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1.
Med Arch ; 74(2): 134-138, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32577056

RESUMO

Introduction: COVID-19 is a new viral illness that can affect the lungs and airways with lethal consequences leading to the death of the patients. The ACE2 receptors were widely disturbed among body tissues such as lung, kidney, small intestine, heart, and others in different percent and considered a target for the nCOVID-19 virus. S-protein of the virus was binding to ACE2 receptors caused downregulation of endogenous anti-viral mediators, upregulation of NF-κB pathway, ROS and pro-apoptotic protein. Nrf2 was a transcription factor that's play a role in generation of anti-oxidant enzymes. Aim: To describe and establish role of Nrf2 activators for treatment COVID-19 positive patients. Methods: We used method of analysis of the published papers with described studies about COVID-19 connected with pharmacological issues and aspects which are included in global fighting against COVID-19 infection, and how using DMF (Nrf2 activator) in clinical trial for nCOVID-19 produce positive effects in patients for reduce lung alveolar cells damage. Results: we are found that Nrf2 activators an important medication that's have a role in reduce viral pathogenesis via inhibit virus entry through induce SPLI gene expression as well as inhibit TRMPSS2, upregulation of ACE2 that's make a competition with the virus on binding site, induce gene expression of anti-viral mediators such as RIG-1 and INFs, induce anti-oxidant enzymes, also they have a role in inhibit NF-κB pathway, inhibit both apoptosis proteins and gene expression of TLRs. Conclusion: We are concluded that use DMF (Nrf2 activator) in clinical trial for nCOVID-19 positive patients to reduce lung alveolar cells damage.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/metabolismo , Células Epiteliais Alveolares/metabolismo , Humanos , Pandemias , Alvéolos Pulmonares/metabolismo
2.
Eur J Radiol ; 129: 109092, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32485335

RESUMO

PURPOSE: To evaluate the diagnostic accuracy and the imaging features of routine admission chest X-ray in patients suspected for novel Coronavirus 2019 (SARS-CoV-2) infection. METHOD: We retrospectively evaluated clinical and X-ray features in all patients referred to the emergency department for suspected SARS-CoV-2 infection between March 1st and March 13th. A single radiologist with more than 15 years of experience in chest-imaging evaluated the presence and extent of alveolar opacities, reticulations, and/or pleural effusion. The percentage of lung involvement (range <25 % to 75-100 %) was also calculated. We stratified patients in groups according to the time interval between symptoms onset and X-ray imaging (≤ 5 and > 5 days) and according to age (≤ 50 and > 50 years old). RESULTS: A total of 518 patients were enrolled. Overall 314 patients had negative and 204 had positive RT-PCR results. Lung lesions in patients with SARS-Cov2 pneumonia primarily manifested as alveolar and interstitial opacities and were mainly bilateral (60.8 %). Lung abnormalities were more frequent and more severe by symptom duration and by increasing age. The sensitivity and specificity of chest X-ray at admission in the overall cohort were 57 % (95 % CI = 47-67) and 89 % (83-94), respectively. Sensitivity was higher for patients with symptom onset > 5 days compared to ≤ 5 days (76 % [62-87] vs 37 % [24-52]) and in patients > 50 years old compared to ≤ 50 years (59 % [48-69] vs 47 % [23-72]), at the expense of a slightly lower specificity (68 % [45-86] and 82 % [73-89], respectively). CONCLUSIONS: Overall chest X-ray sensitivity for SARS-CoV-2 pneumonia was 57 %. Sensitivity was higher when symptoms had started more than 5 days before, at the expense of lesser specificity, while slightly higher in older patients in comparison to younger ones.


