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BACKGROUND: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir). RESULTS: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%). CONCLUSIONS: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Adulto , Humanos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , COVID-19/virologia , Tratamento Farmacológico da COVID-19/métodos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , SARS-CoV-2 , Administração Oral , Método Simples-Cego , Progressão da DoençaRESUMO
The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.
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Transição Epitelial-Mesenquimal , Ácido Láctico , Lipopolissacarídeos , Transportadores de Ácidos Monocarboxílicos , Fibrose Pulmonar , Simportadores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Simportadores/metabolismo , Simportadores/genética , Simportadores/antagonistas & inibidores , Camundongos , Ácido Láctico/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Camundongos Endogâmicos C57BL , Linhagem Celular , Masculino , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of ß-amyloid (Aß) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aß production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.
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Mechanical ventilation (MV) has become a clinical first-line treatment option for patients with respiratory failure. However, it was unclear whether MV further aggravates the process of sepsis-associated pulmonary fibrosis and eventually leads to sepsis and mechanical ventilation-associated pulmonary fibrosis (S-MVPF). This study aimed to explore the mechanism of S-MVPF concerning integrin ß3 activation in glycometabolic reprogramming of lung fibroblasts. We found that MV exacerbated sepsis-associated pulmonary fibrosis induced by lipopolysaccharide, which was accompanied by proliferation of lung fibroblasts, increased deposition of collagen in lung tissue, and increased procollagen type I carboxy-terminal propeptide in the bronchoalveolar lavage fluid. A large number of integrin ß3- and pyruvate kinase M2-positive fibroblasts were detected in lung tissue after stimulation with lipopolysaccharide and MV, with an increase in lactate dehydrogenase A expression and lactate levels. S-MVPF was primarily attenuated in integrin ß3-knockout mice, which also resulted in a decrease in the levels of pyruvate kinase M2, lactate dehydrogenase A, and lactate. In conclusion, MV aggravated sepsis-associated pulmonary fibrosis, with glycometabolic reprogramming mediated by integrin ß3 activation. Thus, integrin ß3-mediated glycometabolic reprogramming might be a potential therapeutic target for S-MVPF.
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Fibrose Pulmonar , Sepse , Camundongos , Animais , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Integrina beta3/metabolismo , Respiração Artificial , Lipopolissacarídeos , Lactato Desidrogenase 5 , Piruvato Quinase , Sepse/complicaçõesRESUMO
Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.
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Lipopolissacarídeos , Fibrose Pulmonar , Aceleração , Fibroblastos/metabolismo , Glicólise , Humanos , Ácido Láctico/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Macrófagos/metabolismo , Fibrose Pulmonar/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Large-scale meta-analyses of genome-wide association studies (GWAS) have identified few susceptibility loci in patients with sporadic PD. The aim of this study was to investigate the association between NMD3 single nucleotide polymorphism (SNP) and symptoms in PD patients in South China. METHODS: A total of 217 PD patients were recruited in this study and genotyped by using the SNaPshot technique and the polymerase chain reaction. All subjects were evaluated by the Mini-Mental State Examination (MMSE), Beijing version Montreal Cognitive Assessment (MoCA), Sniffin' Sticks 16 (SS-16), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, 39-item Parkinson's Disease Questionnaire (PDQ-39) and MDS Unified PD Rating Scale (MDS-UPDRS). RESULTS: NMD3 rs34016896 (C > T) carriers have worse cognitive function than wild types (MMSE: p = 0.042, NMD3 wild type: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p = 0.005, NMD3 wild type: 23.15 ± 4.20, NMD3 carriers: 20.75 ± 6.68). CONCLUSIONS: The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.
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Disfunção Cognitiva/etiologia , Doença de Parkinson/complicações , Doença de Parkinson/genética , Proteínas de Ligação a RNA/genética , Idoso , Povo Asiático/genética , China , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
ABSTRACT: Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis (PF). However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α)-induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. In addition, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates PF associated with sepsis, which is caused by aerobic glycolysis, in mice. Hypoxia-inducible factor 1α knockdown demonstrated similar protective effects in vivo . Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated PF.
