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1.
Ann Acad Med Singapore ; 48(7): 224-232, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31495868

RESUMO

INTRODUCTION: Evidence supporting non-invasive ventilation (NIV) in paediatric acute respiratory distress syndrome (PARDS) remains sparse. We aimed to describe characteristics of patients with PARDS supported with NIV and risk factors for NIV failure. MATERIALS AND METHODS: This is a multicentre retrospective study. Only patients supported on NIV with PARDS were included. Data on epidemiology and clinical outcomes were collected. Primary outcome was NIV failure which was defined as escalation to invasive mechanical ventilation within the first 7 days of PARDS. Patients in the NIV success and failure groups were compared. RESULTS: There were 303 patients with PARDS; 53/303 (17.5%) patients were supported with NIV. The median age was 50.7 (interquartile range: 15.7-111.9) months. The Paediatric Logistic Organ Dysfunction score and oxygen saturation/fraction of inspired oxygen (SF) ratio were 2.0 (1.0-10.0) and 155.0 (119.4- 187.3), respectively. Indications for NIV use were increased work of breathing (26/53 [49.1%]) and hypoxia (22/53 [41.5%]). Overall NIV failure rate was 77.4% (41/53). All patients with sepsis who developed PARDS experienced NIV failure. NIV failure was associated with an increased median paediatric intensive care unit stay (15.0 [9.5-26.5] vs 4.5 [3.0-6.8] days; P <0.001) and hospital length of stay (26.0 [17.0-39.0] days vs 10.5 [5.5-22.3] days; P = 0.004). Overall mortality rate was 32.1% (17/53). CONCLUSION: The use of NIV in children with PARDS was associated with high failure rate. As such, future studies should examine the optimal selection criteria for NIV use in these children.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Hipóxia/terapia , Ventilação não Invasiva/métodos , Síndrome do Desconforto Respiratório do Adulto/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Lactente , Unidades de Terapia Intensiva Pediátrica , Intubação Intratraqueal , Tempo de Internação , Masculino , Mortalidade , Escores de Disfunção Orgânica , Oxigênio/metabolismo , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento , Trabalho Respiratório
2.
Biochimie ; 165: 206-209, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404589

RESUMO

Ongoing efforts are oriented towards the development of novel therapeutic agents to repress lung hyperpermeability responses due to inflammation. The endothelial barrier dysfunction triggered by such events, may eventually lead to severe cardiovascular complications, such as the Acute Respiratory Distress Syndrome. Hsp90 inhibitors are anticancer compounds, associated with strong anti-inflammatory responses in the endothelium. Our latest observations in experimental models of Acute Lung Injury suggest that P53 orchestrates, at least in part, such activities. Remarkably, both Hsp90 inhibition and P53 induction are associated with the activation of the Unfolded Protein Response element. The purpose of the current manuscript, is to introduce the hypotheses that UPR induction protects the vasculature against inflammation.


Assuntos
Lesão Pulmonar Aguda , Endotélio Vascular/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Síndrome do Desconforto Respiratório do Adulto , Proteína Supressora de Tumor p53/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Permeabilidade Capilar , Células Cultivadas , Humanos , Inflamação/metabolismo , Camundongos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/metabolismo
3.
Med Sci Monit ; 25: 5299-5305, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31311916

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) is a common acute and severe disease in clinic. Recent studies indicated that Cxc chemokine ligand 5 (CXCL5), an inflammatory chemokine, was associated with tumorigenesis. The present study investigated the role of the CXCL5/Cxc chemokine receptor 2 (CXCR2) bio-axis in ARDS, and explored the underlying molecular mechanism. MATERIAL AND METHODS The pathological morphology of lung tissue and degree of pulmonary edema were assessed by hematoxylin-eosin staining and pulmonary edema score, respectively. Real-time PCR and Western blot analysis were performed to detect the expression levels of CXCL5, CXCR2, Matrix metalloproteinases 2 (MMP2), and Matrix metalloproteinases 9 (MMP9) in lung tissues. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the expression levels of CXCL5 and inflammatory factors (IL-1ß, IL-6, TNF-alpha, and IL-10) in serum. RESULTS The results demonstrated that diffuse alveolar damage and pulmonary edema appeared in lipopolysaccharide (LPS)-induced ARDS and were positively correlated with the severity of ARDS. In addition, CXCL5 and its receptor CXCR2 were overexpressed by upregulation of MMP2 and MMP9 in lung tissues of ARDS. In addition, CXCL5 neutralizing antibody effectively alleviated inflammatory response, diffuse alveolar damage, and pulmonary edema, and decreased the expression levels of MMP2 and MMP9 compared to LPS-induced ARDS. CONCLUSIONS We found that CXCL5/CXCR2 accelerated the progression of ARDS, partly by upregulation of MMP2 and MMP9 in lung tissues with the release of inflammatory factors.


Assuntos
Quimiocina CXCL5/metabolismo , Receptores de Interleucina-8B/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Animais , Quimiocinas CXC/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
4.
BMC Pulm Med ; 19(1): 110, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221118

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. METHODS: Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. RESULTS: Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1ß) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1ß expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. CONCLUSIONS: These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.