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico/normas , Infecções por Coronavirus/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Adulto , Idoso , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/normas , Dispneia/diagnóstico por imagem , Dispneia/virologia , Serviço Hospitalar de Emergência , Feminino , Febre/diagnóstico por imagem , Febre/virologia , Hospitalização , Humanos , Itália , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Admissão do Paciente/normas , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/virologia , Testes Imediatos/normas , Alvéolos Pulmonares/diagnóstico por imagem , Radiografia , Estudos Retrospectivos , Sensibilidade e Especificidade , Tempo para o Tratamento , Tomografia Computadorizada por Raios X , Raios X , Adulto Jovem
3.
Nat Rev Rheumatol ; 16(8): 465-470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561873

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1ß or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artralgia , Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Assistência à Saúde , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Inibidores de Janus Quinases/uso terapêutico , Mialgia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Reumatologia , Sulfonamidas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
4.
Medicine (Baltimore) ; 99(20): e20284, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443373

RESUMO

INTRODUCTION: Alveolar hemorrhage (AH) is characterized by the acute onset of alveolar bleeding and hypoxemia and can be fatal. Thrombin has been widely used to achieve coagulation and hemostasis. However, the efficacy of thrombin in patients with AH is unclear. Thus, this study aimed to evaluate the efficacy of thrombin administration in patients with hematological malignancy and AH. PATIENT CONCERNS AND DIAGNOSES: This retrospective study included 15 hematological malignancy patients (8 men and 7 women; mean age 47.7 ±â€Š17.3 years) with AH who were administered intrapulmonary thrombin between March 2013 and July 2018. INTERVENTIONS AND OUTCOMES: All patients received bovine-origin thrombin (1000 IU/ml, Reyon Pharmaceutical Co., Ltd., Seoul, Korea) via a fiberoptic bronchoscope. A maximum of 15 ml of thrombin was injected via the working channel to control bleeding. The ability of thrombin to control bleeding was assessed. Additionally, the change in the PaO2/FiO2 (PF) ratio after intrapulmonary thrombin administration was evaluated. Intrapulmonary thrombin was administered a minimum of 3 days after starting mechanical ventilation in all patients, and it immediately controlled the active bleeding in 13 of 15 patients (86.7%). However, AH relapse was noted in 3 of the 13 patients (23.1%). The PF ratio improved in 10 of 15 patients (66.6%), and the mean PF ratio was significantly higher after thrombin administration than before administration (P = .03). No adverse thromboembolic complications or systemic adverse events were observed. CONCLUSION: Thrombin administration was effective in controlling bleeding in hematological malignancy patients with AH. Intrapulmonary thrombin administration might be a good therapeutic option for treating AH.


Assuntos
Neoplasias Hematológicas/complicações , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Pneumopatias/tratamento farmacológico , Trombina/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Hemorragia/etiologia , Hemostáticos/administração & dosagem , Humanos , Pneumopatias/etiologia , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Estudos Retrospectivos , Trombina/administração & dosagem , Adulto Jovem
5.
Cancer Metastasis Rev ; 39(2): 337-340, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32385712

RESUMO

Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/terapia , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Eicosanoides/imunologia , Eicosanoides/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , Síndrome do Desconforto Respiratório do Adulto/imunologia
7.
Jpn J Radiol ; 38(5): 394-398, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32236856

RESUMO

PURPOSE: To review the chest computed tomography (CT) findings on the ultra-high-resolution CT (U-HRCT) in patients with the Novel coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: In February 2020, six consecutive patients with COVID-19 pneumonia (median age, 69 years) underwent U-HR CT imaging. U-HR-CT has a larger matrix size of 1024 × 1024 thinner slice thickness of 0.25 mm and can demonstrate terminal bronchioles in the normal lungs; as a result, Reid's secondary lobules and their abnormalities can be identified. The distribution and hallmarks (ground-glass opacity, consolidation with or without architectural distortion, linear opacity, crazy paving) of the lung opacities on U-HRCT were visually evaluated on a 1 K monitor by two experienced reviewers. The CT lung volume was measured, and the ratio of the measured lung volume to the predicted total lung capacity (predTLC) based on sex, age and height was calculated. RESULTS: All cases showed crazy paving pattern in U-HRCT. In these lesions, the secondary lobules were smaller than those in the un-affected lungs. CT lung volume decreased in two cases comparing predTLC. CONCLUSION: U-HRCT can evaluate not only the distribution and hallmarks of COVID-19 pneumonia but also visualize local lung volume loss.


