RESUMEN
The role of endothelial cells in acute lung injury (ALI) has been widely elaborated, but little is known about the role of different subtypes of endothelial cells in ALI. ALI models were established by lipopolysaccharide. Single-cell RNA sequencing was used to identify differential molecules in endothelial subtypes and the heterogeneity of lung immune cells. Specific antibodies were used to block insulin-like growth factor binding protein 7 (IGFBP7), and AAVshIGP7 was used to specifically knock down IGFBP7. Here, we found that IGFBP7 was the most differentially expressed molecule in diverse subsets of endothelial cells and that IGFBP7 was strongly associated with inflammatory responses. Elevated IGFBP7 significantly exacerbated barrier dysfunction in ALI, whereas blockade of IGFBP7 partially reversed barrier damage. General capillary cells are the primary source of elevated serum IGFBP7 after ALI. Using single-cell RNA sequencing, we identified significantly increased Clec4nhi neutrophils in mice with ALI, whereas IGFBP7 knockdown significantly reduced infiltration of Clec4nhi cells and mitigated barrier dysfunction in ALI. In addition, we found that IGFBP7 activated the NF-κB signaling axis by promoting phosphorylation and ubiquitination degradation of F-box/WD repeat-containing protein 2 (FBXW2), thereby exacerbating barrier dysfunction in ALI. Taken together, our data indicate that blockade of serum IGFBP7 or IGFBP7 depletion in general capillary cells reversed barrier damage in ALI. Therefore, targeting IGFBP7 depletion could be a novel strategy for treating ALI.
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Lesión Pulmonar Aguda , Células Endoteliales , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Neutrófilos , Animales , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Neutrófilos/metabolismo , Ratones , Ratones Endogámicos C57BL , Humanos , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Transducción de Señal , Masculino , FN-kappa B/metabolismo , Pulmón/metabolismo , Pulmón/patología , Lipopolisacáridos/farmacologíaRESUMEN
BACKGROUND: Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. METHODS: The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at - 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. CONCLUSIONS: Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653.
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Bronquiectasia , Humanos , Bronquiectasia/diagnóstico , Bronquiectasia/epidemiología , China/epidemiología , Estudios de Cohortes , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Estudios Prospectivos , Calidad de Vida , Sistema de RegistrosRESUMEN
NGAL is mainly secreted by neutrophils which play the core role in AECOPD. MCP-1 is secreted specifically by monocytes and macrophages. Both biomarkers are involved in the core process of acute inflammatory reaction in COPD. So We analyzed serum NGAL and MCP-1levels to explore their potential clinical values in the chronic obstructive pulmonary disease (COPD) .This study enrolled 97 COPD patients and 50 healthy controls. All participants received blood collection and lung function test and arterial blood gas measurements. The expression levels of serum NGAL and MCP-1 were measured by ELISA. The serum NGAL and MCP-1 levels of COPD with community-acquired pneumonia (COPD-CAP) patients were significantly higher than those of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients and healthy adults. The NGAL levels of the GOLD III and IV groups were significantly higher than those of the GOLD II group. Spearman correlation analysis showed a negative correlation between NGAL and FEV1%pred, FVC% pred. ROC curves indicated that NGAL has a high diagnostic value for both AECOPD and COPD-CAP. NGAL has the value of distinguishing GOLD I and II from GOLD III and IV. MCP-1 have moderate diagnostic value for COPD-CAP and can differentiate COPD-CAP from AECOPD. This study shows NGAL has certain diagnostic value for AECOPD and COPD-CAP, but can not distinguish the two. NGAL is closely related to airway remodeling and can be used as a potential indicator to distinguish the higher GOLD degree. MCP-1 can be used as potential indicator for the diagnosis of COPD-CAP.
