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1.
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
2.
J Neurovirol ; 26(5): 631-641, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32876900

RESUMO

A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.


Assuntos
Betacoronavirus/patogenicidade , Encefalopatias/complicações , Infecções por Coronavirus/complicações , Transtornos do Olfato/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Acidente Vascular Cerebral/complicações , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/imunologia , Encefalopatias/patologia , Encefalopatias/virologia , Efeito Espectador , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/virologia , Neurônios/patologia , Neurônios/virologia , Transtornos do Olfato/imunologia , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia
3.
Nat Commun ; 11(1): 4883, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985528

RESUMO

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Modelos Biológicos , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Circulação Pulmonar/fisiologia , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Humanos , Hipóxia/terapia , Pneumopatias/terapia , Conceitos Matemáticos , Modelos Cardiovasculares , Oxigenoterapia , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Tempo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Relação Ventilação-Perfusão/fisiologia
4.
Sci Adv ; 6(31)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32937590

RESUMO

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Síndrome da Liberação de Citocina/diagnóstico , Proteínas da Matriz Extracelular/imunologia , Leucócitos Mononucleares/imunologia , Pneumonia Viral/diagnóstico , Processamento de Proteína Pós-Traducional , Insuficiência Respiratória/diagnóstico , Fator de Crescimento Transformador beta/imunologia , Acetilação , Anticorpos Neutralizantes/farmacologia , Betacoronavirus/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/genética , Expressão Gênica , Humanos , Unidades de Terapia Intensiva , Contagem de Leucócitos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Lisina/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Cultura Primária de Células , Prognóstico , Insuficiência Respiratória/sangue , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/patologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/genética
5.
Molecules ; 25(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987757

RESUMO

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fármacos do Sistema Respiratório/uso terapêutico , Doença Aguda , Anti-Inflamatórios/síntese química , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptídeos/síntese química , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/virologia , Fármacos do Sistema Respiratório/síntese química , Relação Estrutura-Atividade
6.
J Exp Med ; 217(12)2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-32926097

RESUMO

Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease-19 (COVID-19). While SARS-CoV-2-triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19-unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/fisiologia , Pulmão/irrigação sanguínea , Pulmão/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Idoso , Infecções por Coronavirus/patologia , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia
8.
Br J Radiol ; 93(1113): 20200718, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735457

RESUMO

A potential link between mortality, D-dimer values and a prothrombotic syndrome has been reported in COVID-19 patients. The National Institute for Public Health of the Netherlands published a report for guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19 with a new vascular disease concept. The analysis of all available current medical, laboratory and imaging data on COVID-19 confirms that symptoms and diagnostic tests can not be explained by impaired pulmonary ventilation. Further imaging and pathological investigations confirm that the COVID-19 syndrome is explained by perfusion disturbances first in the lung, but consecutively in all organs of the body. Damage of the microvasculature by SARS 1 and SARS 2 (COVID-19) viruses causes microthrombotic changes in the pulmonary capillaries and organs leading to macrothrombosis and emboli. Therefore anticoagulant profylaxis, close lab and CT imaging monitoring and early anticoagulant therapy are indicated.


Assuntos
Betacoronavirus , Angiografia por Tomografia Computadorizada/métodos , Infecções por Coronavirus/diagnóstico por imagem , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Humanos , Países Baixos , Pandemias
9.
Adv Biol Regul ; 77: 100735, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773098

RESUMO

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Análise de Sobrevida
10.
Adv Biol Regul ; 77: 100744, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773104
11.
PLoS One ; 15(8): e0237939, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813730

