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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.
Yonsei Med J ; 61(10): 891-894, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32975064

RESUMO

The cellular entry of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) is mediated by interaction with the human angiotensin-converting enzyme 2 (ACE2), a receptor that is expressed on both lung and intestinal epithelial cells. We performed a quantitative proteomic analysis to investigate the expression of possible receptors for SARS-CoV-2 in the intestinal mucosa of 23 patients with chronic colitis. ACE2 expression was low and remained unaltered in the gut of patients with ulcerative colitis (UC), Crohn's disease (CD), intestinal Behcet's disease (BD), and intestinal tuberculosis (TB), when compared with that of healthy individuals. Additionally, the expression levels of some probable co-receptors, including dipeptidyl peptidase 4 (DPP4), aminopeptidase N (AMPN), and glutamyl aminopeptidase (AMPE), were unchanged in the affected UC, CD, intestinal BD, and intestinal TB colon mucosa samples. In conclusion, gut inflammation associated with chronic colitis does not mediate a further increase in the cellular entry of SARS-CoV-2.


Assuntos
Infecções por Coronavirus , Enterocolite , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Proteômica , Betacoronavirus , Dipeptidil Peptidase 4/metabolismo , Enterocolite/metabolismo , Microbioma Gastrointestinal , Humanos , Pulmão/metabolismo , Pandemias
3.
Signal Transduct Target Ther ; 5(1): 186, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883951

RESUMO

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Colesterol/biossíntese , Infecções por Coronavirus/genética , Síndrome da Liberação de Citocina/genética , Interações Hospedeiro-Patógeno/genética , Leucócitos Mononucleares/imunologia , Pneumonia Viral/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Unidades de Terapia Intensiva , Interleucina-1beta/genética , Interleucina-1beta/imunologia , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Cultura Primária de Células , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/imunologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Crit Care Resusc ; 22(3): 212-220, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32900327

RESUMO

OBJECTIVE: To quantify aerosol generation from respiratory interventions and the effectiveness of their removal by a personal ventilation hood. DESIGN AND SETTING: Determination of the aerosol particle generation (in a single, healthy volunteer in a clean room) associated with breathing, speaking, wet coughing, oxygen (O2) 15 L/min via face mask, O2 60 L/min via nasal prongs, bilevel non-invasive positive-pressure ventilation (BiPAP) and nebulisation with O2 10 L/min. INTERVENTIONS: Aerosol generation was measured with two particle sizer and counter devices, focusing on aerosols 0.5-5 µm (human-generated aerosols), with and without the hood. An increase from baseline of less than 0.3 particles per mL was considered a low level of generation. MAIN OUTCOME MEASURES: Comparisons of aerosol generation between different respiratory interventions. Effectiveness of aerosol reduction by a personal ventilation hood. RESULTS: Results for the 0.5-5 µm aerosol range. Quiet breathing and talking demonstrated very low increase in aerosols (< 0.1 particles/mL). Aerosol generation was low for wet coughing (0.1 particles/mL), O2 15 L/min via face mask (0.18 particles/mL), and high flow nasal O2 60 L/min (0.24 particles/mL). Non-invasive ventilation generated moderate aerosols (29.7 particles/mL) and nebulisation very high aerosols (1086 particles/mL); the personal ventilation hood reduced the aerosol counts by 98% to 0.5 particles/mL and 8.9 particles/mL respectively. CONCLUSIONS: In this human volunteer study, the administration of O2 15 L/min by face mask and 60 L/min nasal therapy did not increase aerosol generation beyond low levels. Non-invasive ventilation caused moderate aerosol generation and nebulisation therapy very high aerosol generation. The personal ventilation hood reduced the aerosol counts by at least 98%.