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Metformina , Fibrose Pulmonar , Sepse , Camundongos , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Hipóxia , Sepse/complicações , Sepse/tratamento farmacológico , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
Mechanical ventilation (MV) is an essential therapy for acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. However, it can also induce mechanical ventilation-induced pulmonary fibrosis (MVPF) and the underlying mechanism remains unknown. Based on a mouse model of MVPF, the present study aimed to explore the role of the angiotensin-converting enzyme/angiotensin II/angiotensin type 1 receptor (ACE/Ang-2/AT1R) axis in the process of MVPF. In addition, recombinant angiotensin-converting enzyme 2(rACE2), AT1R inhibitor valsartan, AGTR1-directed shRNA and ACE inhibitor perindopril were applied to verify the effect of inhibiting ACE/Ang-2/AT1R axis in the treatment of MVPF. Our study found MV induced an inflammatory reaction and collagen deposition in mouse lung tissue accompanied by the activation of ACE in lung tissue, increased concentration of Ang-2 in bronchoalveolar lavage fluid (BALF), and upregulation of AT1R in alveolar epithelial cells. The process of pulmonary fibrosis could be alleviated by the application of the ACE inhibitor perindopril, ATIR inhibitor valsartan and AGTR1-directed shRNA. Meanwhile, rACE2 could also alleviate MVPF through the degradation of Ang-2. Our finding indicated the ACE/Ang-2/AT1R axis played an essential role in the pathogenesis of MVPF. Pharmacological inhibition of the ACE/Ang-2/AT1R axis might be a promising strategy for the treatment of MVPF.
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Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Receptor Tipo 1 de Angiotensina/metabolismo , Peptidil Dipeptidase A/metabolismo , Perindopril/farmacologia , Perindopril/uso terapêutico , Respiração Artificial , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Valsartana/uso terapêutico , RNA Interferente Pequeno/genética , Angiotensina II/metabolismoRESUMO
Background: Fibrosis is a heavy burden on the global healthcare system. Recently, an increasing number of studies have demonstrated that Extracellular vesicles play an important role in intercellular communication under both physiological and pathological conditions. This study aimed to explore the role of extracellular vesicles' in fibrosis using bibliometric methods. Methods: Original articles and reviews related to extracellular vesicles and fibrosis were obtained from the Web of Science Core Collection database on November 9, 2022. VOSviewer was used to obtain general information, including co-institution, co-authorship, and co-occurrence visualization maps. The CiteSpace software was used to analyze citation bursts of keywords and references, a timeline view of the top clusters of keywords and cited articles, and the dual map. R package "bibliometrix" was used to analyze annual production, citation per year, collaboration network between countries/regions, thematic evolution map, and historiography network. Results: In total, 3376 articles related to extracellular vesicles and fibrosis published from 2013 to 2022 were included in this study, with China and the United States being the top contributors. Shanghai Jiao Tong University has the highest number of publications. The main collaborators were Giovanni Camussi, Stefania Bruno, Marta Tepparo, and Cristina Grange. Journals related to molecular, biology, genetics, health, immunology, and medicine tended to publish literature on extracellular vesicles and fibrosis. "Recovery," "heterogeneity," "degradation," "inflammation," and "mesenchymal stem cells" are the keywords in this research field. Literature on extracellular vesicles and fibrosis associated with several diseases, including "kidney disease," "rheumatoid arthritis," and "skin regeneration" may be the latest hot research field. Conclusions: This study provides a comprehensive perspective on extracellular vesicles and fibrosis through a bibliometric analysis of articles published between 2013 and 2022. We identified the most influential countries, institutions, authors, and journals. We provide information on recent research frontiers and trends for scholars interested in the field of extracellular vesicles and fibrosis. Their role in biological processes has great potential to initiate a new upsurge in future research.
