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1.
Science ; 371(6534)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707239

RESUMO

The lung alveolus is the functional unit of the respiratory system required for gas exchange. During the transition to air breathing at birth, biophysical forces are thought to shape the emerging tissue niche. However, the intercellular signaling that drives these processes remains poorly understood. Applying a multimodal approach, we identified alveolar type 1 (AT1) epithelial cells as a distinct signaling hub. Lineage tracing demonstrates that AT1 progenitors align with receptive, force-exerting myofibroblasts in a spatial and temporal manner. Through single-cell chromatin accessibility and pathway expression (SCAPE) analysis, we demonstrate that AT1-restricted ligands are required for myofibroblasts and alveolar formation. These studies show that the alignment of cell fates, mediated by biophysical and AT1-derived paracrine signals, drives the extensive tissue remodeling required for postnatal respiration.


Assuntos
Linhagem da Célula/genética , Epigênese Genética , Alvéolos Pulmonares/embriologia , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Animais , Células Cultivadas , Sinais (Psicologia) , Epigenômica , Humanos , Camundongos , Camundongos Transgênicos , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , RNA-Seq/métodos , Transdução de Sinais , Análise de Célula Única , Transcriptoma
2.
BMC Pulm Med ; 21(1): 58, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588817

RESUMO

BACKGROUND: Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure. METHODS: Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia. RESULTS: Compared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). CONCLUSIONS: Hyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/metabolismo , Claudinas/genética , Hiperóxia/metabolismo , Proteínas Serina-Treonina Quinases/genética , Alvéolos Pulmonares/metabolismo , Junções Íntimas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/ultraestrutura , Animais , Líquido da Lavagem Broncoalveolar/química , Claudinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hiperóxia/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Permeabilidade , Proteínas Serina-Treonina Quinases/metabolismo , Alvéolos Pulmonares/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Junções Íntimas/ultraestrutura
3.
Medicine (Baltimore) ; 100(6): e23570, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578509

RESUMO

ABSTRACT: The Gas Man simulation software provides an opportunity to teach, understand and examine the pharmacokinetics of volatile anesthetics. The primary aim of this study was to investigate the accuracy of a cardiac output and alveolar ventilation matched Gas Man model and to compare its predictive performance with the standard pharmacokinetic model using patient data.Therefore, patient data from volatile anesthesia were successively compared to simulated administration of desflurane and sevoflurane for the standard and a parameter-matched simulation model with modified alveolar ventilation and cardiac output. We calculated the root-mean-square deviation (RMSD) between measured and calculated induction, maintenance and elimination and the expiratory decrement times during emergence and recovery for the standard and the parameter-matched model.During induction, RMSDs for the standard Gas Man simulation model were higher than for the parameter-matched Gas Man simulation model [induction (desflurane), standard: 1.8 (0.4) % Atm, parameter-matched: 0.9 (0.5) % Atm., P = .001; induction (sevoflurane), standard: 1.2 (0.9) % Atm, parameter-matched: 0.4 (0.4) % Atm, P = .029]. During elimination, RMSDs for the standard Gas Man simulation model were higher than for the parameter-matched Gas Man simulation model [elimination (desflurane), standard: 0.7 (0.6) % Atm, parameter-matched: 0.2 (0.2) % Atm, P = .001; elimination (sevoflurane), standard: 0.7 (0.5) % Atm, parameter-matched: 0.2 (0.2) % Atm, P = .008]. The RMSDs during the maintenance of anesthesia and the expiratory decrement times during emergence and recovery showed no significant differences between the patient and simulated data for both simulation models.Gas Man simulation software predicts expiratory concentrations of desflurane and sevoflurane in humans with good accuracy, especially when compared to models for intravenous anesthetics. Enhancing the standard model by ventilation and hemodynamic input variables increases the predictive performance of the simulation model. In most patients and clinical scenarios, the predictive performance of the standard Gas Man simulation model will be high enough to estimate pharmacokinetics of desflurane and sevoflurane with appropriate accuracy.


