MicroRNAs/genética , Pessoa de Meia-Idade , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/virologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/virologia , Transdução de Sinais/efeitos dos fármacos
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 984-989, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933631

RESUMO

OBJECTIVE: To study the influencing factors for the clinical effect of bronchoalveolar lavage (BAL) in children with Mycoplasma pneumoniae pneumonia (MPP) and atelectasis. METHODS: A total of 75 children with MPP and atelectasis were divided into a good response group with 51 children and a poor response group with 24 children according to the clinical effect of BAL treatment. LASSO logistic regression analysis was used to investigate the factors influencing the clinical effect of BAL treatment. The receiver operating characteristic (ROC) curve and restricted cubic spline model analysis were used to evaluate the value of the course of the disease at the time of BAL treatment in predicting the clinical effect of BAL treatment. RESULTS: Compared with the good response group, the poor response group had a significantly lower percentage of lymphocytes in bronchoalveolar lavage fluid, a significantly higher proportion of children with atelectasis of two or more lung lobes or stenosis of the bronchial cavity or opening caused by inflammation, and a significantly longer course of the disease at the time of BAL treatment and azithromycin treatment (P<0.05). The LASSO logistic regression analysis showed that a prolonged course of the disease at the time of BAL treatment (OR=1.23), atelectasis of two or more lung lobes (OR=11.99), and stenosis of the bronchial cavity or opening caused by inflammation (OR=5.31) were independent risk factors for poor clinical effect of BAL treatment (P<0.05). The ROC curve analysis showed that the course of disease of ≥11.5 days at the time of BAL treatment suggested a poor clinical effect of BAL treatment, with a sensitivity of 91.7% and a specificity of 54.9%. The restricted cubic spline model analysis showed that there was a non-linear dose-response relationship between the course of disease at the time of BAL treatment and the clinical effect of BAL treatment (P<0.05). CONCLUSIONS: Early BAL treatment may have a good clinical effect in children with MPP and atelectasis. Atelectasis of two or more lung lobes and inflammation-induced stenosis of the bronchial cavity or opening shown under bronchoscope may indicate a poor clinical effect of BAL treatment.


Assuntos
Pneumonia por Mycoplasma , Atelectasia Pulmonar , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , Criança , Humanos , Mycoplasma pneumoniae
4.
J Environ Pathol Toxicol Oncol ; 39(3): 213-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865913

RESUMO

Asthma is a chronic, serious allergic inflammatory disease in the airway. The inflammation in the airway is induced by the allergic T-helper 2 cells (Th2 cells), which leads to unfettered production of inflammatory cytokines. The accretion of inflammatory cells in the airway also speeds up the secretion of reactive oxygen species (ROS) and suppresses antioxidative processes. Hence, the present work aimed to study the antiasthmatic efficacy of betulin and its effect in suppressing the inflammatory markers of ovalbumin (OVA) challenged asthmatic mice. The observed results revealed that the levels of inflammatory cells including neutrophils, eosinophils, lymphocytes, and macrophages were effectively decreased by betulin treatment; furthermore, the inflammatory markers IL-4, IL-5, IL-13, and TNF-α levels were notably suppressed by betulin administration in OVA-challenged asthmatic mice. Similarly, the oral administration of betulin showed a reduction in IgE level and elevation in the IFN-γ level in bronchoalveolar lavage fluid (BALF). The elevated levels of antioxidant enzymes like catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) were observed in betulin treated mice. Furthermore, reduced levels of reactive oxygen species like NO2, NO3, and MDA were noted in the betulin treated group. Consistently, airway hyperreactivity (AHR) was depleted in the betulin administered group compared with the OVA-challenged asthmatic group. Betulin treatment was revealed to have noteworthy antiasthmatic effects mediated by the suppression of production of inflammatory cells and the expression of other inflammatory markers. Furthermore, the elevation in the level of antioxidant markers helped to disclose the original regulatory mode of betulin on asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/imunologia , Asma/metabolismo , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/citologia , Feminino , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória , Triterpenos/administração & dosagem
5.
J Environ Pathol Toxicol Oncol ; 39(3): 225-234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865914

