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1.
Viruses ; 12(10)2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081421

RESUMO

To address the expression pattern of the SARS-CoV-2 receptor ACE2 and the viral priming protease TMPRSS2 in the respiratory tract, this study investigated RNA sequencing transcriptome profiling of samples of airway and oral mucosa. As shown, ACE2 has medium levels of expression in both small airway epithelium and masticatory mucosa, and high levels of expression in nasal epithelium. The expression of ACE2 is low in mucosal-associated invariant T (MAIT) cells and cannot be detected in alveolar macrophages. TMPRSS2 is highly expressed in small airway epithelium and nasal epithelium and has lower expression in masticatory mucosa. Our results provide the molecular basis that the nasal mucosa is the most susceptible locus in the respiratory tract for SARS-CoV-2 infection and consequently for subsequent droplet transmission and should be the focus for protection against SARS-CoV-2 infection.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/genética , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/genética , Serina Endopeptidases/biossíntese , Internalização do Vírus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Epitélio/metabolismo , Epitélio/virologia , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Mucosa Nasal/metabolismo , Mucosa Nasal/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Serina Endopeptidases/genética
3.
Nat Commun ; 11(1): 5453, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116139

RESUMO

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/patologia , Expressão Gênica/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Sistema Respiratório/patologia , Fatores Etários , Cílios/metabolismo , Infecções por Coronavirus/virologia , Células Endoteliais , Células Caliciformes/metabolismo , Humanos , Pulmão/patologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Fatores Sexuais , Sinusite/metabolismo , Fumar
4.
Respir Res ; 21(1): 252, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993656

RESUMO

SARS-CoV-2 is causing a pandemic with currently > 29 million confirmed cases and > 900,000 deaths worldwide. The locations and mechanisms of virus entry into the human respiratory tract are incompletely characterized. We analyzed publicly available RNA microarray datasets for SARS-CoV-2 entry receptors and cofactors ACE2, TMPRSS2, BSG (CD147) and FURIN. We found that ACE2 and TMPRSS2 are upregulated in the airways of smokers. In asthmatics, ACE2 tended to be downregulated in nasal epithelium, and TMPRSS2 was upregulated in the bronchi. Furthermore, respiratory epithelia were negative for ACE-2 and TMPRSS2 protein expression while positive for BSG and furin, suggesting a possible alternative entry route for SARS-CoV-2.


Assuntos
Asma/virologia , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Pneumonia Viral/genética , Serina Endopeptidases/genética , Síndrome Respiratória Aguda Grave/virologia , Fumar/epidemiologia , Asma/fisiopatologia , Bases de Dados Factuais , Humanos , Pandemias , Receptores Virais/genética , Valores de Referência , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/metabolismo , Fumar/fisiopatologia , Internalização do Vírus
5.
Am J Physiol Lung Cell Mol Physiol ; 319(5): L843-L847, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32996784

RESUMO

The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.


Assuntos
Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/metabolismo , Sistema Respiratório/metabolismo , Adulto , Idoso , Células Cultivadas , Infecções por Coronavirus/enzimologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Sistema Respiratório/citologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/enzimologia , Fatores Sexuais , Testosterona/metabolismo , Testosterona/farmacologia
6.
EBioMedicine ; 60: 102976, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32971472

RESUMO

BACKGROUND: Zoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the receptor for SARS-CoV-2. Numerous reports describe ACE2 mRNA abundance and tissue distribution; however, mRNA abundance is not always representative of protein levels. Currently, there is limited data evaluating ACE2 protein and its correlation with other SARS-CoV-2 susceptibility factors. MATERIALS AND METHODS: We systematically examined the human upper and lower respiratory tract using single-cell RNA sequencing and immunohistochemistry to determine receptor expression and evaluated its association with risk factors for severe COVID-19. FINDINGS: Our results reveal that ACE2 protein is highest within regions of the sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe disease development, respectively. In the lung parenchyma, ACE2 protein was found on the apical surface of a small subset of alveolar type II cells and colocalized with TMPRSS2, a cofactor for SARS-CoV2 entry. ACE2 protein was not increased by pulmonary risk factors for severe COVID-19. Additionally, ACE2 protein was not reduced in children, a demographic with a lower incidence of severe COVID-19. INTERPRETATION: These results offer new insights into ACE2 protein localization in the human respiratory tract and its relationship with susceptibility factors to COVID-19.