Assuntos
Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/patologia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/patologia , Alvéolos Pulmonares/diagnóstico por imagem , Alvéolos Pulmonares/patologia , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Alvéolos Pulmonares/virologia , Tomografia Computadorizada por Raios X/métodos
8.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(6): 496-502, 2020 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-32241072

RESUMO

Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) shared similar pathogenetic, clinical and pathological features. Fever and cough were the most common symptoms of both diseases, while myalgia and diarrhea were less common in patients with COVID-19. Acute respiratory distress syndrome (ARDS) was the most severe pulmonary complication that caused high mortality rate. Histologically, diffuse alveolar damage (DAD) was the most characteristic finding in non-survivors with either SARS or COVID-19. Cases of patients died less than 10-14 days of disease duration demonstrated acute-phase DAD, while cases beyond 10-14 days of disease duration exhibited organizing-phase DAD in SARS. Meanwhile, organization and fibrosis were usually accompanied by exudation. Coronavirus was mostly detected in pneumocytes, but less in macrophages and bronchiolar epithelial cells. Hemorrhagic necrosis and lymphocyte depletion were found in lymph nodes and spleen in both SARS and COVID-19, indicating a pathological basis of lymphocytopenia. Thrombosis was commonly observed in small vessels and microvasculaturr in lungs accompanying DAD. Microthrombosis was also found in extrapulmonary organs in COVID-19, that was less reported in SARS. Damages in multiple extrapulmonary organs were observed, but coronavirus was not detected in some of those organs, indicating an alternative mechanism beyond viral infection, such as hypoxemia, ischemia and cytokine storm induced immunological injury. DAD due to viral infection and immunological injury, as well as multi-organ dysfunction and extensive microthrombus formation, brought huge challenge to the management of patients with severe SARS or COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Coronavirus , Pulmão/patologia , Pulmão/virologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Surtos de Doenças , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Alvéolos Pulmonares/patologia , Trombose/complicações , Trombose/epidemiologia
9.
Life Sci ; 252: 117662, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298739

RESUMO

AIMS: Bronchopulmonary dysplasia (BPD) is a severe respiratory complication in preterm infants. This study reveals the molecular mechanism of autophagic agonists regulating the Nrf2-ARE pathway via p62 to improve alveolar development in BPD rats. MAIN METHODS: Newborn Sprague-Dawley rats were randomly exposed to a hyperoxic environment (FiO2 = 0.85) for 14 days and rapamycin (RAPA) was intraperitoneally injected on alternate days into hyperoxia-exposed mice. Alveolar development was assessed using HE and RAC values. Markers associated with the p62-Keap1-Nrf2-ARE pathway were detected by western blot, immunohistochemistry, and RT-PCR. Co-localization of proteins was determined using double immunofluorescence staining. KEY FINDINGS: At the levels of lung tissue and primary type II alveolar epithelial cells, the enhanced binding between phosphorylated p62 and Keap1 disrupted the nuclear transport of Nrf2. The activated Nrf2 was insufficient to reverse alveolar simplification. The autophagy agonist was able to inhibit p62 phosphorylation, promote Keap1 degradation, increase Nrf2 nuclear transport, augment downstream antioxidant enzyme expression, and enhance antioxidant capacity, thereby improving the simplification of alveolar structure in BPD rats. SIGNIFICANCE: The use of autophagy agonists to enhance the Nrf2-ARE pathway activity and promote alveolar development could be a novel target in antioxidant therapy for BPD.