RESUMO

Asthma is marked by chronic irritation in the airway lumen of the lungs due to the accretion of inflammatory cells that influence the regular inhalation process. An extended buildup of inflammation leads to oxidative pressure and the repression of antioxidant functions. In the current study, a potential compound, boldine, was tested for the containment of provocative markers along the path of antiasthmatic activity in an ovalbumin (OVA)-induced asthmatic mice model. As an effect, the boldine (10 and 20 mg/kg) treatment suppressed inflammatory cells such as eosinophil, macrophage, neutrophil, lymphocyte, and other inflammatory markers in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. Likewise, immunoglobulin E (IgE) levels were drastically condensed in the serum of boldine-treated animals. Levels of enzymatic and nonenzymatic antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH), were upregulated in the boldine treatment group compared to the asthmatic control group, which displays the antioxidant effects of boldine on asthmatic animals. Interestingly, the reactive oxygen species (ROS) and malonaldehyde (MDA) levels were repressed in the BALF of boldine-treated mice groups. Therefore, the effects of boldine are significant for the management of asthma, reducing the accrual of inflammatory cells, along with other inflammatory markers, while improving antioxidant markers and containing ROS. Hence, boldine may be an option for clinical trials of chronic asthma management.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Aporfinas/uso terapêutico , Asma/tratamento farmacológico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Aporfinas/administração & dosagem , Asma/imunologia , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Modelos Animais de Doenças , Eosinófilos/citologia , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória
6.
BMC Infect Dis ; 20(1): 608, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807082

RESUMO

BACKGROUND: Invasive fungal pneumonia is a severe infectious disease with high mortality in immunocompromised patients. However, the clinical diagnosis of the pathogen(s) remains difficult since microbiological evidence is difficult to acquire. CASE PRESENTATION: Here, we report a case of pulmonary fungal infection detected by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF) in a 61-year-old male with corticosteroid-treated dermatomyositis. Cytomegalovirus and influenza A virus infections were confirmed by nucleic acid detection and treated with antiviral medicine. The patient had been diagnosed with severe pneumonia and treated with empiric broad-spectrum antibacterial and antifungal drugs before bronchoscopy was performed. The patient responded poorly to those empiric treatments. Three fungi were found by NGS in the BALF, namely, Pneumocystis jirovecii, Aspergillus fumigatus and Rhizopus oryzae. After adjusting the patient's treatment plan according to the NGS results, he improved significantly. CONCLUSIONS: This case highlights the combined application of NGS and traditional tests in the clinical diagnosis of pulmonary invasive fungal disease. NGS is proposed as an important adjunctive diagnostic approach for identifying uncommon pathogens.


Assuntos
Líquido da Lavagem Broncoalveolar/microbiologia , Dermatomiosite/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Pneumopatias Fúngicas/diagnóstico , Antifúngicos/uso terapêutico , Aspergillus fumigatus/genética , Aspergillus fumigatus/isolamento & purificação , DNA Fúngico/química , DNA Fúngico/metabolismo , Dermatomiosite/complicações , Humanos , Pulmão/diagnóstico por imagem , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/microbiologia , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii/genética , Pneumocystis carinii/isolamento & purificação , Rhizopus/genética , Rhizopus/isolamento & purificação , Tomografia Computadorizada por Raios X
7.
Mikrobiyol Bul ; 54(3): 418-428, 2020 Jul.
Artigo em Turco | MEDLINE | ID: mdl-32755518