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Quimiocina CCL2/sangre , Infecciones Comunitarias Adquiridas , Lipocalina 2/sangre , Neumonía , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Biomarcadores/sangre , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/diagnóstico , Estudios Transversales , Femenino , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Masculino , Persona de Mediana Edad , Neumonía/sangre , Neumonía/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. METHODS: In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. RESULTS: To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. CONCLUSIONS: Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.
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Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Técnicas para Inmunoenzimas/métodos , Neumonía Viral/diagnóstico , Pruebas Serológicas/métodos , Adulto , COVID-19 , Prueba de COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Pandemias , Péptidos/inmunología , Neumonía Viral/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Sensibilidad y Especificidad , Proteínas Virales/inmunologíaRESUMEN
BACKGROUND: Since December 2019, over 80,000 patients with coronavirus disease 2019 (COVID-19) have been confirmed in China. With the increasing number of recovered patients, more attention should be paid to the follow-up of these patients. METHODS: In the study, 576 patients with COVID-19 discharged from hospital in Chongqing, China from January 24, 2020, to March 10, 2020 were evaluated by viral nucleic acid tests for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) to determine if they could be released from quarantine. Among the 576 patients, 61 patients (10.6%) had positive RT-PCR test results of SARS-CoV-2. We aimed to analyze the demographics, clinical characteristics and treatment of 61 patients. RESULTS: These positive patients were characterized by older age, chronic medical illness and mild conditions. 38 (62.3%) patients who were asymptomatic without abnormalities on chest radiographs were found in the positive with COVID-19. Also, they showed positive results of stool or sputum specimens with negative results of nasal and pharyngeal swab specimens. The median duration of positive result of SARS-CoV-2 was varied from 3 days to 35 days in the patients discharged from hospital with no family member infection. CONCLUSIONS: Multi-site screening of SARS-CoV-2 including nasal and pharyngeal swabs, stool and sputum specimens could be considered to improve the diagnosis, treatment and infection control in patients with COVID-19. Our findings provide the important information and clinical evidence for the improved management of patients recovered from COVID-19.
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Infecciones por Coronavirus/diagnóstico , Alta del Paciente , Neumonía Viral/diagnóstico , Adulto , Anciano , Betacoronavirus , COVID-19 , Prueba de COVID-19 , China , Técnicas de Laboratorio Clínico , Heces/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nariz/virología , Pandemias , Faringe/virología , ARN Viral/aislamiento & purificación , SARS-CoV-2 , Esputo/virologíaRESUMEN
BACKGROUND: Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this. METHODS: Our ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1ß in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 µM) with or without GW9662 (10 µM). The expressions of αENaC and SGK1 were determined 24 h later. RESULTS: A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1ß levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662. CONCLUSIONS: Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.
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Lesión Pulmonar Aguda/metabolismo , Líquido del Lavado Bronquioalveolar/química , Canales Epiteliales de Sodio/metabolismo , PPAR gamma/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Rosiglitazona/farmacología , Transducción de Señal , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Animales , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Baicalin has been reported to attenuate lung edema in the process of lung injury. However, the effect of baicalin on alveolar fluid clearance (AFC) and epithelial sodium channel (ENaC) expression has not been tested. Sprague-Dawley rats were anesthetized and intratracheally injected with either 1 mg/kg lipopolysaccharide (LPS) or saline vehicle. Baicalin with various concentrations (10, 50, and 100 mg/kg) was injected intraperitoneally 30 min before administration of LPS. Then lungs were isolated for measurement of AFC, cyclic adenosine monophosphate (cAMP) level, and cellular localization of α-ENaC. Moreover, mouse alveolar type II (ATII) epithelial cell line was incubated with baicalin (30 µmol/L), adenylate cyclase inhibitor SQ22536 (10 µmol/L), or cAMP-dependent protein kinase inhibitor (PKA) KT5720 (0.3 µmol/L) 15 min before LPS (1 µg/mL) incubation. Protein expression of α-ENaC was detected by Western blot. Baicalin increased cAMP concentration and AFC in a dose-dependent manner in rats with LPS-induced acute lung injury. The increase of AFC induced by baicalin was associated with an increase in the abundance of α-ENaC protein. SQ22536 and KT5720 prevented the increase of α-ENaC expression caused by baicalin in vitro. These findings suggest that baicalin prevents LPS-induced reduction of AFC by upregulating α-ENaC protein expression, which is activated by stimulating cAMP/PKA signaling pathway.