Assuntos
Células Epiteliais Alveolares/metabolismo , Peptidil Dipeptidase A/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Células Epiteliais Alveolares/patologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Criança , Pré-Escolar , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , RNA Mensageiro/metabolismo , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Análise de Célula Única , Adulto Jovem
7.
Med Hypotheses ; 143: 110122, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759007

RESUMO

A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Linfopenia/fisiopatologia , Modelos Imunológicos , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/fisiopatologia , Prostaglandina D2/fisiologia , Sistema Respiratório/metabolismo , Adulto , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Humanos , Linfopenia/etiologia , Células Mieloides/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Prostaglandina D2/biossíntese , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/fisiologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Tromboxano A2/antagonistas & inibidores
8.
Mol Syst Biol ; 16(7): e9610, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32715618

RESUMO

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.


Assuntos
Peptidil Dipeptidase A/metabolismo , Sistema Respiratório/metabolismo , Betacoronavirus , Vasos Sanguíneos/metabolismo , Túnica Conjuntiva/metabolismo , Enterócitos/metabolismo , Feminino , Vesícula Biliar/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Imuno-Histoquímica , Túbulos Renais Proximais/metabolismo , Masculino , Espectrometria de Massas , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Peptidil Dipeptidase A/genética , Placenta/metabolismo , Gravidez , RNA-Seq , Análise de Célula Única , Testículo/metabolismo
11.
Rev Mal Respir ; 37(6): 462-473, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32487422

RESUMO

INTRODUCTION: A significant portion of symptoms in some lung diseases results from an excessive constriction of airways due to the contraction of smooth muscle and bronchial hyperresponsiveness. A better understanding of the extracellular molecules that control smooth muscle contractility is necessary to identify the underlying causes of the problem. STATE OF KNOWLEDGE: Almost a hundred molecules, some of which newly identified, influence the contractility of airway smooth muscle. While some molecules activate the contraction, others activate the relaxation, thus acting directly as bronchoconstrictors and bronchodilators, respectively. Other molecules do not affect contraction directly but rather influence it indirectly by modifying the effect of bronchoconstrictors and bronchodilators. These are called bronchomodulators. Some of these bronchomodulators increase the contractile effect of bronchoconstrictors and could thus contribute to bronchial hyperresponsiveness. PROSPECTS: Considering the high number of molecules potentially involved, as well as the level of functional overlap between some of them, identifying the extracellular molecules responsible for excessive airway constriction in a patient is a major contemporary challenge.


Assuntos
Hiper-Reatividade Brônquica/etiologia , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Animais , Asma/etiologia , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Broncoconstritores/metabolismo , Broncodilatadores/metabolismo , Espaço Extracelular/metabolismo , Humanos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/fisiopatologia
12.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471278

RESUMO

At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. COVID-19 pathology is characterized by extreme inflammation and amplified immune response with activation of a cytokine storm. A subsequent progression to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can take place, which is often followed by death. The causes of these strong inflammatory responses in SARS-CoV-2 infection are still unknown. As uncontrolled pulmonary inflammation is likely the main cause of death in SARS-CoV-2 infection, anti-inflammatory therapeutic interventions are particularly important. Fenretinide N-(4-hydroxyphenyl) retinamide is a bioactive molecule characterized by poly-pharmacological properties and a low toxicity profile. Fenretinide is endowed with antitumor, anti-inflammatory, antiviral, and immunomodulating properties other than efficacy in obesity/diabetic pathologies. Its anti-inflammatory and antiviral activities, in particular, could likely have utility in multimodal therapies for the treatment of ALI/ARDS in COVID-19 patients. Moreover, fenretinide administration by pulmonary delivery systems could further increase its therapeutic value by carrying high drug concentrations to the lungs and triggering a rapid onset of activity. This is particularly important in SARS-CoV-2 infection, where only a narrow time window exists for therapeutic intervention.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fenretinida/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas , Fenretinida/farmacologia , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
PLoS One ; 15(5): e0228606, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392246

