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2.
Nat Commun ; 11(1): 4938, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: covidwho-811573

RESUMO

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fumarato de Dimetilo/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Replicação Viral/efeitos dos fármacos
3.
Nat Commun ; 11(1): 4968, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: covidwho-811547

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread to become a worldwide emergency. Early identification of patients at risk of progression may facilitate more individually aligned treatment plans and optimized utilization of medical resource. Here we conducted a multicenter retrospective study involving patients with moderate COVID-19 pneumonia to investigate the utility of chest computed tomography (CT) and clinical characteristics to risk-stratify the patients. Our results show that CT severity score is associated with inflammatory levels and that older age, higher neutrophil-to-lymphocyte ratio (NLR), and CT severity score on admission are independent risk factors for short-term progression. The nomogram based on these risk factors shows good calibration and discrimination in the derivation and validation cohorts. These findings have implications for predicting the progression risk of COVID-19 pneumonia patients at the time of admission. CT examination may help risk-stratification and guide the timing of admission.


Assuntos
Infecções por Coronavirus/diagnóstico , Progressão da Doença , Pneumonia Viral/diagnóstico , Pneumonia , Tomografia Computadorizada por Raios X/métodos , Adulto , Betacoronavirus , China , Técnicas de Laboratório Clínico , Coinfecção , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Feminino , Hospitalização , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Análise de Regressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
4.
BMC Infect Dis ; 20(1): 747, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: covidwho-846600

RESUMO

BACKGROUND: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking. METHODS: A retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People's Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed. RESULTS: The study found that fibrinogen (FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100 and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P < 0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19. CONCLUSIONS: Based on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.


Assuntos
Técnicas de Laboratório Clínico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Adulto , Betacoronavirus/patogenicidade , China/epidemiologia , Infecções por Coronavirus/diagnóstico , Feminino , Fibrinogênio/análise , Hospitalização , Humanos , Pulmão/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Estudos Retrospectivos , Sensibilidade e Especificidade
5.
Nat Commun ; 11(1): 4913, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004813

RESUMO

Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma de Pulmão/patologia , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Dinaminas/metabolismo , Feminino , Técnicas de Inativação de Genes , Humanos , Proteínas com Domínio LIM/genética , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Prolina/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirrolina Carboxilato Redutases/metabolismo , Análise de Sobrevida
6.
PLoS One ; 15(10): e0239692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031409

RESUMO

BACKGROUND: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. PATIENTS AND TREATMENT: Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. RESULTS: The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. CONCLUSION: Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.


Assuntos
Adenosina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adenosina/administração & dosagem , Administração por Inalação , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Feminino , Hospitalização , Humanos , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos
7.
Nat Commun ; 11(1): 4938, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009401

RESUMO

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fumarato de Dimetilo/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Replicação Viral/efeitos dos fármacos
8.
Nat Commun ; 11(1): 4968, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009413

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread to become a worldwide emergency. Early identification of patients at risk of progression may facilitate more individually aligned treatment plans and optimized utilization of medical resource. Here we conducted a multicenter retrospective study involving patients with moderate COVID-19 pneumonia to investigate the utility of chest computed tomography (CT) and clinical characteristics to risk-stratify the patients. Our results show that CT severity score is associated with inflammatory levels and that older age, higher neutrophil-to-lymphocyte ratio (NLR), and CT severity score on admission are independent risk factors for short-term progression. The nomogram based on these risk factors shows good calibration and discrimination in the derivation and validation cohorts. These findings have implications for predicting the progression risk of COVID-19 pneumonia patients at the time of admission. CT examination may help risk-stratification and guide the timing of admission.