Assuntos
Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/fisiopatologia , Alvéolos Pulmonares/metabolismo , Sirolimo/farmacologia , Animais , Animais Recém-Nascidos , Elementos de Resposta Antioxidante , Antioxidantes/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/complicações , Recém-Nascido , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Toxicol Lett ; 328: 7-18, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32311379

RESUMO

Multi-walled carbon nanotubes (MWCNT) are engineered nanomaterials widely used in industrial and biomedical applications. Yet, MWCNT inhalation may induce pulmonary adverse effects, and the MWCNT-7 (Mitsui-7) has been classified as possibly carcinogenic to humans. However, its molecular mechanisms of action are poorly understood and there are no biomarkers of exposure for occupational monitoring. Several pulmonary diseases, including lung cancer, have been associated with alterations in microRNA expression that are used as biomarkers of disease progression, and differentially-expressed microRNAs (DE miRNAs) can also allow understanding the molecular effects induced by a toxicant. In this study, we identify DE miRNAs in A549 alveolar epithelial cells following 24 h exposure to MWCNT-7 or crocidolite, as well as their enriched cellular functional pathways. These indicate that both materials change cell survival, differentiation and proliferative properties under the influence of AMPK, FoxO, TGF-ß and Hippo pathways, and their metabolic activity and cell-to-cell communication. In addition, MWCNT-7 affects the actin cytoskeleton, ubiquitin mediated proteolysis, and ECM-receptor interactions; crocidolite the PI3K-Akt and mTOR pathways, endocytosis, and central carbon metabolism. Since deregulation of these pathways may be related to carcinogenesis, an interaction network of DE miRNAs and corresponding target cancer-related genes was constructed, highlighting the carcinogenic potential of Mitsui-7.


Assuntos
Asbesto Crocidolita/toxicidade , Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Nanotubos de Carbono/toxicidade , Alvéolos Pulmonares/efeitos dos fármacos , Células A549 , Carbono/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia
11.
Science ; 368(6494): 1012-1015, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32303590

RESUMO

The current pandemic coronavirus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), was recently identified in patients with an acute respiratory syndrome, coronavirus disease 2019 (COVID-19). To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or Middle East respiratory syndrome (MERS)-CoV and compared the pathology and virology with historical reports of SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in the absence of clinical signs and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, whereas they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 causes COVID-19-like disease in macaques and provides a new model to test preventive and therapeutic strategies.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pulmão/patologia , Macaca fascicularis , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Envelhecimento , Animais , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Feminino , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Vírus da SARS/isolamento & purificação , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Replicação Viral , Eliminação de Partículas Virais
12.
Am J Physiol Lung Cell Mol Physiol ; 318(4): L787-L800, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32129084

RESUMO

Clinical studies have established that the capacity of removing excess fluid from alveoli is impaired in most patients with acute respiratory distress syndrome. Impaired alveolar fluid clearance (AFC) correlates with poor outcomes. Adenosine A2B receptor (A2BAR) has the lowest affinity with adenosine among four adenosine receptors. It is documented that A2BAR can activate adenylyl cyclase (AC) resulting in elevated cAMP. Based on the understanding that cAMP is a key regulator of epithelial sodium channel (ENaC), which is the limited step in sodium transport, we hypothesized that A2BAR signaling may affect AFC in acute lung injury (ALI) through regulating ENaC via cAMP, thus attenuating pulmonary edema. To address this, we utilized pharmacological approaches to determine the role of A2BAR in AFC in rats with endotoxin-induced lung injury and further focused on the mechanisms in vitro. We observed elevated pulmonary A2BAR level in rats with ALI and the similar upregulation in alveolar epithelial cells exposed to LPS. A2BAR stimulation significantly attenuated pulmonary edema during ALI, an effect that was associated with enhanced AFC and increased ENaC expression. The regulatory effects of A2BAR on ENaC-α expression were further verified in cultured alveolar epithelial type II (ATII) cells. More importantly, activation of A2BAR dramatically increased amiloride-sensitive Na+ currents in ATII cells. Moreover, we observed that A2BAR activation stimulated cAMP accumulation, whereas the cAMP inhibitor abolished the regulatory effect of A2BAR on ENaC-α expression, suggesting that A2BAR activation regulates ENaC-α expression via cAMP-dependent mechanism. Together, these findings suggest that signaling through alveolar epithelial A2BAR promotes alveolar fluid balance during endotoxin-induced ALI by regulating ENaC via cAMP pathway, raising the hopes for treatment of pulmonary edema due to ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/metabolismo , AMP Cíclico/metabolismo , Alvéolos Pulmonares/metabolismo , Receptor A2B de Adenosina/metabolismo , Transdução de Sinais/fisiologia , Lesão Pulmonar Aguda/induzido quimicamente , Adenosina/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Endotoxinas/farmacologia , Canais Epiteliais de Sódio/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Alvéolos Pulmonares/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Am J Physiol Lung Cell Mol Physiol ; 318(4): L831-L843, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186397