RESUMO

INTRODUCTION: Quantitative analysis of multi-detector computed tomography (MDCT) plays an increasingly important role in assessing airway disease. Depending on the algorithms used, airway dimensions may be over- or underestimated, primarily if contrast material was used. Therefore, we tested a modified integral-based method (IBM) to address this problem. METHODS: Temporally resolved cine-MDCT was performed in seven ventilated pigs in breath-hold during iodinated contrast material (CM) infusion over 60s. Identical slices in non-enhanced (NE), pulmonary-arterial (PA), systemic-arterial (SA), and venous phase (VE) were subjected to an in-house software using a standard and a modified IBM. Total diameter (TD), lumen area (LA), wall area (WA), and wall thickness (WT) were measured for ten extra- and six intrapulmonary airways. RESULTS: The modified IBM significantly reduced TD by 7.6%, LA by 12.7%, WA by 9.7%, and WT by 3.9% compared to standard IBM on non-enhanced CT (p<0.05). Using standard IBM, CM led to a decrease of all airway parameters compared to NE. For example, LA decreased from 80.85±49.26mm2 at NE, to 75.14±47.96mm2 (-7.1%) at PA (p<0.001), 74.96±48.55mm2 (-7.3%) at SA (p<0.001), and to 78.95±48.94mm2 (-2.4%) at VE (p = 0.200). Using modified IBM, the differences were reduced to -3.1% at PA, -2.9% at SA and -0.7% at VE (p<0.001; p<0.001; p = 1.000). CONCLUSIONS: The modified IBM can optimize airway wall segmentation and reduce the influence of CM on quantitative CT. This allows a more precise measurement as well as potentially the comparison of enhanced with non-enhanced scans in inflammatory airway disease.


Assuntos
Algoritmos , Meios de Contraste/química , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Tomografia Computadorizada Multidetectores , Animais , Feminino , Pulmão/anatomia & histologia , Reprodutibilidade dos Testes , Suínos
12.
Ann Rheum Dis ; 79(9): 1210-1217, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32606043

RESUMO

OBJECTIVE: To prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function. METHODS: Seventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% <80, DLco%<80), isolated DLco% reduction (iDLco- FVC%≥80, DLco%<80) and normals (FVC%≥80, DLco%≥80). Spearman ρ, Mann-Whitney tests and logistic regressions were used to assess for correlations, differences among groups and relationships between continuous variables. RESULTS: Absolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%). CONCLUSIONS: Chest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/irrigação sanguínea , Escleroderma Sistêmico/diagnóstico por imagem , Espirometria/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto , Feminino , Humanos , Modelos Logísticos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Espirometria/métodos , Estatísticas não Paramétricas , Tomografia Computadorizada por Raios X/métodos , Capacidade Vital
13.
J Vis Exp ; (160)2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32628170

RESUMO

Blood vessels form intricate networks in 3-dimensional space. Consequently, it is difficult to visually appreciate how vascular networks interact and behave by observing the surface of a tissue. This method provides a means to visualize the complex 3-dimensional vascular architecture of the lung. To accomplish this, a catheter is inserted into the pulmonary artery and the vasculature is simultaneously flushed of blood and chemically dilated to limit resistance. Lungs are then inflated through the trachea at a standard pressure and the polymer compound is infused into the vascular bed at a standard flow rate. Once the entire arterial network is filled and allowed to cure, the lung vasculature may be visualized directly or imaged on a micro-CT (µCT) scanner. When performed successfully, one can appreciate the pulmonary arterial network in mice ranging from early postnatal ages to adults. Additionally, while demonstrated in the pulmonary arterial bed, this method can be applied to any vascular bed with optimized catheter placement and endpoints.


Assuntos
Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Microcirculação , Artéria Pulmonar/diagnóstico por imagem , Microtomografia por Raio-X/métodos , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Endogâmicos C57BL
14.
Am J Respir Crit Care Med ; 202(5): 690-699, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667207

RESUMO

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pulmão/irrigação sanguínea , Pneumonia Viral/complicações , Circulação Pulmonar/fisiologia , Doenças Vasculares/etiologia , Adulto , Idoso , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Tomografia Computadorizada por Raios X , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologia
15.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32614178