Assuntos
Infecções por Coronavirus/diagnóstico , Progressão da Doença , Pneumonia Viral/diagnóstico , Pneumonia , Tomografia Computadorizada por Raios X/métodos , Adulto , Betacoronavirus , China , Técnicas de Laboratório Clínico , Coinfecção , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Feminino , Hospitalização , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Análise de Regressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
9.
PLoS One ; 15(10): e0240078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017451

RESUMO

BACKGROUND: To evaluate chest-computed-tomography (CT) scans in coronavirus-disease-2019 (COVID-19) patients for signs of organizing pneumonia (OP) and microinfarction as surrogate for microscopic thromboembolic events. METHODS: Real-time polymerase-chain-reaction (RT-PCR)-confirmed COVID-19 patients undergoing chest-CT (non-enhanced, enhanced, pulmonary-angiography [CT-PA]) from March-April 2020 were retrospectively included (COVID-19-cohort). As control-groups served 175 patients from 2020 (cohort-2020) and 157 patients from 2019 (cohort-2019) undergoing CT-PA for pulmonary embolism (PE) during the respective time frame at our institution. Two independent readers assessed for presence and location of PE in all three cohorts. In COVID-19 patients additionally parenchymal changes typical of COVID-19 pneumonia, infarct pneumonia and OP were assessed. Inter-reader agreement and prevalence of PE in different cohorts were calculated. RESULTS: From 68 COVID-19 patients (42 female [61.8%], median age 59 years [range 32-89]) undergoing chest-CT 38 obtained CT-PA. Inter-reader-agreement was good (k = 0.781). On CT-PA, 13.2% of COVID-19 patients presented with PE whereas in the control-groups prevalence of PE was 9.1% and 8.9%, respectively (p = 0.452). Up to 50% of COVID-19 patients showed changes typical for OP. 21.1% of COVID-19 patients suspected with PE showed subpleural wedge-shaped consolidation resembling infarct pneumonia, while only 13.2% showed visible filling defects of the pulmonary artery branches on CT-PA. CONCLUSION: Despite the reported hypercoagulability in critically ill patients with COVID-19, we did not encounter higher prevalence of PE in our patient cohort compared to the control cohorts. However, patients with suspected PE showed a higher prevalence of lung changes, resembling patterns of infarct pneumonia or OP and CT-signs of pulmonary-artery hypertension.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Artéria Pulmonar/patologia , Infarto Pulmonar/diagnóstico por imagem , Tromboembolia/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
10.
Medicine (Baltimore) ; 99(40): e22458, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019434

RESUMO

RATIONALE: Endo-bronchial ultrasound guided trans-bronchial needle aspiration (EBUS-TBNA) has been widely accepted as a safe and efficient technique for diagnosing patients with mediastinal/hilar lymphadenopathy and suspected cases of lung cancer. An effective anesthetic technique should provide comfort and quick recovery of patients while allowing the clinicians to obtain adequate tissue sample. Therefore we combined mask ventilation support (SIMV), BIS monitoring, and short-acting medication to achieve the effect mentioned above. PATIENT CONCERNS: In this report, both patients had lung mass accompanied by cough that lasted for >2 weeks, and were admitted to hospital for further diagnosis and treatment to clarify the nature of the mass. To make a definite diagnosis, EBUS-TBNA examination was performed under general anesthesia. Both patients had no salient past history. DIAGNOSIS: Case 1 was diagnosed as tumor or pneumonia based on the right lung shadow. Case 2 was diagnosed with squamous cell carcinoma of the right lung with right hilar lymph node metastasis. The diagnostic results of both patients were based on pathological examination of tissues obtained by EBUS-TBNA, of which case 1 required further confirmation by lung biopsy. INTERVENTION: Both the patients received antibiotic treatment before EBUS-TBNA. We used the mask ventilation supported by SIMV mode without using muscle relaxant, thus providing a guarantee for rapid and high-quality recovery of patients. OUTCOMES: During EBUS-TBNA, the vital signs of the 2 patients were stable. Both patients recovered within 5 minutes after we stopped pumping general anesthetics. None of the patient complained of any discomfort and felt comfortable. No complications occurred during and 3 months after EBUS-TBNA examination. LESSONS: The obtained results showed that this anesthesia scheme can provide appropriate depth of anesthesia for patients undergoing EBUS-TBNA examination, while ensuring rapid and high-quality recovery of patients.