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Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments.
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Background: Acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high incidence and mortality rate in intensive care unit (ICU) admissions. Early identification of patients at high risk for developing ARDS is crucial for timely intervention and improved clinical outcomes. However, the complex pathophysiology of ARDS makes early prediction challenging. This study aimed to develop an artificial intelligence (AI) model for automated lung lesion segmentation and early prediction of ARDS to facilitate timely intervention in the intensive care unit. Methods: A total of 928 ICU patients with chest computed tomography (CT) scans were included from November 2018 to November 2021 at three centers in China. Patients were divided into a retrospective cohort for model development and internal validation, and three independent cohorts for external validation. A deep learning-based framework using the UNet Transformer (UNETR) model was developed to perform the segmentation of lung lesions and early prediction of ARDS. We employed various data augmentation techniques using the Medical Open Network for AI (MONAI) framework, enhancing the training sample diversity and improving the model's generalization capabilities. The performance of the deep learning-based framework was compared with a Densenet-based image classification network and evaluated in external and prospective validation cohorts. The segmentation performance was assessed using the Dice coefficient (DC), and the prediction performance was assessed using area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. The contributions of different features to ARDS prediction were visualized using Shapley Explanation Plots. This study was registered with the China Clinical Trial Registration Centre (ChiCTR2200058700). Findings: The segmentation task using the deep learning framework achieved a DC of 0.734 ± 0.137 in the validation set. For the prediction task, the deep learning-based framework achieved AUCs of 0.916 [0.858-0.961], 0.865 [0.774-0.945], 0.901 [0.835-0.955], and 0.876 [0.804-0.936] in the internal validation cohort, external validation cohort I, external validation cohort II, and prospective validation cohort, respectively. It outperformed the Densenet-based image classification network in terms of prediction accuracy. Moreover, the ARDS prediction model identified lung lesion features and clinical parameters such as C-reactive protein, albumin, bilirubin, platelet count, and age as significant contributors to ARDS prediction. Interpretation: The deep learning-based framework using the UNETR model demonstrated high accuracy and robustness in lung lesion segmentation and early ARDS prediction, and had good generalization ability and clinical applicability. Funding: This study was supported by grants from the Shanghai Renji Hospital Clinical Research Innovation and Cultivation Fund (RJPY-DZX-008) and Shanghai Science and Technology Development Funds (22YF1423300).
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ABSTRACT: Background: Acute kidney injury (AKI) is a prevalent and serious complication among patients with sepsis-associated acute respiratory distress syndrome (ARDS). Prompt and accurate prediction of AKI has an important role in timely intervention, ultimately improving the patients' survival rate. This study aimed to establish machine learning models to predict AKI via thorough analysis of data derived from electronic medical records. Method: The data of eligible patients were retrospectively collected from the Medical Information Mart for Intensive Care III database from 2001 to 2012. The primary outcome was the development of AKI within 48 hours after intensive care unit admission. Four different machine learning models were established based on logistic regression, support vector machine, random forest, and extreme gradient boosting (XGBoost). The performance of all predictive models was evaluated using the area under receiver operating characteristic curve, precision-recall curve, confusion matrix, and calibration plot. Moreover, the discrimination ability of the machine learning models was compared with that of the Sequential Organ Failure Assessment (SOFA) model. Results; Among 1,085 sepsis-associated ARDS patients included in this research, 375 patients (34.6%) developed AKI within 48 hours after intensive care unit admission. Twelve predictive variables were selected and further used to establish the machine learning models. The XGBoost model yielded the most accurate predictions with the highest area under receiver operating characteristic curve (0.86) and accuracy (0.81). In addition, a novel shiny application based on the XGBoost model was established to predict the probability of developing AKI among patients with sepsis-associated ARDS. Conclusions: Machine learning models could be used for predicting AKI in patients with sepsis-associated ARDS. Accordingly, a user-friendly shiny application based on the XGBoost model with reliable predictive performance was released online to predict the probability of developing AKI among patients with sepsis-associated ARDS.