Assuntos
Débito Cardíaco/efeitos dos fármacos , Desflurano/farmacocinética , Expiração/fisiologia , Ventilação Pulmonar/fisiologia , Sevoflurano/farmacocinética , Adulto , Idoso , Algoritmos , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/farmacocinética , Débito Cardíaco/fisiologia , Ensaios Clínicos como Assunto , Simulação por Computador/estatística & dados numéricos , Desflurano/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Pulmão/metabolismo , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiologia , Sevoflurano/administração & dosagem
4.
Int J Pharm ; 595: 120241, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33484917

RESUMO

Inhaled ciclesonide (CIC), a corticosteroid used to treat asthma that is also being investigated for the treatment of corona virus disease 2019, hydrolyzes to desisobutyryl-ciclesonide (des-CIC) followed by reversible esterification when exposed to fatty acids in lungs. While previous studies have described the distribution and metabolism of the compounds after inhalation, spatial localization in the lungs remains unclear. We visualized two-dimensional spatial localization of CIC and its metabolites in rat lungs after administration of a single dose of a CIC aerosol (with the mass median aerodynamic diameter of 0.918-1.168 µm) using desorption electrospray ionization-time of flight mass spectrometry imaging (DESI-MSI). In the analysis, CIC, des-CIC, and des-CIC-oleate were imaged in frozen lung sections at high spatial and mass resolutions in negative-ion mode. MSI revealed the coexistence of CIC, des-CIC, and des-CIC-oleate on the airway epithelium, and the distribution of des-CIC and des-CIC-oleate in peripheral lung regions. In addition, a part of CIC independently localized on the airway epithelium. These results suggest that distribution of CIC and its metabolites in lungs is related to both the intended delivery of aerosols to pulmonary alveoli and peripheral regions, and the potential deposition of CIC particles on the airway epithelium.


Assuntos
Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pregnenodionas/administração & dosagem , Pregnenodionas/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Administração por Inalação , Aerossóis/química , Animais , Células Epiteliais/metabolismo , Glucocorticoides/sangue , Pregnenodionas/sangue , Pregnenodionas/metabolismo , Alvéolos Pulmonares/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
5.
Sci Rep ; 10(1): 19522, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177594

RESUMO

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin-kallikrein system, resulting in acute lung inflammatory edema; the renin-angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.


Assuntos
Betacoronavirus/genética , Coagulação Sanguínea , Perfilação da Expressão Gênica , Sistema Calicreína-Cinina/genética , Peptidil Dipeptidase A/genética , Alvéolos Pulmonares/citologia , Sistema Renina-Angiotensina/genética , Betacoronavirus/enzimologia , Betacoronavirus/fisiologia , Humanos , Alvéolos Pulmonares/metabolismo , Serina Endopeptidases/genética
7.
Anesth Analg ; 131(5): 1551-1556, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079878

RESUMO

BACKGROUND: Recently, there has been significant focus on the effects of anesthesia on the developing brain. Concern is heightened in children <3 years of age requiring lengthy and/or multiple anesthetics. Hypospadias correction is common in otherwise healthy children and may require both lengthy and repeated anesthetics. At academic centers, many of these cases are performed with the assistance of anesthesia and surgical trainees. We sought to identify both the incidence of these children undergoing additional anesthetics before age 3 as well as to understand the effect of trainees on duration of surgery and anesthesia and thus anesthetic exposure (AE), specifically focusing on those cases >3 hours. METHODS: We analyzed all cases of hypospadias repair from December 2011 through December 2018 at Texas Children's Hospital. In all, 1326 patients undergoing isolated hypospadias repair were analyzed for anesthesia time, surgical time, provider types involved, AE, caudal block, and additional AE related/unrelated to hypospadias. RESULTS: For the primary aim, a total of 1573 anesthetics were performed in children <3 years of age, including 1241 hypospadias repairs of which 1104 (89%) were completed with <3 hours of AE. For patients with <3 hours of AE, 86.1% had a single surgical intervention for hypospadias. Of patients <3 years of age, 17.3% required additional nonrelated surgeries. There was no difference in anesthesia time in cases performed solely by anesthesia attendings versus those performed with trainees/assistance (16.8 vs 16.8 minutes; P = .98). With regard to surgery, cases performed with surgical trainees were of longer duration than those performed solely by surgical attendings (83.5 vs 98.3 minutes; P < .001). Performance of surgery solely by attending surgeon resulted in a reduced total AE in minimal alveolar concentration (MAC) hours when compared to procedures done with trainees (1.92 vs 2.18; P < .001). Finally, comparison of patients undergoing initial correction of hypospadias with subsequent revisions revealed a longer time (117.7 vs 132.2 minutes; P < .001) and AE during the primary stage. CONCLUSIONS: The majority of children with hypospadias were repaired within a single AE. In general, most children did not require repeated AE before age 3. While presence of nonattending surgeons was associated with an increase in AE, this might at least partially be due to differences in case complexity. Moreover, the increase is likely not clinically significant. While it is critical to maintain a training environment, attempts to minimize AE are crucial. This information facilitates parental consent, particularly with regard to anesthesia duration and the need for additional anesthetics in hypospadias and nonhypospadias surgeries.