Assuntos
Anestesia Geral/métodos , Biópsia por Agulha Fina/métodos , Biópsia Guiada por Imagem , Administração Intravenosa , Feminino , Humanos , Intubação Intratraqueal/efeitos adversos , Máscaras Laríngeas , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade
11.
BMC Infect Dis ; 20(1): 747, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046047

RESUMO

BACKGROUND: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking. METHODS: A retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People's Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed. RESULTS: The study found that fibrinogen (FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100 and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P < 0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19. CONCLUSIONS: Based on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.


Assuntos
Técnicas de Laboratório Clínico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Adulto , Betacoronavirus/patogenicidade , China/epidemiologia , Infecções por Coronavirus/diagnóstico , Feminino , Fibrinogênio/análise , Hospitalização , Humanos , Pulmão/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Estudos Retrospectivos , Sensibilidade e Especificidade
13.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(5): 609-612, 2020 May 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879115

RESUMO

The coronavirus disease 2019 (COVID-19) is a new infectious disease, which has a strong virus transmission power and complex transmission routes. This disease is prone to outbreak of cluster infection. It is difficult for medical workers to provide a better perioperative treatment for surgery patient with COVID-19 while avoiding hospital spread effectively. The perioperative management for such patients needs to fully consider the possible lung injury factors caused by anesthesia and surgery. It also needs to choose the suitable timing of the operation, carry out preoperative infection screening and evaluation, and implement lung protection strategies during and after the operation to avoid aggravating the lung injury. Meanwhile, it is necessary to pay more attention to infection prevention and control in order to avoid nosocomial infection.


Assuntos
Infecções por Coronavirus/terapia , Assistência Perioperatória , Pneumonia Viral/terapia , Betacoronavirus , Infecção Hospitalar/prevenção & controle , Humanos , Pulmão/patologia , Pulmão/virologia , Pandemias
14.
J Korean Med Sci ; 35(34): e316, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32864912

RESUMO

BACKGROUND: The predictors of poor prognosis in patients with coronavirus disease 2019 (COVID-19) using computed tomography (CT) have not been investigated in a large cohort. Therefore, the purpose of this study was to investigate the adverse initial CT features to predict poor prognosis in COVID-19. METHODS: From February to April 2020, 281 COVID-19 patients who underwent CT at the time of admission were included. We divided the patients into the severe and non-severe disease groups. The severe group included patients with severe pneumonia or critical events. Intensive care unit admission or death were the critical events in this study. We compared the clinical and CT findings between the severe and non-severe groups and investigated the prognostic factors and critical events of the severe group using the regression analysis. RESULTS: Among the 281 patients, 36 (12.8%) patients were in the severe group and 245 (87.2%) patients were in the non-severe group. Critical events occurred in 10 patients (3.6%). In the severe group, patients showed significantly more pneumonia with consolidation, crazy-paving appearance, pleural effusion, and higher CT scores than those in the non-severe group (all, P < 0.05). In the multivariate regression, pleural effusion (odds ratio [OR], 8.96; 95% confidence interval [CI], 1.81-44.42; P = 0.007), CT score > 5 (OR, 3.70; 95% CI, 1.44-9.53; P = 0.007), old age (> 77 years, OR, 9.96; 95% CI, 3.78-26.28; P < 0.001), and elevated C-reactive protein (OR, 4.15; 95% CI, 1.62-10.6; P = 0.003) were significant prognostic factors of severe disease. CT score > 5 (OR, 7.29; 95% CI, 1.37-38.68; P = 0.020), pleural effusion (OR, 5.67; 95% CI, 1.04-30.8; P = 0.045) and old age (OR, 8.6; 95% CI, 1.80-41.0; P = 0.007) were also significant predictors of critical events. CONCLUSION: Pleural effusion and the extent of pneumonia on initial CT scans are associated with poor prognosis in patients with COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/patologia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Betacoronavirus , Proteína C-Reativa/análise , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
15.
Eur J Immunol ; 50(9): 1283-1294, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32910469