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Injúria Renal Aguda , Síndrome do Desconforto Respiratório , Sepse , Humanos , Estudos Retrospectivos , Aprendizado de MáquinaRESUMO
Recent research has revealed that mechanical ventilation (MV) could initiate ventilator-induced lung injury along with the initiation of the process of pulmonary fibrosis (PF), leading to MV-induced PF (MVPF). However, the underlying mechanism remains unclear. This study aimed to explore the role of MV-induced extracellular vesicles (MV-EVs) and the c-Jun N-terminal kinase (JNK) signalling pathway in the pathogenesis of MVPF in vivo and in vitro. The process of MV is accompanied by the secretion of MV-EVs, which could induce lung fibroblast activation. Furthermore, single-cell RNA-sequencing analysis revealed that the JNK pathway in lung fibroblasts was activated after MV initiation. Inhibiting the JNK pathway could both restrain MV-EV-induced lung fibroblast activation in vitro or reduce the severity of MVPF in vivo. In conclusion, this study demonstrated that MV-EVs contribute to MVPF progression by activating lung fibroblasts via the JNK signalling pathway and that inhibiting the secretion of EV and the activation of the JNK signalling pathway is a promising strategy for treating MVPF.
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Vesículas Extracelulares , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/etiologia , Sistema de Sinalização das MAP Quinases , Respiração Artificial/efeitos adversos , Fibroblastos , PulmãoRESUMO
OBJECTIVE: To demonstrate the mechanism of mechanical ventilation (MV) induced endoplasmic reticulum stress (ERS) promoting mechanical ventilation-induced pulmonary fibrosis (MVPF), and to clarify the role of angiotensin receptor 1 (AT1R) during the process. METHODS: The C57BL/6 mice were randomly divided into four groups: Sham group, MV group, AT1R-shRNA group and MV+AT1R-shRNA group, with 6 mice in each group. The MV group and MV+AT1R-shRNA group mechanically ventilated for 2 hours after endotracheal intubation to establish MVPF animal model (parameter settings: respiratory rate 70 times/minutes, tidal volume 20 mL/kg, inhated oxygen concentration 0.21). The Sham group and AT1R-shRNA group only underwent intubation after anesthesia and maintained spontaneous breathing. AT1R-shRNA group and MV+AT1R-shRNA group were airway injected with the adeno-associated virus one month before modeling to inhibit AT1R gene expression in lung tissue. The expressions of AT1R, ERS signature proteins [immunoglobulin heavy chain-binding protein (BIP), protein disulfide isomerase (PDI)], fibrosis signature proteins [collagen I (COL1A1), α-smooth muscle actin (α-SMA)] in lung tissues were detected by immunofluorescence and Western blotting. Hematoxylin-eosin (HE) staining was used to evaluate lung injury and Masson staining was used to evaluate pulmonary fibrosis. RESULTS: Compared with the Sham group, the degree of pulmonary fibrosis and lung injury were more significant in the MV group. In the MV group, the protein expressions of AT1R, BIP, PDI, COL1A1 and α-SMA were increased (AT1R/ß-actin: 1.40±0.02 vs. 1, BIP/ß-actin: 2.79±0.07 vs. 1, PDI/ß-actin: 2.07±0.02 vs. 1, COL1A1/α-Tubulin: 2.60±0.15 vs. 1, α-SMA/α-Tubulin: 2.80±0.25 vs. 1, all P < 0.01). The number of E-cad+/AT1R+ and E-cad+/BIP+ cells in lung tissue increased, and the fluorescence intensity of COL1A1 and α-SMA increased. Compared with the MV group, the degree of pulmonary fibrosis and lung injury were significantly relieved in the MV+AT1R-shRNA group. In the MV+AT1R-shRNA group, the protein expressions of AT1R, BIP, PDI, COL1A1 and α-SMA were decreased (AT1R/ß-actin: 0.53±0.03 vs. 1.40±0.02, BIP/ß-actin: 1.73±0.15 vs. 2.79±0.07, PDI/ß-actin: 1.04±0.07 vs. 2.07±0.02, COL1A1/α-Tubulin: 1.29±0.11 vs. 2.60±0.15, α-SMA/α-Tubulin: 1.27±0.10 vs. 2.80±0.25, all P < 0.01). The number of E-cad+/AT1R+ and E-cad+/BIP+ cells in lung tissue decreased, and the fluorescence intensity of COL1A1 and α-SMA decreased. There was no statistically significant difference in the indicators between AT1R-shRNA group and Sham group. CONCLUSIONS: MV up-regulate the expression of AT1R in alveolar epithelial cells, activate the AT1R pathway, induce ERS and promote the progression of MVPF.