RESUMO

Pneumocystis jirovecii is a human-specific species and causes fatal infections like P.jirovecii pneumonia (PCP) in immunocompromised persons. Although direct microscopy is the gold standard in the diagnosis of the microorganism, molecular methods such as polymerase chain reaction (PCR) are needed in non-human immune deficiency virus (HIV) immunosuppresive patients with low P.jirovecii burden. In this study, we aimed to evaluate the value of real-time PCR (Rt-PCR) in the laboratory diagnosis of P.jirovecii. Bronchoalveolar lavage (BAL) specimens of 658 patients sent to Dokuz Eylul University Hospital Central Medical Parasitology Laboratory on suspicion of PCP were included in the study. BAL fluids were evaluated for identification of P.jirovecii mitochondrial gene coding ribosomal large subunit (mtLSUrRNA) using Rt-PCR. In addition, Giemsa and Gomori's methenamine silver (GMG) staining assays were applied to all samples and nested PCR (n-PCR) assay was applied to positive samples detected by real time PCR. Ninety-two (14.3%) of these samples were positive by Rt-PCR. Of these 92 patients, 85 (92.4%) were positive with n-PCR. Only seven of the specimens had P.jirovecii cysts and trophozoites with microscopic examination. The mean cycle threshold (CT ) value of Rt-PCR positive patients was 29.7 (18.17 ≤ CT ≤ 37.96). P.jirovecii load in these patients was calculated as 2.6 x 101-6.15 x 107 copies/ml. The difference between the mean CT values of n-PCR positive and negative results was statistically significant (p< 0.01). The CT values of Rt-PCR of the samples with positive microscopy were; 18.2, 20.9, 22.2, 24.3, 24.7, 26.5, 29.7. The difference between the CT means of the samples with positive and negative microscopy was statistically significant (p< 0.05). When positive patients were grouped according to their diagnosis; the lowest mean CT value (CTmean= 24.8) was found in HIV-positive patients. On the other hand, CT values were found to be significantly lower in the organ transplantation patients (CTmean= 26.15) and in the collagen-vascular-inflammatory patient group (CTmean= 27.8). This study demonstrated that Rt-PCR was the effective method in the diagnosis of P.jirovecii in the laboratory. Conventional n-PCR method was found to be more unsuccessful than Rt-PCR in the presence of very low density organism; direct microscopy is generally found to be positive in samples with a higher burden of P.jirovecii.


Assuntos
Pneumocystis carinii , Pneumonia por Pneumocystis , Reação em Cadeia da Polimerase em Tempo Real , Líquido da Lavagem Broncoalveolar/microbiologia , Técnicas de Laboratório Clínico/normas , Humanos , Pneumocystis carinii/genética , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/microbiologia , Reação em Cadeia da Polimerase em Tempo Real/normas , Sensibilidade e Especificidade
8.
Chem Biol Interact ; 329: 109210, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32726580

RESUMO

Cigarette smoke is a complex mixture capable of triggering inflammation and oxidative damage in animals at pulmonary and systemic levels. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) reduces tissue injury associated with inflammation in vivo by mechanisms that are not completely understood. Here we evaluated the effect of tempol on inflammation and oxidative damage induced by acute exposure to cigarette smoke in vivo. Male C57BL/6 mice (n = 32) were divided into 4 groups (n = 8 each): 1) control group exposed to ambient air (GC), 2) animals exposed to cigarette smoke for 5 days (CSG), mice treated 3) prior or 4) concomitantly with tempol (50 mg/kg/day) and exposed to cigarette smoke for 5 days. The results showed that the total number of leukocytes and neutrophils increased in the respiratory tract and lung parenchyma of mice exposed to cigarette smoke. Likewise, MPO levels and activity as well as lipid peroxidation and lung protein nitration and carbonylation also increased. Administration of tempol before or during exposure to cigarette smoke inhibited all the above parameters. Tempol also reduced the pulmonary expression of the inflammatory cytokines Il-6, Il-1ß and Il-17 to basal levels and of Tnf-α by approximately 50%. In contrast, tempol restored Il-10 and Tgf-ß levels and enhanced the expression of Nrf2-associated genes, such as Ho-1 and Gpx2. Accordingly, total GPx activity increased in lung homogenates of tempol-treated animals. Taken together, our results show that tempol protects mouse lungs from inflammation and oxidative damage resulting from exposure to cigarette smoke, likely through reduction of leukocyte infiltration and increased transcription of some of the Nrf2-controlled genes.


Assuntos
Óxidos N-Cíclicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fumar/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Interleucina-10/genética , Interleucina-10/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Nitritos/análise , Peroxidase/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Marcadores de Spin , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
10.
Elife ; 92020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32633718

RESUMO

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.