RESUMO

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Isotipos de Imunoglobulinas/sangue , Pulmão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/classificação , Linfócitos B/virologia , Betacoronavirus/imunologia , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Proliferação de Células , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Estudos Transversais , Citocinas/genética , Citocinas/imunologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Humanos , Imunidade Humoral , Memória Imunológica , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Cultura Primária de Células , Índice de Gravidade de Doença , Análise de Sobrevida
16.
Nat Commun ; 11(1): 4400, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879306

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmitted through the respiratory route, but potential extra-respiratory routes of SARS-CoV-2 transmission remain uncertain. Here we inoculated five rhesus macaques with 1 × 106 TCID50 of SARS-CoV-2 conjunctivally (CJ), intratracheally (IT), and intragastrically (IG). Nasal and throat swabs collected from CJ and IT had detectable viral RNA at 1-7 days post-inoculation (dpi). Viral RNA was detected in anal swabs from only the IT group at 1-7 dpi. Viral RNA was undetectable in tested swabs and tissues after intragastric inoculation. The CJ infected animal had a higher viral load in the nasolacrimal system than the IT infected animal but also showed mild interstitial pneumonia, suggesting distinct virus distributions. This study shows that infection via the conjunctival route is possible in non-human primates; further studies are necessary to compare the relative risk and pathogenesis of infection through these different routes in more detail.


Assuntos
Betacoronavirus/fisiologia , Túnica Conjuntiva/virologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pneumonia Viral/virologia , Animais , Anticorpos Antivirais , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Intestino Grosso/virologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino , Cavidade Nasal/virologia , Pandemias , Pneumonia Viral/patologia , RNA Viral/análise , RNA Viral/genética , Traqueia/virologia , Carga Viral , Replicação Viral
17.
J Am Heart Assoc ; 9(18): e017368, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896206

RESUMO

E-cigarette or vaping product use-associated lung injury was recognized in the United States in the summer of 2019 and is typified by acute respiratory distress, shortness of breath, chest pain, cough, and fever, associated with vaping. It can mimic many of the manifestations of coronavirus disease 2019 (COVID-19). Some investigators have suggested that E-cigarette or vaping product use-associated lung injury was due to tetrahydrocannabinol or vitamin E acetate oil mixed with the electronic cigarette liquid. In experimental rodent studies initially designed to study the effect of electronic cigarette use on the cardiovascular system, we observed an E-cigarette or vaping product use-associated lung injury-like condition that occurred acutely after use of a nichrome heating element at high power, without the use of tetrahydrocannabinol, vitamin E, or nicotine. Lung lesions included thickening of the alveolar wall with foci of inflammation, red blood cell congestion, obliteration of alveolar spaces, and pneumonitis in some cases; bronchi showed accumulation of fibrin, inflammatory cells, and mucus plugs. Electronic cigarette users should be cautioned about the potential danger of operating electronic cigarette units at high settings; the possibility that certain heating elements may be deleterious; and that E-cigarette or vaping product use-associated lung injury may not be dependent upon tetrahydrocannabinol, vitamin E, or nicotine.


Assuntos
Dronabinol/toxicidade , Vapor do Cigarro Eletrônico/toxicidade , Sistemas Eletrônicos de Liberação de Nicotina , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Pneumonia/induzido quimicamente , Vaping/efeitos adversos , Vitamina E/toxicidade , Animais , Exposição por Inalação , Pulmão/patologia , Lesão Pulmonar/patologia , Modelos Animais , Óleos , Pneumonia/patologia , Ratos , Medição de Risco
18.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
19.
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
20.
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
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