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Lesión Pulmonar Aguda/metabolismo , Canales Epiteliales de Sodio/metabolismo , Flavonoides/farmacología , Pulmón/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/fisiopatología , Inhibidores de Adenilato Ciclasa/farmacología , Animales , Antiinflamatorios no Esteroideos/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Carbazoles/farmacología , Células Cultivadas , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Edema/complicaciones , Edema/tratamiento farmacológico , Edema/fisiopatología , Células Epiteliales/metabolismo , Células Epiteliales/fisiología , Flavonoides/antagonistas & inhibidores , Flavonoides/uso terapéutico , Ionomicina/farmacología , Lipopolisacáridos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Ratas , Agua/metabolismoRESUMEN
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by proteinaceous pulmonary edema and severe arterial hypoxemia with a mortality of approximately 40%. Stimulation of epithelial sodium channel (ENaC) promotes Na(+) transport, a rate-limiting step for pulmonary edema reabsorption. Insulin is known to participate in the ion transport; however, its role in pulmonary edema clearance and the regulatory mechanism involved have not been fully elucidated. In the current study, in a lipopolysaccharide-based mouse model of ALI, we found that insulin alleviated pulmonary edema by promoting ENaC-mediated alveolar fluid clearance through serum and glucocorticoid induced kinase-1 (SGK1). In alveolar epithelial cells, insulin increased the expression of α-, ß-, and γ-ENaC, which was blocked by the mammalian target of rapamycin complex 2 (mTORC2) inhibitor or knockdown of Rictor (a necessary component of mTORC2), and SGK1 inhibitor, respectively. In addition, an immunoprecipitation study demonstrated that SGK1(Ser422) phosphorylation, the key step for complete SGK1 activation by insulin, was conducted through PI3K/mTORC2 pathway. Finally, we testified the role of mTORC2 in vivo by demonstrating that PP242 prevented insulin-stimulated SGK1 activation and ENaC increase during ALI. The data revealed that during ALI, insulin stimulates alveolar fluid clearance by upregulating the expression of α-, ß-, and γ-ENaC at the cell surface, which was, at least, partially through activating mTROC2/SGK1 signaling pathway.
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Lesión Pulmonar Aguda/metabolismo , Modelos Animales de Enfermedad , Canales Epiteliales de Sodio/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Insulina/farmacología , Complejos Multiproteicos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Alveolos Pulmonares/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Animales , Western Blotting , Canales Epiteliales de Sodio/genética , Humanos , Hipoglucemiantes/farmacología , Proteínas Inmediatas-Precoces/genética , Técnicas para Inmunoenzimas , Inmunoprecipitación , Técnicas In Vitro , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Endogámicos C57BL , Complejos Multiproteicos/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: The epithelial sodium channel (ENaC) is the driving force for pulmonary edema absorption in acute lung injury (ALI). Netrin-1 is a newly found anti-inflammatory factor that works by activating the adenosine 2B receptor (A2BAR). Meanwhile, activated A2BAR has the potential to enhance ENaC-dependent alveolar fluid clearance (AFC). However, whether netrin-1 can increase ENaC-mediated AFC by activating A2BAR remains unclear. OBJECTIVES: To investigate the effect of netrin-1 on AFC in ALI and clarify the pathway via which netrin-1 regulates the expression of ENaC in vivo and in vitro. METHODS: An ALI model was established by intratracheal instillation of lipopolysaccharide (LPS; 5 mg/kg) in C57BL/J mice, followed by netrin-1 with or without pretreatment with PSB1115, via the caudal vein. Twenty-four hours later, the lungs were isolated for determination of the bronchoalveolar lavage fluid, the lung wet/dry weight (W/D) ratio, AFC, the expressions of α-, ß-, and γ-ENaC, and cyclic adenosine monophosphate (cAMP) levels. LPS-stimulated MLE-12 cells were incubated with netrin-1 with or without preincubation with PSB1115. Twenty-four hours later, the expressions of α-, ß-, and γ-ENaC were detected. RESULTS: In vivo, netrin-1 expression was significantly decreased during ALI. Substituted netrin-1 significantly dampened the lung injury, decreased the W/D ratio, and enhanced AFC, the expressions of α-, ß-, and γ-ENaC, and cAMP levels in ALI, which were abolished by specific A2BAR inhibitor PSB1115. In vitro, netrin-1 increased the expressions of α-, ß-, and γ-ENaC, which were prevented by PSB1115. CONCLUSION: These results indicate that netrin-1 dampens pulmonary inflammation and increases ENaC-mediated AFC to alleviate pulmonary edema in LPS-induced ALI by enhancing cAMP levels through the activation of A2BAR.