Assuntos
Aerossóis , Pulmão/metabolismo , Máscaras , Oxigênio , Respiração , Administração por Inalação , Humanos , Pulmão/diagnóstico por imagem , Resultado do Tratamento
5.
Gene ; 762: 145042, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777529

RESUMO

OBJECTIVES: Inhibitory effect of allicin with broad-spectrum antimicrobial activity on A. fumigatus and the regulation mechanism of inflammation and autophagy in vitro and in vivo. METHODS: The corresponding concentration of allicin was prepared according to the needs of the experiment. In vitro, 2 ml 5 × 104 of fungal spores suspension was added to the 6-well plate per hole, and different final concentrations of allicin (1 µl/ml, 2.5 µl/ml, 5 µl/ml, 10 µl/ml, 20 µl/ml, 30 µl/ml) were added. The fungal spores were stained by fluorescent dye SYTO 9 (green) every day, and the spore germination inhibition was detected by flow cytometry in different PH. RAW264.7 cells were cultured and stimulated by A. fumigatus spores for 3 h, then allicin solution was added. Then some cells were stained with ROS probe (green) and hochest33342 (blue). The effect of allicin on ROS was observed by fluorescence microscope. The other part of cells extracted protein from cell lysate and detected the effect of allicin on inflammatory factors and autophagy by Western-blotting. The green and red spots of RAW264.7 cells stably transfected with GFP-RFP-LC3 were observed by fluorescence microscopy. In vivo, A. fumigatus spore was injected intratracheally into mice, then allicin was injected intravenously at a concentration of 5 mg/kg/day for 7 consecutive days. The survival status, pulmonary fungal load and weight of mice was recorded continuously for 30 days and detected the changes of lung by pathological examination and immunohistochemistry. RESULTS: In vitro, allicin significantly inhibited the spore germination of A. fumigatus within 24 h in a dose-dependent manner and it had a stable inhibition on the spore germination of A. fumigatus in acidic environment. Cell experiments showed that allicin inhibited intracellular spore germination by inhibiting ROS production, inflammation and autophagy. In the animal experiment, the survival rate and body weight of allicin injection group were higher than that of non injection group, while the spore load of lung was lower than that of non injection group (P < 0.05). CONCLUSIONS: These results support that allicin reduces inflammation and autophagy resistance to A. fumigatus infection, It also provides a possible treatment for Aspergillus infectious diseases, i.e. early anti-inflammation, antibiotics or drugs that inhibit excessive autophagy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aspergilose/tratamento farmacológico , Autofagia , Depuradores de Radicais Livres/uso terapêutico , Ácidos Sulfínicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Aspergillus fumigatus/patogenicidade , Aspergillus fumigatus/fisiologia , Feminino , Depuradores de Radicais Livres/farmacologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Esporos Fúngicos/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia
6.
PLoS Pathog ; 16(8): e1008823, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32845931

RESUMO

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.


Assuntos
Vírus da Influenza A/metabolismo , Pulmão , Macrófagos , Infecções por Orthomyxoviridae , Proteínas PrPC/metabolismo , Transdução de Sinais , Animais , Anticorpos Monoclonais Murinos/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/virologia , Camundongos , Camundongos Mutantes , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Proteínas PrPC/antagonistas & inibidores , Quinases da Família src/genética , Quinases da Família src/metabolismo
7.
Anesthesiology ; 133(3): 534-547, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784343

RESUMO

BACKGROUND: According to the "three-compartment" model of ventilation-perfusion ((Equation is included in full-text article.)) inequality, increased (Equation is included in full-text article.)scatter in the lung under general anesthesia is reflected in increased alveolar deadspace fraction (VDA/VA) customarily measured using end-tidal to arterial (A-a) partial pressure gradients for carbon dioxide. A-a gradients for anesthetic agents such as isoflurane are also significant but have been shown to be inconsistent with those for carbon dioxide under the three-compartment theory. The authors hypothesized that three-compartment VDA/VA calculated using partial pressures of four inhalational agents (VDA/VAG) is different from that calculated using carbon dioxide (VDA/VACO2) measurements, but similar to predictions from multicompartment models of physiologically realistic "log-normal" (Equation is included in full-text article.)distributions. METHODS: In an observational study, inspired, end-tidal, arterial, and mixed venous partial pressures of halothane, isoflurane, sevoflurane, or desflurane were measured simultaneously with carbon dioxide in 52 cardiac surgery patients at two centers. VDA/VA was calculated from three-compartment model theory and compared for all gases. Ideal alveolar (PAG) and end-capillary partial pressure (Pc'G) of each agent, theoretically identical, were also calculated from end-tidal and arterial partial pressures adjusted for deadspace and venous admixture. RESULTS: Calculated VDA/VAG was larger (mean ± SD) for halothane (0.47 ± 0.08), isoflurane (0.55 ± 0.09), sevoflurane (0.61 ± 0.10), and desflurane (0.65 ± 0.07) than VDA/VACO2 (0.23 ± 0.07 overall), increasing with lower blood solubility (slope [Cis], -0.096 [-0.133 to -0.059], P < 0.001). There was a significant difference between calculated ideal PAG and Pc'G median [interquartile range], PAG 5.1 [3.7, 8.9] versus Pc'G 4.0[2.5, 6.2], P = 0.011, for all agents combined. The slope of the relationship to solubility was predicted by the log-normal lung model, but with a lower magnitude relative to calculated VDA/VAG. CONCLUSIONS: Alveolar deadspace for anesthetic agents is much larger than for carbon dioxide and related to blood solubility. Unlike the three-compartment model, multicompartment (Equation is included in full-text article.)scatter models explain this from physiologically realistic gas uptake distributions, but suggest a residual factor other than solubility, potentially diffusion limitation, contributes to deadspace.