Assuntos
Bradicinina/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/metabolismo , Betacoronavirus/isolamento & purificação , Líquido da Lavagem Broncoalveolar/química , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/virologia , Renina/metabolismo , Transcriptoma , Vasodilatação
11.
J Crit Care ; 59: 149-155, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32674001

RESUMO

PURPOSE: Pathological data of critical ill COVID-19 patients is essential in the search for optimal treatment options. MATERIAL AND METHODS: We performed postmortem needle core lung biopsies in seven patients with COVID-19 related ARDS. Clinical, radiological and microbiological characteristics are reported together with histopathological findings. MEASUREMENT AND MAIN RESULTS: Patients age ranged from 58 to 83 years, five males and two females were included. Time from hospital admission to death ranged from 12 to 36 days, with a mean of 20 ventilated days. ICU stay was complicated by pulmonary embolism in five patients and positive galactomannan on bronchoalveolar lavage fluid in six patients, suggesting COVID-19 associated pulmonary aspergillosis. Chest CT in all patients showed ground glass opacities, commonly progressing to nondependent consolidations. We observed four distinct histopathological patterns: acute fibrinous and organizing pneumonia, diffuse alveolar damage, fibrosis and, in four out of seven patients an organizing pneumonia. None of the biopsy specimens showed any signs of invasive aspergillosis. CONCLUSIONS: In this case series common late histopathology in critically ill COVID patients is not classic DAD but heterogeneous with predominant pattern of organizing pneumonia. Postmortem biopsy investigations in critically COVID-19 patients with probable COVID-19 associated pulmonary aspergillosis obtained no evidence for invasive aspergillosis.


Assuntos
Infecções por Coronavirus/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Aspergilose Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Betacoronavirus , Biópsia , Biópsia com Agulha de Grande Calibre , Líquido da Lavagem Broncoalveolar/química , Coinfecção , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Estado Terminal , Feminino , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Masculino , Mananas/metabolismo , Pessoa de Meia-Idade , Pandemias , Fenótipo , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/diagnóstico por imagem , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Adulto/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Adulto/etiologia , Tomografia Computadorizada por Raios X
12.
Zhongguo Zhong Yao Za Zhi ; 45(11): 2619-2625, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32627497

RESUMO

To observe the efficacy of San'ao Decoction(SAD) in diffusing the lung and relieving asthma, and its intervention effect on the expression of transient receptor potential V2(TRPV2) during alleviating asthma, this study replicated an ovalbumin(OVA)-induced asthmatic mice model, and investigated the intervention effect of SAD on the airway inflammation and airway hyperresponsiveness. The regulatory mechanisms of SAD on the mRNA and protein expressions of TRPV2 in lung tissues and the levels of interleukin-4(IL-4),-10(IL-10), nerve growth factor(NGF), prostaglandin D_2(PGD_2) in bronchoalveolar lavage fluid(BALF) were discussed. Compared with the control group, the model group showed typical asthmatic phenotype, the level of eosinophils(EOS) in peripheral blood and BALF as well as the airway hyperresponsiveness were increased(P<0.01), and pathological damage in lung tissue was serious. The mRNA and protein expressions of TRPV2 in lung tissue were increased significantly, while the levels of IL-4, IL-10, NGF and PGD_2 in BALF were elevated(P<0.05,P<0.01). SAD could relieve bronchial asthma manifested as repaired lung patholo-gical changes(P<0.05), reduce the level of EOS in blood and BALF(P<0.05, P<0.01), and improve pulmonary resistance and lung compliance(P<0.05, P<0.01). SAD could also regulate the inflammatory cytokine levels of IL-4, IL-10, NGF, PGD_2 in BALF, and reduce the gene and protein expression of TRPV2 in the lung tissue(P<0.05, P<0.01). It is verified that SAD could reduce the lung inflammation, and improve lung function in asthmatic mice. The regulatory mechanism of SAD on asthma induced by OVA might be related to the regulation of TRPV2 expression and the induced decrease of Th2-related cytokines and neuropeptides, which provides the evidences for the treatment of asthma with SAD.