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Lesión Pulmonar Aguda/metabolismo , AMP Cíclico/metabolismo , Canales Epiteliales de Sodio/metabolismo , Pulmón/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Edema Pulmonar/metabolismo , Receptor de Adenosina A2B/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Antagonistas del Receptor de Adenosina A2 , Animales , Modelos Animales de Enfermedad , Canales Epiteliales de Sodio/efectos de los fármacos , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/farmacología , Netrina-1 , Edema Pulmonar/inducido químicamente , Receptor de Adenosina A2B/efectos de los fármacos , Absorción a través del Sistema Respiratorio/efectos de los fármacos , Proteínas Supresoras de Tumor/farmacología , XantinasRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe respiratory condition characterized by a high mortality rate, the management of which relies on supportive care and a profound understanding of its pathophysiology. Heparin, with its anticoagulant and potential anti-inflammatory properties, offers a new therapeutic opportunity for the treatment of ARDS. METHODS: In this retrospective cohort study, we examined the MIMIC-IV database for ARDS patients who received prophylactic heparin within the first 72 h of ICU admission. Employing propensity score matching and inverse probability weighting (IPW) analysis, we evaluated the impact of early heparin use on patient outcomes, focusing on mortality rates. RESULTS: Patients who received prophylactic heparin had a significantly lower in-hospital mortality rate compared to those who did not (13.55% vs 17.93%, HR = 0.71, 95% CI: 0.54-0.93, P = 0.012). This result remained significant after propensity score matching (12.75% vs 17.93%, HR = 0.65, 95% CI 0.47-0.90, P = 0.010). Analysis using five different statistical models indicated that early use of heparin significantly reduced the in-hospital mortality rate, with HR = 0.669 (95% CI 0.487-0.919, P = 0.013) in the doubly robust model without balanced covariates; HR = 0.705 (95% CI 0.515-0.965, P = 0.029) with all covariates considered; HR = 0.660 (95% CI 0.491-0.888, P = 0.006) in the propensity score (IPW) model; HR = 0.650 (95% CI 0.470-0.900, P = 0.010) in the propensity score matching model; and HR = 0.706 (95% CI 0.536-0.930, P = 0.013) in the multivariate Cox regression model. Secondary outcomes indicated that heparin use was also associated with reduced mortality rates at 60 days, and 90 days. CONCLUSION: This research highlights that early prophylactic administration of heparin may substantially lower mortality in ARDS patients. These findings underscore the potential of heparin as a key component in the management of ARDS, offering a new perspective and novel strategies for clinical treatment.