Assuntos
Anestesia/métodos , Anestésicos/administração & dosagem , Hipospadia/cirurgia , Anestesia/efeitos adversos , Anestesia Caudal , Anestesiologistas , Anestésicos/efeitos adversos , Pré-Escolar , Humanos , Incidência , Lactente , Internato e Residência , Masculino , Enfermeiras Anestesistas , Duração da Cirurgia , Alvéolos Pulmonares/metabolismo , Reoperação/estatística & dados numéricos , Cirurgiões , Apoio ao Desenvolvimento de Recursos Humanos , Resultado do Tratamento
8.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 212-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093785

RESUMO

Background: Zonal aggregates of elastic fibres (zonal elastosis) and intraalveolar collagenosis with septal elastosis are histologic components of subpleural fibroelastosis of idiopathic pleuroparenchymal fibroelastosis (IPPFE). Zonal elastosis is considered to result from alveolar collapse, but this mechanism has not been fully justified. Methods: We immunohistochemically attempted to identify epithelial cells in zonal elastosis of 10 patients with IPPFE. The thickness of the zonal elastosis in relation to the total thickness of the fibroelastosis was examined to estimate the influence of zonal elastosis on the occurrence and development of IPPFE. Results: In 9 of the 10 patients, multi-cytokeratin-positive cells were found lining the inner surface of slit-like spaces embedded in the zonal elastosis. Zonal elastosis was predominant when fibroelastosis was < 1 mm thick but less predominant when it was ≥1 mm. Conclusion: The zonal elastosis was proven to result from alveolar collapse, which might be an initial lesion in IPPFE. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 212-217).


Assuntos
Tecido Elástico/patologia , Fibrose Pulmonar Idiopática/patologia , Alvéolos Pulmonares/metabolismo , Adulto , Idoso , Células Epiteliais Alveolares/química , Células Epiteliais Alveolares/patologia , Biomarcadores/análise , Tecido Elástico/química , Feminino , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Queratinas/análise , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/química , Estudos Retrospectivos , Adulto Jovem
10.
Adv Mater ; 32(43): e2004901, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32924219

RESUMO

The COVID-19 pandemic has taken a significant toll on people worldwide, and there are currently no specific antivirus drugs or vaccines. Herein it is a therapeutic based on catalase, an antioxidant enzyme that can effectively breakdown hydrogen peroxide and minimize the downstream reactive oxygen species, which are excessively produced resulting from the infection and inflammatory process, is reported. Catalase assists to regulate production of cytokines, protect oxidative injury, and repress replication of SARS-CoV-2, as demonstrated in human leukocytes and alveolar epithelial cells, and rhesus macaques, without noticeable toxicity. Such a therapeutic can be readily manufactured at low cost as a potential treatment for COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Catalase/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacocinética , Antioxidantes/farmacocinética , Betacoronavirus/fisiologia , Catalase/farmacocinética , Linhagem Celular , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucócitos/virologia , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , Replicação Viral/efeitos dos fármacos
11.
Int J Legal Med ; 134(6): 2209-2214, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767018

RESUMO

A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse crazy-paving lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumonia Viral/patologia , Idoso , Células Epiteliais Alveolares/patologia , Autopsia , Fibrina/metabolismo , Humanos , Hiperplasia , Masculino , Pandemias , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Tomografia Computadorizada por Raios X
12.
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
13.
Life Sci ; 259: 118260, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32795541