Assuntos
Asma , Medicamentos de Ervas Chinesas , Animais , Líquido da Lavagem Broncoalveolar , Canais de Cálcio , Modelos Animais de Doenças , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Canais de Cátion TRPV
13.
Pathog Dis ; 78(4)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667665

RESUMO

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5-7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Ribavirina/farmacologia , Saquinavir/farmacologia , Líquido da Lavagem Broncoalveolar/química , Degranulação Celular/imunologia , Endocitose/imunologia , Perfilação da Expressão Gênica , Humanos , Lisossomos/imunologia , Simulação de Acoplamento Molecular , Ativação de Neutrófilo/imunologia , Pandemias , Transcriptoma
14.
Sci Total Environ ; 742: 140545, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629262

RESUMO

Despite growing applications of molybdenum(IV) sulfide (MoS2) nano- and microparticles in their capacity as lubricants, data available on their safety are scarce. In this study the effect of MoS2 nano- and microparticles after single intratracheal instillation in rats has been analyzed. MoS2 suspensions were administered at the dose of 1.5 or 5 mg MoS2/kg body weight. The analysis after 24 h and 7 days included: blood biochemical parameters, hematological parameters, bronchoalveolar lavage fluid (BALF) parameters with selected cytokines, a comet assay and histopathological examination. In the BALF cells isolated from animals exposed to both forms, numerous macrophages loaded with particles were observed. The hematological and biochemical parameters analyzed 24 h or 7 days after the exposure to both forms did not show any biologically meaningful changes. Comet assay results showed no genotoxic effect. The histopathological analysis of the lungs revealed inflammatory changes in the respiratory system of the treated animals, slightly stronger for the microsized form. The deposits of particles observed in the lung tissue up to 7 days after the instillation indicate their easy penetration through the epithelium and prolonged clearance. Concluding, no meaningful acute systemic effects were observed, however some pathological changes were noted in the lung tissue.


Assuntos
Pulmão , Molibdênio , Animais , Líquido da Lavagem Broncoalveolar , Dissulfetos , Contagem de Leucócitos , Ratos
15.
Front Immunol ; 11: 1636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670298

RESUMO

The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/sangue , Infecções por Coronavirus/imunologia , Interferon Tipo I/sangue , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Infecções por Coronavirus/patologia , Perfilação da Expressão Gênica , Humanos , Inflamação/virologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Neutrófilos/citologia , Fosforilação Oxidativa , Pandemias , Pneumonia Viral/patologia , Transcriptoma/genética
16.
Medicine (Baltimore) ; 99(28): e20930, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664089

RESUMO

Surgical lung biopsy is regarded as the golden standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). Here, we attempted to show the diagnostic accuracy of multidisciplinary classifications based on transbronchial pathology including transbronchial lung cryobiopsy (TBLC) , bronchoalveolar lavage fluid (BALF) and endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA).Patients with suspected interstitial lung diseases admitted from June 1, 2016 to December 31, 2018 were involved. Patients with known causes of interstitial lung diseases and typical idiopathic pulmonary fibrosis diagnosed through clinical, radiological information were excluded. Patients with atypical idiopathic pulmonary fibrosis and possible IIPs accepted transbronchial pathological evaluation. Initial multidisciplinary diagnosis (MDD) classifications were made depending on clinical, radiological and transbronchial pathological information by a multidisciplinary team (MDT). The final MDD classifications were confirmed by subsequent therapeutic effects. All patients were followed up for at least 6 months.A total of 70 patients were finally involved. The samples of lung parenchyma extracted through TBLC were enough for confirmation of pathological diagnoses in 68.6% (48/70) cases. Samples of 6 cases were extracted by EBUS-TBNA. Bacteriological diagnoses were positive in 1 case by BALF. Pathological diagnoses of 77.1% (54/70) cases were achieved through TBLC, EBUS-TBNA and BALF. During the follow up study, the pulmonary lesions of 60% patients were improved, 11.43% were relapsed when glucocorticoid was reduced to small dose or withdrawal, 14.29% were leveled off and 8.57% were progressed. The diagnoses of 4 patients with progressed clinical feature were revised. As a result, 94.3% initial MDD classifications based on transbronchial pathology were consistent with the final MDD, and the difference of diagnostic yield wasn't significant between initial and final MDD (Z = -1.414, P = .157).Classifications of IIPs based on transbronchial pathology were useful and quite agreed with final MDD.