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Lesão Pulmonar , Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Respiração Artificial/efeitos adversos , Actinas/metabolismo , Tubulina (Proteína) , Camundongos Endogâmicos C57BL , Estresse do Retículo Endoplasmático , RNA Interferente PequenoRESUMO
Background: The coronavirus disease 2019 (COVID-19) is an acute infectious pneumonia caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection previously unknown to humans. However, predictive studies of acute respiratory distress syndrome (ARDS) in patients with COVID-19 are limited. In this study, we attempted to establish predictive models to predict ARDS caused by COVID-19 via a thorough analysis of patients' clinical data and CT images. Method: The data of included patients were retrospectively collected from the intensive care unit in our hospital from April 2022 to June 2022. The primary outcome was the development of ARDS after ICU admission. We first established two individual predictive models based on extreme gradient boosting (XGBoost) and convolutional neural network (CNN), respectively; then, an integrated model was developed by combining the two individual models. The performance of all the predictive models was evaluated using the area under receiver operating characteristic curve (AUC), confusion matrix, and calibration plot. Results: A total of 103 critically ill COVID-19 patients were included in this research, of which 23 patients (22.3%) developed ARDS after admission; five predictive variables were selected and further used to establish the machine learning models, and the XGBoost model yielded the most accurate predictions with the highest AUC (0.94, 95% CI: 0.91-0.96). The AUC of the CT-based convolutional neural network predictive model and the integrated model was 0.96 (95% CI: 0.93-0.98) and 0.97 (95% CI: 0.95-0.99), respectively. Conclusion: An integrated deep learning model could be used to predict COVID-19 ARDS in critically ill patients.
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Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disease. In this study, we generated an induced pluripotent stem cell (iPSC) line from the dermal fibroblasts of a 69-year-old female patient carrying APOEε3/ε4 allele and diagnosed with sporadic AD. The iPSC line will be a useful tool for investigating the pathogenesis mechanisms and for drug tests in AD.
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Doença de Alzheimer , Linhagem Celular , Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Idoso , Feminino , Humanos , Doença de Alzheimer/patologia , População do Leste Asiático , Células-Tronco Pluripotentes Induzidas/metabolismo , Doenças Neurodegenerativas/metabolismoRESUMO
Objective: For respiratory failure patients, mechanical ventilation (MV) is a life-saving therapy to maintain respiratory function. However, MV could also cause damage to pulmonary structures, result in ventilator-induced lung injury (VILI) and eventually progress to mechanical ventilation-induced pulmonary fibrosis (MVPF). Mechanically ventilated patients with MVPF are closely related to increased mortality and poor quality of life in long-term survival. Thus, a thorough understanding of the involved mechanism is necessary. Methods: We used next-generation sequencing to identify differentially expressed non-coding RNAs (ncRNAs) in BALF EVs which were isolated from Sham and MV mice. Bioinformatics analysis was conducted to identify the engaged ncRNAs and related signaling pathways in the process of MVPF. Results: We found 1801 messenger RNAs (mRNA), 53 micro RNAs (miRNA), 273 circular RNAs (circRNA) and 552 long non-coding RNAs (lncRNA) in mice BALF EVs of two groups, which showed significant differential expression. TargetScan predicted that 53 differentially expressed miRNAs targeted 3105 mRNAs. MiRanda revealed that 273 differentially expressed circRNAs were associated with 241 mRNAs while 552 differentially expressed lncRNAs were predicated to target 20528 mRNAs. GO, KEGG pathway analysis and KOG classification showed that these differentially expressed ncRNA-targeted mRNAs were enriched in fibrosis related signaling pathways and biological processes. By taking the intersection of miRNAs target genes, circRNAs target genes and lncRNAs target genes, we found 24 common key genes and 6 downregulated genes were confirmed by qRT-PCR. Conclusions: Changes in BALF-EV ncRNAs may contribute to MVPF. Identification of key target genes involved in the pathogenesis of MVPF could lead to interventions that slow or reverse fibrosis progression.