RESUMO

Cigarette smoke (CS), the major risk factor of chronic obstructive pulmonary disease (COPD), contains numerous free radicals that can cause oxidative stress and exaggerated inflammatory responses in the respiratory system. Lipid peroxidation which is oxidative degradation of polyunsaturated fatty acids and results in cell damage has also been associated with COPD pathogenesis. Increased levels of lipid peroxidation as well as its end product 4-hydroxynonenal have indeed been detected in COPD patients. Additionally, reactive oxygen species such as those contained in CS can activate nuclear factor-κB signaling pathway, initiating cascades of proinflammatory mediator expression. As emerging evidence attests to the antioxidative and anti-inflammatory properties of tea catechins, we sought to determine whether epigallocatechin gallate, the most abundant tea catechin, can provide protection against oxidative stress, lipid peroxidation, and inflammatory responses caused by CS. We found that EGCG treatment blocked cigarette smoke extract (CSE)-induced oxidative stress as indicated by decreased production and accumulation of reactive oxygen species in airway epithelial cells (AECs). Likewise, lipid peroxidation in CSE-stimulated AECs was suppressed by EGCG. Our findings further suggest that EGCG sequestered 4-hydroxynonenal and interfered with its protein adduct formation. Lastly, we show that EGCG inhibited nuclear factor-κB activation and the downstream expression of proinflammatory mediators. In summary, our study describing the antioxidative and anti-inflammatory effects of EGCG in CSE-exposed AECs provide valuable information about the therapeutic potential of this tea catechin for COPD.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Catequina/análogos & derivados , Fumar Cigarros/tratamento farmacológico , Aldeídos/farmacologia , Células Epiteliais Alveolares/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Brônquios/metabolismo , Catequina/metabolismo , Catequina/farmacologia , Linhagem Celular , Fumar Cigarros/efeitos adversos , Fumar Cigarros/fisiopatologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Fumaça/efeitos adversos , Fumar/efeitos adversos
14.
Am J Physiol Lung Cell Mol Physiol ; 319(3): L576-L584, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755324

RESUMO

Prevention of bronchopulmonary dysplasia (BPD) in premature-birth babies continues to be an unmet medical need. Intramuscular vitamin A is currently employed in preterm neonates to prevent BPD but requires intramuscular injections in fragile neonates. We hypothesized that noninvasive inhaled delivery of vitamin A, targeted to lung, would be a more effective and tolerable strategy. We employed our well-established hyperoxia-injury neonatal rat model, exposing newborn rats to 7 days of constant extreme (95% O2) hyperoxia, comparing vitamin A dosed every 48 h via either aerosol inhalation or intramuscular injection with normoxic untreated healthy animals and vehicle-inhalation hyperoxia groups as positive and negative controls, respectively. Separately, similar vitamin A dosing of normoxia-dwelling animals was performed. Analyses after day 7 included characterization of alveolar histomorphology and protein biomarkers of alveolar maturation [surfactant protein C (SP-C), peroxisome proliferator-activated receptor (PPAR) γ, cholinephosphate cytidylyl transferase, vascular endothelial growth factor and its receptor, FLK-1, and retinoid X receptors (RXR-α, -ß, and -γ], apoptosis (Bcl2 and Bax) key injury repair pathway data including protein markers (ALK-5 and ß-catenin) and neutrophil infiltration, and serum vitamin A levels. Compared with intramuscular dosing, inhaled vitamin A significantly enhanced biomarkers of alveolar maturation, mitigated hyperoxia-induced lung damage, and enhanced surfactant protein levels, suggesting that it may be more efficacious in preventing BPD in extremely premature infants than the traditionally used IM dosing regimen. We speculate lung-targeted inhaled vitamin A may also be an effective therapy against other lung damaging conditions leading to BPD or, more generally, to acute lung injury.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Displasia Broncopulmonar/metabolismo , Hiperóxia/metabolismo , Pulmão/metabolismo , Vitamina A/metabolismo , Animais , Animais Recém-Nascidos , Alvéolos Pulmonares/metabolismo , Surfactantes Pulmonares/metabolismo , Ratos
15.
Am J Respir Cell Mol Biol ; 63(4): 452-463, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32663413

RESUMO

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.


Assuntos
Elastase Pancreática/metabolismo , Peptídeos/metabolismo , Enfisema Pulmonar/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose/fisiologia , Simulação por Computador , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Alvéolos Pulmonares/metabolismo , Fumaça/efeitos adversos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Am J Physiol Cell Physiol ; 319(2): C316-C320, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32639871

RESUMO

Pulmonary surfactant is a heterogeneous active surface complex made up of lipids and proteins. The major glycoprotein in surfactant is surfactant protein A (SP-A), which is released into the alveolar lumen from cytoplasmic lamellar bodies in type II alveolar epithelial cells. SP-A is involved in phospholipid absorption. SP-A together with other surfactant proteins and phospholipids prevent alveolar collapse during respiration by decreasing the surface tension of the air-liquid interface. Additionally, SP-A interacts with pathogens to prevent their propagation and regulate host immune responses. Studies in human and animal models have shown that deficiencies or mutations in surfactant components result in various lung or kidney pathologies, suggesting a role for SP-A in the development of lung and kidney diseases. In this mini-review, we discuss the current understanding of SP-A functions, recent findings of its dysfunction in specific lung and kidney pathologies, and how SP-A has been used as a biomarker to detect the outcome of lung diseases.