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MT-1207 (MT) as a new antihypertensive drug is under clinical trial. However, its hypotensive mechanism has not been experimentally explored, and it is unknown whether MT can be used for bilateral renal artery stenosis hypertension. Using two-kidney two-clip (2K2C) to mimic bilateral renal artery stenosis in rats, a stroke-prone renovascular hypertension model, the present study further verified its antihypertensive effect, cardiovascular and renal protection, mortality reduction and lifespan prolongation, as well as demonstrated its two novel pharmacological effects for uric acid-lowering and cognition-improving. Notably, MT did not aggravate renal dysfunction; instead, it had beneficial effects on reducing serum uric acid level and maintaining serum K+ at a relatively stable level in 2K2C rats. In contrast, angiotensin receptor blocker losartan aggravated renal dysfunction in 2K2C rats. Mechanistically, MT hypotensive effect was dependent on its blockade of α1 and 5-HT2 receptors, since MT pretreatment abolished these receptor agonists-induced blood pressure elevations in vivo. Further evidence showed MT bound to and interacted with these receptor subtypes including α1A, α1B, α1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors known for control of blood pressure. In conclusion, MT may be used for treatment of bilateral renal artery stenosis hypertension, different from losartan that is prohibited for treatment of bilateral renal artery stenosis hypertension. Targets validation of MT hypotensive mechanism and beneficial effects of MT on uric acid and cognitive function provide new insights for this novel multitarget drug, deserving clinical trial attention.
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Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2â weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750â mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300â mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300â mg tobramycin and 750â mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36â weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.
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OBJECTIVE: To investigate the smoking status, knowledge of smoking hazards, attitude of tobacco control and skill of assisting smoking cessation in respiratory physicians in the city of Chongqing and therefore to provide references for their further participation in social tobacco control. METHODS: With a self-designed questionnaire, a cross-sectional study was conducted on respiratory physicians of 8 hospitals in Chongqing, which were selected with stratified random sampling method. All the data were inputted with software Epidata 3.1 and were analyzed with SPSS 13.0. RESULTS: A total of 428 valid questionnaires were retrieved, with a valid rate of 95.1% (428/450). The total smoking rate was 12.4% (95%CI: 9.3% - 15.5%), with 7.4% in physicians of teaching hospitals, 8.13% in those of hospitals located in urban areas, and 19.0% in those of hospitals located in suburban district counties. The differences in smoking rates in the respiratory physicians among different hospitals showed statistical significance (χ(2) = 11.734, P = 0.014). The smoking rate of the male was higher than that of the female. Of the surveyed doctors, 80.14% had awareness that tobacco dependence was a neuropsychiatric disease characterized as nicotine addiction, while 34.8% claimed that they had no idea about quitting smoking drugs. Although all participants claimed that they knew the harm of secondhand smoke, 16.36% of them still had never come forward to prevent smoking behavior in hospitals. There was only 27.4% of the surveyed discouraging smoking behavior with the reason of unwillingness to breath in secondhand smoke, while 53.9% of the surveyed discouraged smoking behavior because of regulations of hospitals. Most of the surveyed did relatively well in routinely inquiring and recording the smoking status of patients, but only 27.1% of them had recommended specific quitting smoking methods to patients, and there were few successful cases in practice. The situations of smoking cessation assistance in hospitals located in urban areas and suburban district counties were better than that in teaching hospitals. CONCLUSIONS: The smoking rate of the respiratory physicians (especially male doctors) in Chongqing is high. There is lack of enthusiasm in preventing smoking behavior in public area of hospitals. The knowledge and skills of smoking cessation are lacking as well. Therefore more training programs for smoking control are needed. Respiratory physicians in primary hospitals or community health centers can play a more important role in smoking control.