RESUMO

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipotensão/fisiopatologia , Pulmão/irrigação sanguínea , Microvasos/fisiopatologia , Pneumonia Viral/fisiopatologia , Edema Pulmonar/fisiopatologia , Núcleo Solitário/fisiopatologia , Trombose/fisiopatologia , Betacoronavirus , Permeabilidade Capilar/fisiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Nervo Facial , Nervo Glossofaríngeo , Humanos , Inflamação , Pulmão/imunologia , Microvasos/imunologia , Pandemias , Sistema Nervoso Parassimpático/fisiopatologia , Pneumonia Viral/imunologia , Edema Pulmonar/imunologia , Núcleo Solitário/imunologia , Nervo Vago , Vasoconstrição
16.
Medicine (Baltimore) ; 99(28): e21046, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664116

RESUMO

RATIONALE: Although there have been several studies describing clinical and radiographic features about the novel coronavirus (COVID-19) infection, there is a lack of pathologic data conducted on biopsies or autopsies. PATIENT CONCERNS: A 56-year-old and a 70-year-old men with fever, cough, and respiratory fatigue were admitted to the intensive care unit and intubated for respiratory distress. DIAGNOSIS: The nasopharyngeal swab was positive for COVID-19 and the chest Computed Tomography (CT) scan showed the presence of peripheral and bilateral ground-glass opacities. INTERVENTIONS: Both patients developed pneumothoraces after intubation and was managed with chest tube. Due to persistent air leak, thoracoscopies with blebs resection and pleurectomies were performed on 23rd and 16th days from symptoms onset. OUTCOMES: The procedures were successful with no evidence of postoperative air-leak, with respiratory improvement. Pathological specimens were analyzed with evidence of diffuse alveolar septum disruption, interstitium thickness, and infiltration of inflammatory cells with diffuse endothelial dysfunction and hemorrhagic thrombosis. LESSONS: Despite well-known pulmonary damages induced by the COVID-19, the late-phase histological changes include diffused peripheral vessels endothelial hyperplasia, in toto muscular wall thickening, and intravascular hemorrhagic thrombosis.


Assuntos
Infecções por Coronavirus/patologia , Endotélio Vascular/patologia , Pulmão , Pandemias , Pleura , Pneumonia Viral/patologia , Trombose/patologia , Trombose/parasitologia , Idoso , Betacoronavirus/isolamento & purificação , Biópsia/métodos , Tubos Torácicos/efeitos adversos , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Humanos , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/cirurgia , Masculino , Pessoa de Meia-Idade , Pleura/patologia , Pleura/cirurgia , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Pneumotórax/etiologia , Pneumotórax/terapia , Respiração Artificial/métodos , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Toracoscopia/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
17.
J Mol Cell Cardiol ; 146: 32-40, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681845

RESUMO

SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Betacoronavirus/imunologia , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Tempo de Tromboplastina Parcial , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/mortalidade , Embolia Pulmonar/virologia , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/virologia , Análise de Sobrevida
18.
Nat Med ; 26(7): 1102-1113, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32661401

RESUMO

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.


Assuntos
Lesão Pulmonar Aguda/terapia , Transplante de Pulmão/métodos , Pulmão/irrigação sanguínea , Preservação de Órgãos/métodos , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/fisiopatologia , Animais , Circulação Extracorpórea/métodos , Humanos , Pulmão/fisiopatologia , Perfusão/métodos , Suínos , Doadores de Tecidos
19.
Artigo em Inglês | MEDLINE | ID: mdl-32551862

RESUMO

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pneumopatias/etiologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Pneumonia Viral/complicações , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Citocinas/sangue , Dano ao DNA , Traumatismos Cardíacos/etiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Hipóxia/etiologia , Mediadores da Inflamação/sangue , Pulmão/virologia , Pneumopatias/fisiopatologia , Pneumopatias/virologia , Mitocôndrias/fisiologia , Miocárdio , Estresse Oxidativo , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Circulação Pulmonar , Embolia Pulmonar/etiologia , Receptores Virais/fisiologia , Fatores de Risco , Vasculite/etiologia
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