RESUMO

Bordetella pertussis, the causative agent of whopping cough, produces an adenylate cyclase toxin (CyaA) that plays a key role in the host colonization by targeting innate immune cells which express CD11b/CD18, the cellular receptor of CyaA. CyaA is also able to invade non-phagocytic cells, via a unique entry pathway consisting in a direct translocation of its catalytic domain across the cytoplasmic membrane of the cells. Within the cells, CyaA is activated by calmodulin to produce high levels of cyclic adenosine monophosphate (cAMP) and alter cellular physiology. In this study, we explored the effects of CyaA toxin on the cellular and molecular structure remodeling of A549 alveolar epithelial cells. Using classical imaging techniques, biochemical and functional tests, as well as advanced cell mechanics method, we quantify the structural and functional consequences of the massive increase of intracellular cyclic AMP induced by the toxin: cell shape rounding associated to adhesion weakening process, actin structure remodeling for the cortical and dense components, increase in cytoskeleton stiffness, and inhibition of migration and repair. We also show that, at low concentrations (0.5 nM), CyaA could significantly impair the migration and wound healing capacities of the intoxicated alveolar epithelial cells. As such concentrations might be reached locally during B. pertussis infection, our results suggest that the CyaA, beyond its major role in disabling innate immune cells, might also contribute to the local alteration of the epithelial barrier of the respiratory tract, a hallmark of pertussis.


Assuntos
Toxina Adenilato Ciclase/genética , Bordetella pertussis/enzimologia , Imunidade Inata/genética , Coqueluche/genética , Toxina Adenilato Ciclase/metabolismo , Bordetella pertussis/patogenicidade , Calmodulina/metabolismo , Membrana Celular/metabolismo , AMP Cíclico/genética , Células Epiteliais/microbiologia , Humanos , Sistema Respiratório/metabolismo , Sistema Respiratório/microbiologia , Sistema Respiratório/patologia , Coqueluche/microbiologia , Coqueluche/patologia
15.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1280-L1281, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432918

RESUMO

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Estrogênios/farmacologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Estrogênios/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo
16.
PLoS One ; 15(5): e0233352, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442188

RESUMO

BACKGROUND: MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children. METHODS: Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1ß, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters. RESULTS: A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses. CONCLUSIONS: The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease.


Assuntos
Citocinas/metabolismo , MicroRNAs/metabolismo , Sistema Respiratório/metabolismo , Infecções Respiratórias/metabolismo , Citocinas/genética , Feminino , Humanos , Lactente , Masculino , MicroRNAs/genética , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Sistema Respiratório/virologia , Infecções Respiratórias/genética , Infecções Respiratórias/virologia , Rhinovirus/isolamento & purificação
17.
Am J Respir Cell Mol Biol ; 63(2): 185-197, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32338995

RESUMO

The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.