Assuntos
Anestésicos Inalatórios/farmacocinética , Desflurano/farmacocinética , Halotano/farmacocinética , Isoflurano/farmacocinética , Alvéolos Pulmonares/metabolismo , Sevoflurano/farmacocinética , Idoso , Artérias/fisiologia , Dióxido de Carbono/metabolismo , Feminino , Humanos , Pulmão/metabolismo , Masculino , Pressão Parcial , Estudos Prospectivos , Estudos Retrospectivos
8.
Hum Cell ; 33(4): 907-918, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32780299

RESUMO

Acute respiratory distress syndrome (ARDS) is the main cause for the COVID-19 infection-related morbidity and mortality. Recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. The immunomodulatory effect of mesenchymal stem cells (MSCs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. Several studies have also revealed that similar therapeutic impacts of parent MSCs are also exhibited by MSCs-derived extracellular vesicles (EVs) including exosomes. In this review, we explored the therapeutic potential of both MSCs and exosomes in mitigating the COVID-19 induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. The preliminary studies have demonstrated the safety and efficacy of MSCs and exosomes in mitigating symptoms associated with COVID-19. Thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19. However, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy.


Assuntos
Infecções por Coronavirus/terapia , Exossomos , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Células-Tronco Mesenquimais/imunologia , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/terapia
9.
Life Sci ; 258: 118201, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781070

RESUMO

Fibrotic lung diseases qualify among the most dreaded irreversible interstitial pulmonary complications with progressive yet largely unpredictable clinical course. Idiopathic pulmonary fibrosis (IPF) is the most challenging prototype characterized by unknown and complex molecular etiology, severe dearth of non-invasive therapeutic options and average lifespan of 2-5 years in patients post diagnosis. Lung fibrosis (LF) is a leading cause of death in the industrialized world with the propensity to contract, significantly increasing with age. Approximately 45% deaths in US are attributed to fibrotic diseases while around 7% respiratory disease-associated deaths, annually in UK, are actually attributed to IPF. Recent developments in the field of LF have unambiguously pointed towards the pivotal role of Sirtuins (SIRTs) in regulating disease progression, thereby qualifying as potential anti-fibrotic drug targets. These NAD+-dependent lysine deacetylases, deacylases and ADP-ribosyltransferases are evolutionarily conserved proteins, regulated by diverse metabolic/environmental factors and implicated in age-related degenerative and inflammatory disorders. While SIRT1, SIRT6 and SIRT7 are predominantly nuclear, SIRT3, SIRT4, SIRT5 are mainly mitochondrial and SIRT2 is majorly cytosolic with occasional nuclear translocation. SIRT1, SIRT3, SIRT6 and SIRT7 are documented as cytoprotective sirtuins implicated in cardiovascular, pulmonary and metabolic diseases including fibrosis; however functional roles of remaining sirtuins in pulmonary pathologies are yet elusive. Here, we provide a comprehensive recent update on the regulatory role of sirtuins on LF along with discussion on potential therapeutic modulation of endogenous Sirtuin expression through synthetic/plant-derived compounds which can help synthetic chemists and ethnopharmacologists to design new-generation cheap, non-toxic Sirtuin-based drugs against LF.