Assuntos
Broncoscopia/métodos , Pneumonias Intersticiais Idiopáticas/classificação , Pneumonias Intersticiais Idiopáticas/patologia , Biópsia Guiada por Imagem/métodos , Idoso , Biópsia/tendências , Líquido da Lavagem Broncoalveolar/microbiologia , Broncoscopia/efeitos adversos , Broncoscopia/tendências , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Comunicação Interdisciplinar , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Tomografia Computadorizada por Raios X/métodos
17.
Eur Rev Med Pharmacol Sci ; 24(10): 5830-5841, 2020 May.
Artigo em Inglês | MEDLINE | ID: covidwho-547471

RESUMO

OBJECTIVE: Recent worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of respiratory coronavirus disease 2019 (COVID-19), is a current, ongoing life-threatening crisis, and international public health emergency. The early diagnosis and management of the disease remains a major challenge. In this review, we aim to summarize the updated epidemiology, causes, clinical manifestation and diagnosis, as well as prevention and control of the novel coronavirus SARS-CoV-2. MATERIALS AND METHODS: A broad search of the literature was performed in "PubMed" "Medline" "Web of Science", "Google Scholar" and "World Health Organization-WHO" using the keywords "severe acute respiratory syndrome coronavirus", "2019-nCoV", "COVID-19, "SARS", "SARS-CoV-2" "Epidemiology" "Transmission" "Pathogenesis" "Clinical Characteristics". We reviewed and documented the information obtained from literature on epidemiology, pathogenesis and clinical appearances of SARS-CoV-2 infection. RESULTS: The global cases of COVID-19 as of April 2, 2020, have risen to more than 900,000 and morbidity has reached more than 47,000. The incidence rate for COVID-19 has been predicted to be higher than the previous outbreaks of other coronavirus family members, including those of SARS-CoV and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The main clinical presentation of SARS-CoV-2 infection ranges from asymptomatic stages to severe lower respiratory infection in the form of pneumonia. Most of the patients also presented with fever, cough, sore throat, headache, fatigue, myalgia and breathlessness. Individuals at higher risk for severe illness include elderly people and patients with a weakened immune system or that are suffering from an underlying chronic medical condition like hypertension, diabetes mellitus, cancer, respiratory illness or cardiovascular diseases. CONCLUSIONS: SARS-Cov-2 has emerged as a worldwide threat, currently affecting 170 countries and territories across the globe. There is still much to be understood regarding SARS-CoV-2 about its virology, epidemiology and clinical management strategies; this knowledge will be essential to both manage the current pandemic and to conceive comprehensive measures to prevent such outbreaks in the future.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Líquido da Lavagem Broncoalveolar/virologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Quarentena , RNA Viral/genética , RNA Viral/metabolismo , Escarro/virologia
18.
Respir Res ; 21(1): 154, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552811

RESUMO

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.


Assuntos
Infecções por Coronavirus/epidemiologia , Sistemas Eletrônicos de Liberação de Nicotina , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia/metabolismo , Vaping/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Gasometria , Western Blotting , Líquido da Lavagem Broncoalveolar , Citocinas/análise , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pandemias , Pneumonia/fisiopatologia , Distribuição Aleatória , Valores de Referência , Papel (figurativo) , Síndrome Respiratória Aguda Grave/epidemiologia , Transdução de Sinais/genética
20.
J Allergy Clin Immunol ; 146(2): 315-324.e7, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531372

RESUMO

BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.


Assuntos
Asma/epidemiologia , Asma/genética , Infecções por Coronavirus/epidemiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Adolescente , Adulto , Asma/classificação , Asma/imunologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Brônquios/imunologia , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Coortes , Infecções por Coronavirus/virologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Receptores Virais/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Linfócitos T/classificação , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Estados Unidos/epidemiologia
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