Assuntos
Apolipoproteínas E/metabolismo , Asma/metabolismo , Quimiocina CXCL5/metabolismo , Células Epiteliais/metabolismo , Sistema Respiratório/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Quimiocinas/metabolismo , Humanos , Inflamação/metabolismo , Neutrófilos/metabolismo , RNA Mensageiro/metabolismo
18.
Subcell Biochem ; 95: 151-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32297299

RESUMO

Retinoic acid (RA), the bioactive metabolite of vitamin A (VA), has long been recognized as a critical regulator of the development of the respiratory system. During embryogenesis, RA signaling is involved in the development of the trachea, airways, lung, and diaphragm. During postnatal life, RA continues to impact respiratory health. Disruption of RA activity during embryonic development produces dramatic phenotypes in animal models and human diseases, including tracheoesophageal fistula, tracheomalacia, congenital diaphragmatic hernia (CDH), and lung agenesis or hypoplasia. Several experimental methods have been used to target RA pathways during the formation of the embryonic lung. These have been performed in different animal models using gain- and loss-of-function strategies and dietary, pharmacologic, and genetic approaches that deplete retinoid stores or disrupt retinoid signaling. Experiments utilizing these methods have led to a deeper understanding of RA's role as an important signaling molecule that influences all stages of lung development. Current research is uncovering RA cross talk interactions with other embryonic signaling factors, such as fibroblast growth factors, WNT, and transforming growth factor-beta.


Assuntos
Sistema Respiratório/embriologia , Sistema Respiratório/metabolismo , Transdução de Sinais , Tretinoína/metabolismo , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pneumopatias/embriologia , Pneumopatias/metabolismo
19.
Phytother Res ; 34(9): 2214-2229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32249518

RESUMO

Carvacrol is a monoterpene present in the essential oil of a number of plants and has been widely used in traditional medicine because it is considered to have a range of therapeutic effects including in relation to respiratory disease. To conduct a systematic review and meta-analysis to assess the anti-inflammatory and antioxidant activities of carvacrol when used in the treatment of respiratory disorders. A comprehensive literature search using Scopus, MEDLINE-PubMed, Cochrane and Web of Science was undertaken. Papers related to the anti-inflammatory or antioxidant properties of carvacrol in the treatment of an injury in the respiratory system in in vivo studies and published in the period up to and including August 2019. A total of 152 studies were initially identified, with only 17 meeting the inclusion criteria. Five of the studies were performed in humans, and 12 were performed in rodents. Among the 17 studies included in the systematic review, we performed the meta-analysis with nine of the studies with animals. Carvacrol had a positive effect on the reduction of interleukin (IL)-1ß, IL-4, IL-8 and malondialdehyde (MDA); however, the analysis indicated that carvacrol had no effect on IL-6 and tumor necrosis factor alpha (TNF-α), probably due to the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory effects of carvacrol, but its relationship with the reduction of some inflammatory mediators in animals with lung injury needs further elucidation.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cimenos/farmacologia , Sistema Respiratório/efeitos dos fármacos , Animais , Cobaias , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Malondialdeído/metabolismo , Camundongos , Monoterpenos/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia
20.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1270-L1279, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32348677

RESUMO

The organization of the normal airway mucus system differs in small experimental animals from that in humans and large mammals. To address normal murine airway mucociliary clearance, Alcian blue-stained mucus transport was measured ex vivo on tracheal tissues of naïve C57BL/6, Muc5b-/-, Muc5ac-/-, and EGFP-tagged Muc5b reporter mice. Close to the larynx with a few submucosal glands, the mucus appeared as thick bundles. More distally in the trachea and in large bronchi, Alcian blue-stained mucus was organized in cloud-like formations based on the Muc5b mucin. On tilted tissue, the mucus clouds moved upward toward the larynx with an average velocity of 12 µm/s compared with 20 µm/s for beads not associated with clouds. In Muc5ac-/- mice, Muc5b formed mucus strands attached to the tissue surface, while in Muc5b-/- mice, Muc5ac had a more variable appearance. The normal mouse lung mucus thus appears as discontinuous clouds, clearly different from the stagnant mucus layer in diseased lungs.


Assuntos
Mucina-5B/metabolismo , Muco/metabolismo , Sistema Respiratório/metabolismo , Animais , Transporte Biológico , Fluorescência , Células Caliciformes/metabolismo , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Membrana Mucosa/metabolismo , Traqueia/metabolismo
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