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Vesículas Extracelulares , MicroRNAs , Fibrose Pulmonar , RNA Longo não Codificante , Camundongos , Animais , RNA Circular/genética , Respiração Artificial/efeitos adversos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fibrose Pulmonar/genética , Líquido da Lavagem Broncoalveolar , Qualidade de Vida , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , Fibrose , Vesículas Extracelulares/metabolismoRESUMO
Recent clinical research has revealed that mechanical ventilation (MV) can initiate pulmonary fibrosis and induce mechanical ventilation-induced pulmonary fibrosis (MVPF). However, the underlying mechanism remains largely uncharacterized. Based on a mouse model of MVPF and an alveolar epithelial cell cyclic strain model, the present study explores the possible mechanism of MVPF. Single-cell RNA-sequencing and EV RNA-sequencing analysis revealed that MV promoted apoptosis signal-regulating kinase 1 (ASK1)-mediated endoplasmic reticulum (ER) stress pathway activation and extracellular vesicle (EV) release from alveolar epithelial cells. Furthermore, the ASK1-ER stress pathway was shown to mediate mechanical stretch (MS)- or MV-induced EV release and lung fibroblast activation in vivo and in vitro. These processes were suppressed by ER stress inhibitors or by silencing ASK1 with ASK1- short hairpin RNA (shRNA). In addition, MVPF was suppressed by inhibiting ASK1 and ER stress in vivo. Therefore, the present study demonstrates that ASK1-ER stress pathway-mediated fibrotic-EV release from alveolar epithelial cells contributes to fibroblast activation and the initiation of pulmonary fibrosis during MV. The inhibited release of EVs targeting the ASK1-ER stress pathway might be a promising treatment strategy for MVPF.
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Células Epiteliais Alveolares , MAP Quinase Quinase Quinase 5 , Fibrose Pulmonar , Animais , Camundongos , Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Fibroblastos , Fibrose , Pulmão/patologia , MAP Quinase Quinase Quinase 5/genética , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Respiração Artificial , RNARESUMO
Background: The coronavirus disease 2019 (COVID-19) becomes a worldwide public health threat. Increasing evidence proves that COVID-19-induced acute injuries could be reversed by a couple of therapies. After that, post-COVID-19 fibrosis (PCF), a sequela of "Long COVID," earns rapidly emerging concerns. PCF is associated with deteriorative lung function and worse quality of life. But the process of PCF remains speculative. Therefore, we aim to conduct a bibliometric analysis to explore the overall structure, hotspots, and trend topics of PCF. Materials and methods: A comprehensive search was performed in the Web of Science core database to collect literature on PCF. Search syntax included COVID-19 relevant terms: "COVID 19," "COVID-19 Virus Disease," "COVID-19 Virus Infection," "Coronavirus Disease-19," "2019 Novel Coronavirus Disease," "2019 Novel Coronavirus Infection," "SARS Coronavirus 2 Infection," "COVID-19 Pandemic," "Coronavirus," "2019-nCoV," and "SARS-CoV-2"; and fibrosis relevant terms: "Fibrosis," "Fibroses," and "Cirrhosis." Articles in English were included. Totally 1,088 publications were enrolled. Searching results were subsequentially exported and collected for the bibliometric analysis. National, organizational, and individual level data were analyzed and visualized through biblioshiny package in the R, VOSviewer software, the CiteSpace software, and the Graphical Clustering Toolkit (gCLUTO) software, respectively. Results: The intrinsic structure and development in the field of PCF were investigated in the present bibliometric analysis. The