Assuntos
Nefropatias/genética , Pneumopatias/genética , Alvéolos Pulmonares/metabolismo , Proteína A Associada a Surfactante Pulmonar/genética , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Citoplasma/genética , Citoplasma/metabolismo , Progressão da Doença , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/patologia , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , Alvéolos Pulmonares/patologia , Surfactantes Pulmonares/metabolismo
17.
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
18.
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 , /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 , /imunologia
19.
Eur J Histochem ; 64(2)2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32378837

RESUMO

Sialic acids, particularly N-acetylneuraminic acid (Neu5Ac), are present as terminal components of rich and complex oligosaccharide chains, which are termed glycans, and are exhibited on the cell surfaces, especially on epithelial cells. Crucial in the 'social behavior' of the cell, sialic acids play vital roles in many physiological and pathological phenomena. The aim of the present study was to separate, identify, and quantify Neu5Ac in purified lung membranes from 4-, 14-, and 21-day-old animals, followed by the statistical analysis of these results with our previously reported data (0-day-old and adult results). Complementary, ultrastructural methodologies were used. The differences in the Neu5Ac values obtained across the examined postnatal-lung development relevant ages studied were found to be statistically significant. A substantial increase in the mean level of this compound was found during the period of 'bulk' alveolarization, which takes place from postnatal day 4 to 14 (P4-P14). The comparison of the mean levels of Neu5Ac, during microvascular maturation (mainly between P12 and P21), reveals that the difference, although statistically significant, is the least significant difference among all the pair-wise differences between the developmental stages. The presence of sub-terminal N-acetylgalactosamine (GalNAc)/Galactose (Gal) residues with terminal sialic acids on the bronchioloalveolar cell surfaces was confirmed using lung ultra-thin sections of adult and 0-day-old animals. These results showed that, although Neu5Ac levels increase throughout postnatal lung development, this sialic acid was substantially added to epithelial cell surfaces during the "bulk" alveolarization period, while its presence was less important during the microvascular maturation period. Bearing in mind that sialic acids are negatively charged and create charge repulsions between adjacent cells, we hypothesized that they can substantially contribute to postnatal alveolar formation and maturation.


Assuntos
Ácido N-Acetilneuramínico/metabolismo , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Alvéolos Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Ratos
20.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L173-L184, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432919

RESUMO

The alveolar epithelium is comprised of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells, the latter being capable of self-renewal and transdifferentiation into AT1 cells for normal maintenance and restoration of epithelial integrity following injury. MicroRNAs (miRNAs) are critical regulators of several biological processes, including cell differentiation; however, their role in establishment/maintenance of cellular identity in adult alveolar epithelium is not well understood. To investigate this question, we performed genome-wide analysis of sequential changes in miRNA and gene expression profiles using a well-established model in which human AT2 (hAT2) cells transdifferentiate into AT1-like cells over time in culture that recapitulates many aspects of transdifferentiation in vivo. We defined three phases of miRNA expression during the transdifferentiation process as "early," "late," and "consistently" changed, which were further subclassified as up- or downregulated. miRNAs with altered expression at all time points during transdifferentiation were the largest subgroup, suggesting the need for consistent regulation of signaling pathways to mediate this process. Target prediction analysis and integration with previously published gene expression data identified glucocorticoid signaling as the top pathway regulated by miRNAs. Serum/glucocorticoid-regulated kinase 1 (SGK1) emerged as a central regulatory factor, whose downregulation correlated temporally with gain of hsa-miR-424 and hsa-miR-503 expression. Functional validation demonstrated specific targeting of these miRNAs to the 3'-untranslated region of SGK1. These data demonstrate the time-related contribution of miRNAs to the alveolar transdifferentiation process and suggest that inhibition of glucocorticoid signaling is necessary to achieve the AT1-like cell phenotype.


Assuntos
Diferenciação Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Genoma Humano , MicroRNAs/metabolismo , Alvéolos Pulmonares/metabolismo , Transcriptoma/genética , Sequência de Bases , Diferenciação Celular/genética , Linhagem Celular , Transdiferenciação Celular/genética , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Humanos , Proteínas Imediatamente Precoces/metabolismo , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/metabolismo
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