RESUMO

PDGF-A is a key contributor to lung development in mice. Its expression is needed for secondary septation of the alveoli and deletion of the gene leads to abnormally enlarged alveolar air spaces in mice. In humans, the same phenotype is the hallmark of bronchopulmonary dysplasia (BPD), a disease that affects premature babies and may have long lasting consequences in adulthood. So far, the knowledge regarding adult effects of developmental arrest in the lung is limited. This is attributable to few follow-up studies of BPD survivors and lack of good experimental models that could help predict the outcomes of this early age disease for the adult individual. In this study, we used the constitutive lung-specific Pdgfa deletion mouse model to analyze the consequences of developmental lung defects in adult mice. We assessed lung morphology, physiology, cellular content, ECM composition and proteomics data in mature mice, that perinatally exhibited lungs with a BPD-like morphology. Histological and physiological analyses both revealed that enlarged alveolar air spaces remained until adulthood, resulting in higher lung compliance and higher respiratory volume in knockout mice. Still, no or only small differences were seen in cellular, ECM and protein content when comparing knockout and control mice. Taken together, our results indicate that Pdgfa deletion-induced lung developmental arrest has consequences for the adult lung at the morphological and functional level. In addition, these mice can reach adulthood with a BPD-like phenotype, which makes them a robust model to further investigate the pathophysiological progression of the disease and test putative regenerative therapies.


Assuntos
Pulmão/patologia , Fator de Crescimento Derivado de Plaquetas/genética , Animais , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Feminino , Seguimentos , Hiperóxia/genética , Hiperóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/patologia
15.
PLoS Genet ; 16(3): e1008651, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150563

RESUMO

Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation.


Assuntos
Doenças Pulmonares Intersticiais/genética , Proteína 3 de Membrana Associada ao Lisossomo/genética , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Cães , Feminino , Estudo de Associação Genômica Ampla , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/fisiopatologia , Proteína 3 de Membrana Associada ao Lisossomo/metabolismo , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Mutação de Sentido Incorreto , Organelas/metabolismo , Alvéolos Pulmonares/metabolismo , Surfactantes Pulmonares , Vesículas Secretórias/metabolismo
16.
Occup Environ Med ; 77(6): 386-392, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32132182