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Conocimientos, Actitudes y Práctica en Salud , Médicos/estadística & datos numéricos , Cese del Hábito de Fumar/estadística & datos numéricos , Fumar , Adulto , Actitud del Personal de Salud , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Muestreo , Distribución por Sexo , Fumar/efectos adversos , Fumar/epidemiología , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar , Encuestas y Cuestionarios , Contaminación por Humo de Tabaco/prevención & control , Adulto JovenRESUMEN
Background: Correct diagnosis of bronchioloalveolar carcinoma (BAC) is often delayed due to the lack of familiarity with the condition among clinicians as its sporadic nature and its symptoms are similar to other respiratory issues. Among these, acute respiratory failure (ARF) caused by massive bronchorrhea is rarely associated with BAC. Here we first reported osimertinib in the treatment of BAC with bronchorrhea and ARF. Case Description: A 38-year-old woman presented with massive bronchorrhea and progressive dyspnea. A chest computed tomography (CT) scan showed consolidation with air bronchograms and multiple nodules in both lungs. The patient had no history of chronic pulmonary disease, diabetes mellitus, hypertension or smoke. The patient was initially diagnosed with pneumonia, but ARF developed despite the antibiotic therapy provided. Lung biopsy results revealed nonmucinous BAC. Osimertinib (80 mg daily) was prescribed and proved effective for the first time with an improved ARF and a decreased multiple nodules or consolidation in the lungs during the follow-up period. Conclusions: It is important for physicians to recognize the typical symptoms and radiological manifestations of BAC to avoid misdiagnosis or late diagnosis. This is especially important since early diagnosis allows for immediate epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, which is a potentially beneficial treatment for patients with BAC.
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Introduction: Chlamydia psittaci infection in humans is a rare cause that mainly present as community-acquired pneumonia. Severe Chlamydia psittaci pneumonia can lead to acute respiratory distress syndrome (ARDS), septic shock, or multiple organ dysfunction with a mortality rate of 15%-20% before accurate diagnosis and targeted treatment. Metagenomic next-generation sequencing (mNGS) has an advantage in achieving early diagnosis. In the study, omadacycline implementation was described to provide a better understanding of effectiveness in severe psittacosis pneumonia with ARDS. Methods: Sixteen patients with severe psittacosis pneumonia with ARDS were selected between September 2021 and October 2022. They were diagnosed using mNGS and treated with omadacycline. Retrospective analysis of clinical manifestations, laboratory data, disease progression, diagnostic tool, treatment, and prognosis was summarized. Results: Common symptoms included fever, dyspnea, and cough. All patients developed ARDS, accompanied by septic shock (43.7%) and pulmonary embolism (43.7%). Laboratory data showed normal leucocytes, increased creatine kinase isoenzyme, and decreased albumin with liver dysfunction in most patients. All patients had increased neutrophils, C-reactive protein, procalcitonin, and D-dimer with decreased lymphocytes. Airspace consolidation, ground glass opacity, and pleural effusion were found on chest CT. mNGS results were obtained in 24-48 h to identify the diagnosis of Chlamydia psittacosis. All patients received mechanical ventilation with omadacycline treatment. Fourteen patients experienced complete recovery, while the other two patients died from multidrug-resistant bacterial infection and renal failure. Conclusion: mNGS has a significant value in the diagnosis of Chlamydia psittaci infection. Timely treatment of omadacycline can improve prognosis and provide a promising new option for the treatment of severe Chlamydia psittaci pneumonia with ARDS.
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Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.