Assuntos
Pulmão/metabolismo , Pulmão/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Sirtuínas/metabolismo , Animais , Humanos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais
10.
Chem Biol Interact ; 329: 109209, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32750325

RESUMO

Kinetic modeling of the behavior of complex chemical and biochemical systems is an effective approach to study of the mechanisms of the process. A kinetic model of coronaviral infection development with a description of the dynamic behavior of the main variables, including the concentration of viral particles, affected cells, and pathogenic microflora, is proposed. Changes in the concentration of hydrogen ions in the lungs and the pH -dependence of carbonic anhydrase activity (a key breathing enzyme) are critical. A significant result is the demonstration of an acute bifurcation transition that determines life or system collapse. This transition is connected with exponential growth of concentrations of the process participants and with functioning of the key enzyme carbonic anhydrase in development of toxic effects. Physical and chemical interpretations of the therapeutic effects of the body temperature rise and the potential therapeutic effect of "thermoheliox" (respiration with a thermolized mixture of helium and oxygen) are given. The phenomenon of "thermovaccination" is predicted, which involves stimulation of the immune response by "thermoheliox".


Assuntos
Infecções por Coronaviridae/metabolismo , Hélio/química , Oxigênio/química , Imunidade Adaptativa , Temperatura Corporal , Anidrases Carbônicas/metabolismo , Infecções por Coronaviridae/patologia , Infecções por Coronaviridae/terapia , Hélio/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Cinética , Pulmão/metabolismo , Modelos Teóricos , Oxigênio/uso terapêutico
11.
Medicine (Baltimore) ; 99(30): e21302, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791715

RESUMO

INTRODUCTION: By detecting the metabolic difference of the Heart and Lung meridians, the present study aims to investigate the specificity of different meridians and verify whether functional near infrared spectroscopy is validated as an add-on technique to assist diagnosis of chronic obstructive pulmonary disease (COPD). METHODS AND ANALYSIS: The Lung and Heart meridians are chosen as the target for comparison; accordingly, 120 eligible participants will be included and divided into the COPD group, healthy control group, and healthy intervention group. Functional near infrared spectroscopy will be adopted to measure the metabolic characteristics of the Heart and Lung meridians. On one hand, the specificity of the meridian-visceral association will be investigated by comparing the metabolic difference in the Heart and Lung meridians between the healthy control group and COPD group. On the other hand, the specificity of site-to-site association will be determined by comparing the metabolic change between the 2 meridians that induced by moxibustion in the Heart meridian and Lung meridian, respectively, in the healthy control group. The primary outcome will be regional oxygen saturation of corresponding regions along the Heart and Lung meridians. TRIAL REGISTRATION: ClinicalTrials.gov NCT04046666.


Assuntos
Coração/fisiologia , Pulmão/metabolismo , Moxibustão/métodos , Doença Pulmonar Obstrutiva Crônica/terapia , Espectrofotometria Infravermelho/métodos , Pontos de Acupuntura , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Masculino , Meridianos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Oxigênio/metabolismo , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Sensibilidade e Especificidade
12.
Ecotoxicol Environ Saf ; 202: 110932, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800216

RESUMO

Adverse health effects arising from exposure to fine particulates have become a major concern. Angiogenesis is a vital physiological process for the growth and development of cells and structures in the human body, whereby excessive or insufficient vessel growth could contribute to pathogenesis of diseases. We therefore evaluated indirect effects of carbon black (CB) and inhalable airborne particles on the angiogenic ability of unexposed Human Umbilical Vein Endothelial Cells (HUVECs) by co-culturing HUVECs with pre-exposed Small Airway Epithelial Cells (SAECs). As endothelial cells are major components of blood vessels and potential targets of fine particles, we investigated if lung epithelial cells exposed to ambient PM2.5 surrogates could induce bystander effects on neighboring unexposed endothelial cells in an alveolar-capillary co-culture lung model. Epithelial exposure to CB at a non-toxic dose of 25 µg/mL reduced endothelial tube formation and cell adhesion in co-cultured HUVECs, and decreased expression of angiogenic genes in SAECs. Similarly, exposure of differentiated SAECs to PM2.5 surrogates reduced cell reproductive ability, adhesion and tube formation of neighboring HUVECs. This indicates epithelial exposure to CB and urban PM2.5 surrogates both compromised the angiogenic ability of endothelial cells through bystander effects, thereby potentially perturbing the ventilation-perfusion ratio and affecting lung function.


Assuntos
Poluentes Atmosféricos/toxicidade , Material Particulado/toxicidade , Testes de Toxicidade , Técnicas de Cocultura , Células Epiteliais , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pulmão/metabolismo , Neovascularização Patológica , Fuligem
13.
Pathol Res Pract ; 216(9): 153086, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32825954

RESUMO

A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin-angiotensin-aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.