RESUMO

OBJECTIVES: Four machine manufacturing facility workers had a novel occupational lung disease of uncertain aetiology characterised by lymphocytic bronchiolitis, alveolar ductitis and emphysema (BADE). We aimed to evaluate current workers' respiratory health in relation to job category and relative exposure to endotoxin, which is aerosolised from in-use metalworking fluid. METHODS: We offered a questionnaire and spirometry at baseline and 3.5 year follow-up. Endotoxin exposures were quantified for 16 production and non-production job groups. Forced expiratory volume in one second (FEV1) decline ≥10% was considered excessive. We examined SMRs compared with US adults, adjusted prevalence ratios (aPRs) for health outcomes by endotoxin exposure tertiles and predictors of excessive FEV1 decline. RESULTS: Among 388 (89%) baseline participants, SMRs were elevated for wheeze (2.5 (95% CI 2.1 to 3.0)), but not obstruction (0.5 (95% CI 0.3 to 1.1)). Mean endotoxin exposures (range: 0.09-28.4 EU/m3) were highest for machine shop jobs. Higher exposure was associated with exertional dyspnea (aPR=2.8 (95% CI 1.4 to 5.7)), but not lung function. Of 250 (64%) follow-up participants, 11 (4%) had excessive FEV1 decline (range: 403-2074 mL); 10 worked in production. Wheeze (aPR=3.6 (95% CI 1.1 to 12.1)) and medium (1.3-7.5 EU/m3) endotoxin exposure (aPR=10.5 (95% CI 1.3 to 83.1)) at baseline were associated with excessive decline. One production worker with excessive decline had BADE on subsequent lung biopsy. CONCLUSIONS: Lung function loss and BADE were associated with production work. Relationships with relative endotoxin exposure indicate work-related adverse respiratory health outcomes beyond the sentinel disease cluster, including an incident BADE case. Until causative factors and effective preventive strategies for BADE are determined, exposure minimisation and medical surveillance of affected workforces are recommended.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Bronquiolite/epidemiologia , Enfisema/epidemiologia , Endotoxinas/efeitos adversos , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Adulto , Idoso , Poluentes Ocupacionais do Ar/análise , Bronquiolite/induzido quimicamente , Enfisema/induzido quimicamente , Endotoxinas/análise , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Instalações Industriais e de Manufatura , Pessoa de Meia-Idade , National Institute for Occupational Safety and Health, U.S. , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/análise , Alvéolos Pulmonares/patologia , Inquéritos e Questionários , Estados Unidos
17.
Am J Physiol Lung Cell Mol Physiol ; 318(4): L619-L630, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022591

RESUMO

Mouse lung developmental maturation and final alveolarization phase begin at birth. During this dynamic process, alveolar cells modify their morphology and anchorage to the extracellular matrix. In particular, alveolar epithelial cell (AEC) type I undergo cytoplasmic flattening and folding to ensure alveoli lining. We developed FACS conditions for simultaneous isolation of alveolar epithelial and endothelial cells in the absence of specific reporters during the early and middle alveolar phase. We evidenced for the first time a pool of extractable epithelial cell populations expressing high levels of podoplanin at postnatal day (pnd)2, and we confirmed by RT-qPCR that these cells are already differentiated but still immature AEC type I. Maturation causes a decrease in isolation yields, reflecting the morphological changes that these cell populations are undergoing. Moreover, we find that major histocompatibility complex II (MHCII), reported as a good marker of AEC type II, is poorly expressed at pnd2 but highly present at pnd8. Combined experiments using LysoTracker and MHCII demonstrate the de novo acquisition of MCHII in AEC type II during lung alveolarization. The lung endothelial populations exhibit FACS signatures from vascular and lymphatic compartments. They can be concomitantly followed throughout alveolar development and were obtained with a noticeable increased yield at the last studied time point (pnd16). Our results provide new insights into early lung alveolar cell isolation feasibility and represent a valuable tool for pure AEC type I preparation as well as further in vitro two- and three-dimensional studies.


Assuntos
Células Epiteliais Alveolares/citologia , Células Endoteliais/citologia , Células Epiteliais/citologia , Pulmão/citologia , Alvéolos Pulmonares/citologia , Animais , Diferenciação Celular/fisiologia , Separação Celular/métodos , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Organogênese/fisiologia
18.
Nat Commun ; 11(1): 1103, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107376

RESUMO

Lipid-protein complexes are the basis of pulmonary surfactants covering the respiratory surface and mediating gas exchange in lungs. Cardiolipin is a mitochondrial lipid overexpressed in mammalian lungs infected by bacterial pneumonia. In addition, increased oxygen supply (hyperoxia) is a pathological factor also critical in bacterial pneumonia. In this paper we fabricate a micrometer-size graphene-based sensor to measure oxygen permeation through pulmonary membranes. Combining oxygen sensing, X-ray scattering, and Atomic Force Microscopy, we show that mammalian pulmonary membranes suffer a structural transformation induced by cardiolipin. We observe that cardiolipin promotes the formation of periodic protein-free inter-membrane contacts with rhombohedral symmetry. Membrane contacts, or stalks, promote a significant increase in oxygen gas permeation which may bear significance for alveoli gas exchange imbalance in pneumonia.