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Dislipidemias , Hígado Graso , Enfermedades no Transmisibles , Ratones , Animales , Dieta Alta en Grasa , Nicotinamida Fosforribosiltransferasa/metabolismo , Ácidos Grasos no Esterificados , Hígado Graso/metabolismo , Triglicéridos/metabolismo , HDL-ColesterolRESUMEN
BACKGROUND: Stimulation of epithelial sodium channel (ENaC) increases Na(+) transport, a driving force of alveolar fluid clearance (AFC) to keep alveolar spaces free of edema fluid that is beneficial for acute lung injury (ALI). It is well recognized that regulation of ENaC by insulin via PI3K pathway, but the mechanism of this signaling pathway to regulate AFC and ENaC in ALI remains unclear. The aim of this study was to investigate the effect of insulin on AFC in ALI and clarify the pathway in which insulin regulates the expression of ENaC in vitro and in vivo. METHODS: A model of ALI (LPS at a dose of 5.0 mg/kg) with non-hyperglycemia was established in Sprague-Dawley rats receiving continuous exogenous insulin by micro-osmotic pumps and wortmannin. The lungs were isolated for measurement of bronchoalveolar lavage fluid(BALF), total lung water content(TLW), and AFC after ALI for 8 hours. Alveolar epithelial type II cells were pre-incubated with LY294002, Akt inhibitor and SGK1 inhibitor 30 minutes before insulin treatment for 2 hours. The expressions of α-,ß-, and γ-ENaC were detected by immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. RESULTS: In vivo, insulin decreased TLW, enchanced AFC, increased the expressions of α-,ß-, and γ-ENaC and the level of phosphorylated Akt, attenuated lung injury and improved the survival rate in LPS-induced ALI, the effects of which were blocked by wortmannin. Amiloride, a sodium channel inhibitor, significantly reduced insulin-induced increase in AFC. In vitro, insulin increased the expressions of α-,ß-, and γ-ENaC as well as the level of phosphorylated Akt but LY294002 and Akt inhibitor significantly prevented insulin-induced increase in the expression of ENaC and the level of phosphorylated Akt respectively. Immunoprecipitation studies showed that levels of Nedd4-2 binding to ENaC were decreased by insulin via PI3K/Akt pathway. CONCLUSIONS: Our study demonstrated that insulin alleviated pulmonary edema and enhanced AFC by increasing the expression of ENaC that dependent upon PI3K/Akt pathway by inhibition of Nedd4-2.
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Lesión Pulmonar Aguda/metabolismo , Canales Epiteliales de Sodio/metabolismo , Insulina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Alveolos Pulmonares/metabolismo , Transducción de Señal/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Glucemia/metabolismo , Células Cultivadas , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Técnicas In Vitro , Insulina/sangre , Interleucina-6/metabolismo , Lipopolisacáridos/efectos adversos , Masculino , Modelos Animales , Ubiquitina-Proteína Ligasas Nedd4 , Peroxidasa/metabolismo , Alveolos Pulmonares/patología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Miliary tuberculosis (TB) is an uncommon cause of acute respiratory distress syndrome (ARDS) with a high mortality. The aim of the present study was to evaluate the clinical characteristics, predictors and outcome of patients with ARDS caused by miliary TB. METHODS: A retrospective study was conducted among patients with a diagnosis of ARDS with miliary TB in four hospitals from 2006 to 2010. Medical records and laboratory examinations of these patients were taken during the first 24 h of admission. RESULTS: Eighty-five patients with miliary TB developed ARDS, 45 of whom survived (52.9%). The median age was 36.6 ± 12.5 years with 38 males (44.7%). Diabetes mellitus (DM) was the most common underlying disease (18.8%).ICU mortality was 47.1%. The time from admission to anti-tuberculosis therapy was 4.5 ± 2.0 days. Mean duration of mechanical ventilation was 8.5 ± 3.0 days in all patients. Duration of time to diagnosis, time from diagnosis to mechanical ventilation, and time to anti-tuberculosis therapy were significantly shorter in survivors than those in non-survivors. Diabetes mellitus (OR 5.431, 95%CI 1.471-20.049; P = 0.005), ALT (70-100U/L, OR 10.029, 95%CI 2.764-36.389; P = 0.001), AST (>94U/L,OR 8.034, 95%CI 2.200-29.341; P = 0.002), D-dimer (>1.6mg/L, OR 3.167, 95%CI 0.896-11.187; P = 0.042), hemoglobin (<90g/L, OR 14.824, 95%CI 3.713-59.179; P = 0.001), albumin (<25g/L, OR 15.896, 95%CI 3.975-63.566; P = 0.001) were independent predictors of ARDS development in the setting of miliary TB. CONCLUSIONS: Accurate diagnosis, early initiation of anti-tuberculosis therapy and mechanical ventilation are important for the outcome of patients with ARDS caused by miliary TB. DM, ALT, AST, D-dimer, hemoglobin, and albumin are independent predictors of ARDS development in patients with miliary TB.