Assuntos
Betacoronavirus/patogenicidade , Doenças Cardiovasculares/etiologia , Infecções por Coronavirus/virologia , Pulmão/virologia , Pneumonia Viral/virologia , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/virologia , Infecções por Coronavirus/complicações , Humanos , Pulmão/metabolismo , Pandemias , Pneumonia Viral/complicações , Sistema Renina-Angiotensina/fisiologia
14.
Nat Commun ; 11(1): 3998, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778730

RESUMO

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunidade Inata/imunologia , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Células Th2/metabolismo , Transcriptoma
15.
Nat Commun ; 11(1): 4222, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839436

RESUMO

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical.


Assuntos
Edema/metabolismo , Homeostase/fisiologia , Sódio/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia , Envelhecimento/metabolismo , Animais , Edema/diagnóstico , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Especificidade de Órgãos , Concentração Osmolar , Potássio/metabolismo , Ratos Endogâmicos WKY , Pele/metabolismo , Fatores de Transcrição/metabolismo
16.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
17.
Nat Commun ; 11(1): 3929, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764559

RESUMO

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.


Assuntos
Terapia Genética/métodos , Vetores Genéticos , Parvovirinae/genética , Proteinose Alveolar Pulmonar/congênito , Proteína B Associada a Surfactante Pulmonar/deficiência , Animais , Animais Recém-Nascidos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Precursores de Proteínas/genética , Proteolipídeos/genética , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Proteinose Alveolar Pulmonar/terapia , Proteína B Associada a Surfactante Pulmonar/genética , Proteína B Associada a Surfactante Pulmonar/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/genética , Transdução Genética
18.
Sci Adv ; 6(33): eabb7238, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32851183

RESUMO

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1, which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2. Concomitant partial loss of NF-κB/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.


Assuntos
Células Epiteliais/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Pulmão/metabolismo , Peptidil Dipeptidase A/metabolismo , Fenótipo , Proteínas Inibidoras de STAT Ativados/genética , Doença Pulmonar Obstrutiva Crônica/genética , Ubiquitina-Proteína Ligases/genética , Regulação para Cima/genética , Animais , Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Transdução de Sinais/genética , Fumar/efeitos adversos , Fator de Transcrição RelA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
AAPS PharmSciTech ; 21(5): 183, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632576

RESUMO

Pulmonary drug delivery is a noninvasive therapeutic approach that offers many advantages including localized drug delivery and higher patient compliance. As with all formulations, the low aqueous solubility of a drug often poses a challenge in the formulation development. Thus, strategies such as cyclodextrin (CD) complexation have been utilized to overcome this challenge. Resveratrol (RES), a natural stilbene, has shown abundant anti-cancer properties. Due to many drawbacks of conventional chemotherapeutics, RES has been proposed as an emerging alternative with promising pharmacological effects. However, RES has limited therapeutic applications due to low water solubility, chemical stability, and bioavailability. This study was aimed at developing an inhalable therapy that would increase the aqueous solubility and stability of RES by complexation with sulfobutylether-ß-cyclodextrin (SBECD). Phase solubility profiles indicated an optimal stoichiometric inclusion complex at 1:1 (SBECD:RES) ratio for formulation considerations. Physiochemical characterizations were performed to analyze CD-RES. Stability studies at pH 7.4 and in plasma indicated significant improvement in RES stability after complexation, with a much longer half-life. The mass median aerodynamic diameter (MMAD) of CD-RES was 2.6 ± 0.7 µm and fine particle fraction (FPF) of 83.4 ± 3.0% are suitable for pulmonary delivery and efficient deposition. Lung cancer was selected as the respiratory model disease, owing to its high relevance as the major cause of cancer deaths worldwide. Cell viability studies in 5 non-small-cell-lung-cancer (NSCLC) cell lines suggest CD-RES retained significant cytotoxic potential of RES. Taken together, CD-RES proves to be a promising inhalation treatment for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclodextrinas/química , Neoplasias Pulmonares/tratamento farmacológico , Resveratrol/administração & dosagem , Administração por Inalação , Disponibilidade Biológica , Portadores de Fármacos/metabolismo , Estabilidade de Medicamentos , Humanos , Pulmão/metabolismo , Solubilidade
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