topmost keywords were "COVID-19" (occurrences, 636) surrounded by "SARS-CoV-2" (occurrences, 242), "coronavirus" (occurrences, 123), "fibrosis" (occurrences, 120), and "pneumonia" (occurrences, 94). The epidemiology, physiopathology, diagnosis, and therapy of PCF were extensively studied. After this, based on dynamic analysis of keywords, hot topics sharply changed from "Wuhan," "inflammation," and "cytokine storm" to "quality of life" and "infection" through burst detection; from "acute respiratory syndrome," "cystic-fibrosis" and "fibrosis" to "infection," "COVID-19," "quality-of-life" through thematic evolution; from "enzyme" to "post COVID." Similarly, co-cited references analysis showed that topics of references with most citations shift from "pulmonary pathology" (cluster 0) to "COVID-19 vaccination" (cluster 6). Additionally, the overview of contributors, impact, and collaboration was revealed. Summarily, the USA stood out as the most prolific, influential, and collaborative country. The Udice French Research University, Imperial College London, Harvard University, and the University of Washington represented the largest volume of publications, citations, H-index, and co-authorships, respectively. Dana Albon was the most productive and cited author with the strongest co-authorship link strength. Journal of Cystic Fibrosis topped the list of prolific and influential journals. Conclusion: Outcomes gained from this study assisted professionals in better realizing PCF and would guide future practices. Epidemiology, pathogenesis, and therapeutics were study hotspots in the early phase of PCF research. As the spread of the COVID-19 pandemic and progress in this field, recent attention shifted to the quality of life of patients and post-COVID comorbidities. Nevertheless, COVID-19 relevant infection and vaccination were speculated to be research trends with current and future interest. International cooperation as well as in-depth laboratory experiments were encouraged to promote further explorations in the field of PCF.
Assuntos
COVID-19 , Bibliometria , COVID-19/complicações , COVID-19/epidemiologia , Cicatriz , Citocinas , Humanos , Pandemias , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
Background: Mechanical ventilation (MV) can induce pulmonary fibrosis. This study aims to investigate whether MV-induced pulmonary fibrosis is associated with aerobic glycolysis and seeks to uncover the underlying mechanisms mediated by integrin ß3-pyruvate kinase M2 (PKM2) pathway. Methods: PKM2 knockdown or inhibition, integrin ß3 knockout or inhibition and wild-type mice were exposed to MV (20 mL/kg) for 2 h. Results: Mice exposed to MV exhibited increased expression of collagen deposition, and upregulation of α-smooth muscle actin and collagen I in lung tissues. Single cells analysis showed that MV-induced pulmonary fibrosis was associated with increased gene expression of integrin and glycolysis in pulmonary fibroblasts, as well as upregulation of glycolytic products tested by metabolomics. Meanwhile, increased protein level of integrin ß3 and PKM2 was confirmed by western blot and immunohistochemistry. Double immunofluorescence staining and flow cytometric analysis showed increased number of fibronectin+/integrin ß3+ and fibronectin+/PKM2+ fibroblasts in lung tissues. Furthermore, MV-induced aerobic glycolysis and pulmonary fibrosis were ameliorated after treatment with PKM2 knockdown-AAV and inhibition, or in integrin ß3 knockout and inhibition mice. Conclusions: Integrin ß3-PKM2 pathway-mediated aerobic glycolysis contributes to MV-induced pulmonary fibrosis. The inhibition of aerobic glycolysis targeting integrin ß3-PKM2 pathway may be a promising treatment for MV-induced pulmonary fibrosis.