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Síndrome de Dificultad Respiratoria/etiología , Tuberculosis Miliar/complicaciones , Adulto , Alanina Transaminasa/sangre , Albúminas/metabolismo , Antituberculosos/uso terapéutico , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , China , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Hemoglobinas/metabolismo , Humanos , Masculino , Pronóstico , Respiración Artificial , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
RATIONALE: Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing damage to small-vessel vasculitis and mainly occurs in the kidney or lung. We report a rare case of AAV manifesting as alveolar hemorrhage and a renal aneurysm. PATIENT CONCERNS: A 50-year-old Chinese man presented with repeated coughing, expectoration, fever, hypoxemia, and respiratory failure. The patient suffered from rupture of the renal aneurysm during immunosuppressive therapy. DIAGNOSIS: Considering the clinical picture (fever, progressive hypoxemia, renal insufficiency, hemorrhagic bronchoalveolar lavage fluid, and left retroperitoneal hematoma) along with cANCA-PR3 positivity, and lung biopsy findings, the patient was finally diagnosed with granulomatosis with polyangiitis complicated by alveolar hemorrhage and renal aneurysm. INTERVENTIONS: The patient was initially treated with immunosuppressive therapy combined with plasma exchange and subsequently with renal arterial embolization due to rupture of the renal aneurysm. OUTCOMES: The general condition and inflammatory reaction improved with immunosuppressive therapy combined with plasma exchange. Unfortunately, the patient did not respond to treatment and eventually died of respiratory failure and acute kidney injury after the rupture of the renal aneurysm. LESSONS: We encountered unprecedented difficulties and challenges with renal aneurysm rupture. The possibility of aneurysmal rupture should be carefully considered and frequently checked for immunosuppressive therapy for AAV.
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Lesión Renal Aguda , Aneurisma Roto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Terapia de Inmunosupresión/efectos adversos , Insuficiencia Respiratoria , Aneurisma Roto/complicaciones , Aneurisma Roto/terapia , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Anticuerpos Anticitoplasma de Neutrófilos , Hemorragia/etiología , Hemorragia/terapia , Humanos , Hipoxia , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , RoturaRESUMEN
ABSTRACT: With-No lysine Kinases (WNKs) have been newly implicated in alveolar fluid clearance (AFC). Epithelial sodium channels (ENaCs) serve a vital role in AFC. The potential protective effect of WNK4 in acute respiratory distress syndrome (ARDS), mediated by ENaC-associated AFC was investigated in the study. A model of lipopolysaccharide (LPS)-induced ARDS was established in C57BL/6 mice. WNK4, Sterile 20-related proline-alanine-rich kinase (SPAK), small interfering RNA (siRNA)-WNK4 or siRNA-SPAK were transfected into mouse lung or primary alveolar epithelial type II (ATII) cells. AFC, bronchoalveolar lavage fluid and lung histomorphology were determined. The expression of ENaC was determined to investigate the regulation of AFC by WNK4-SPAK signaling pathway. Activation of WNK4-SPAK signaling improved lung injury and survival rate, with enhanced AFC and reduced pulmonary edema via the upregulation of ENaC in ARDS. In primary rat ATII cells, gene-silencing by siRNA transfection reduced ENaC expression and the level of WNK4-associated SPAK phosphorylation. Immunoprecipitation revealed that the level of neural precursor cell-expressed developmentally downregulated gene 4 (Nedd4-2) binding to ENaC was decreased as a result of WNK4-SPAK signaling. The present study demonstrated that the WNK4/SPAK pathway improved AFC during LPS-induced ARDS, which is mainly dependent on the upregulation of ENaC with Nedd4-2-mediated ubiquitination.