Assuntos
Cardiolipinas/metabolismo , Grafite/química , Bicamadas Lipídicas/metabolismo , Oxigênio/metabolismo , Alvéolos Pulmonares/metabolismo , Animais , Permeabilidade da Membrana Celular/fisiologia , Humanos , Microscopia de Força Atômica/instrumentação , Microscopia Confocal/instrumentação , Microtecnologia/instrumentação , Pneumonia Bacteriana/fisiopatologia , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/ultraestrutura , Troca Gasosa Pulmonar/fisiologia , Espalhamento a Baixo Ângulo , Transistores Eletrônicos , Difração de Raios X/instrumentação
19.
Nat Med ; 26(2): 259-269, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32042191

RESUMO

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Sistema Imunitário/fisiologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Animais , Brônquios/metabolismo , Diferenciação Celular , Linhagem da Célula , Análise por Conglomerados , Bases de Dados Genéticas , Progressão da Doença , Endoderma/metabolismo , Feminino , Humanos , Hidrogéis/química , Células Matadoras Naturais/metabolismo , Pulmão/patologia , Camundongos , Fenótipo , Alvéolos Pulmonares/metabolismo , Regeneração , Transdução de Sinais
20.
Am J Respir Cell Mol Biol ; 62(4): 454-465, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913651

RESUMO

During pulmonary secondary alveolar septation, the rudimentary distal saccule subdivides by extending tissue sheets into the saccular air space, creating alveoli, which open into the alveolar duct. The sheets originate from saccular mesenchymal cells, which contain α-SMA (αSMA [ACTA2]) and abut elastic fibers (myofibroblasts [MF]), characteristics that are shared by cells that subsequently occupy the secondary septal tips. During elongation, collagen fibers are positioned to provide a scaffold for translocating septal mesenchymal cells. We hypothesized that collagen fibers direct the migration, orientation, and location of MFs during septal elongation. To address this hypothesis, we examined how electrospun collagen fibers direct the migration of fibroblasts bearing targeted deletions of PDGFRα (platelet-derived growth factor receptor-α) or Nrp1 (neuropilin-1), after their isolation from lungs that exhibit reduced secondary septation. We observed that deletion of either gene reduced Rac1 activation and the speed of migration of lung fibroblasts (LF) along electrospun fibers. The deletions did not reduce the proportion of LF that displayed collagen-binding integrins and increased the proportion of LF bearing activated ß1-integrin. LF bearing the PDGFRα deletion failed to localize focal adhesions over electrospun fibers, suggesting that they may not appropriately sense and respond to regionally increased stiffness near the fibers. In lungs of mice bearing the PDGFRα deletion, collagen fibers are delocalized from ACTA2-containing MF, and their orientation deviated from the plane of the alveolar walls. Diminished PDGFRα or Nrp1 reduces LF localization to stiffer regions of fibrillar collagen substrates, suggesting that signaling through these receptors enables responsiveness to regional differences in extracellular matrix rigidity.


Assuntos
Colágeno/metabolismo , Fibroblastos/metabolismo , Pulmão/metabolismo , Miofibroblastos/metabolismo , Neuropilina-1/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Actinas/metabolismo , Animais , Matriz Extracelular/metabolismo , Feminino , Adesões Focais/metabolismo , Masculino , Camundongos , Alvéolos Pulmonares/metabolismo , Transdução de Sinais/fisiologia
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