Assuntos
Vesículas Extracelulares/metabolismo , Inflamassomos/metabolismo , MicroRNAs/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fatores Desencadeantes , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente
5.
Cell Tissue Res ; 378(2): 255-265, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31214773

RESUMO

Fibrosis in the lungs usually occurs in the initial phase of acute respiratory distress syndrome (ARDS), which exacerbates poor prognosis among patients. MicroRNAs (miRs) have the ability to modulate the expression profiles of many genes, thus essentially altering cell phenotypes. We hypothesize that miRs may be involved in the development of lung fibrosis in mice. In this study, mice were treated with lipopolysaccharide (LPS) to establish the lung fibrosis animal model. Hematoxylin and eosin (H&E) staining and western blot (WB) were performed to confirm the successful establishment of the model. Quantitative PCR (qPCR) and WB were utilized to monitor the expression of miRs and proteins. A dual-luciferase reporter assay was used to detect the interaction between miR and genes. We observed miR-506 downregulation in lung tissues during lung fibrosis after ARDS rat modeling by LPS exposure. We also observed that its expression level was similar to that observed in TGF-ß1-induced human MRC-5 cells. The proportion of apoptotic cells decreased, while levels of inflammatory cytokines were upregulated in lung tissues during lung fibrosis and in fibroblasts after TGF-ß1 treatment. In order to elucidate the possible role of miR-506, it was overexpressed in mice with ARDS. It was revealed that miR-506 significantly ameliorated the degree and spread of pulmonary damage stimulated by LPS. miR-506 also induced apoptosis in vivo and in vitro, while also ameliorating the inflammatory response. Notably, p65, a subunit of NF-κB, acts as a target of miR-506. p65 expression was downregulated in TGF-ß1-treated MRC-5 cells upon transfection with miR-506 mimic. Indeed, the 3'-UTR of human p65 contained functional human miR-506-responsive sequences. LPS induction and TGF-ß1 stimulation in mice led to p65 upregulation. In addition, p65 knockdown in the ARDS mouse model partially ameliorated the severity of lung lesions, induced apoptosis and reduced inflammation in lung tissue. Our findings revealed that miR-506 could be an important modulator of apoptosis and inflammation and a regulator of lung fibrosis.


Assuntos
Citocinas/metabolismo , Pulmão , MicroRNAs/fisiologia , Fibrose Pulmonar/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Ratos
6.
Respir Res ; 20(1): 118, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186017

RESUMO

OBJECTIVE: The mechanisms of lung injury in acute respiratory distress syndrome (ARDS) are not well understood.Piezo1 was recently identified as a mechanotransduction protein. The present study found the expression of Piezo1 in type II pneumocytes and investigated its role in mediating ARDS-related lung injury. METHODS: Sprague-Dawley rats were used to establish an ARDS model, the expression of Piezo1,lung injuries, apoptosis as well as calcium influx were assessed. RESULTS: Piezo1 was expressed in type II pneumocytes as shown by immunofluorescence staining and expression was increased in the ARDS model. Knockdown of Piezo1 reduced apoptosis which was related to the elevation of Bcl-2.Calcium influx played a vital role in Piezo1-induced apoptosis. CONCLUSION: Piezo1 was expressed in type II pneumocytes. Mechanical stretch of alveoli during ARDS induced activation of the Piezo1 channel,which resulted in calcium influx. The increased intracellular Ca2+ induced the apoptosis of type II pneumocytes, which may be related to the Bcl-2 pathway.


Assuntos
Células Epiteliais Alveolares/metabolismo , Apoptose/fisiologia , Proteínas de Membrana/biossíntese , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Estresse Mecânico , Células A549 , Células Epiteliais Alveolares/patologia , Animais , Humanos , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório do Adulto/patologia
7.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(5): 571-576, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31198142

RESUMO

OBJECTIVE: To observe the dynamic changes in extra vascular lung water index (EVLWI) and angiopoietin-2 (Ang-2) in severe multiple trauma patients with acute respiratory distress syndrome (ARDS), analyze the risk factor for short-term mortality, and to evaluate their prognostic values for prognosis. METHODS: A total of 54 severe multiple trauma patients with ARDS admitted to emergency intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from June 2014 to December 2018 were enrolled. The acute physiology and chronic health evaluation II (APACHE II), injury severity score (ISS) and oxygenation index (PaO2/FiO2), EVLWI [pulse-induced contour cardiac output (PiCCO) monitor] and plasma Ang-2 level [enzyme-linked immunosorbent assay (ELISA)] at 0 (immediately), 24, 48 and 72 hours after ICU admission, and the differences in PaO2/FiO2, EVLWI and Ang-2 between 0 hour and 72 hours (ΔPaO2/FiO2, ΔEVLWI, ΔAng-2) were calculated. The 28-day survival of patients was recorded, and the patients were divided into survival group and non-survival group. The differences in above mentioned parameters between the two groups were compared. Multivariate Logistic regression was used to analyze the independent risk factors associated with the prognosis. Receiver operating characteristic (ROC) curve was drawn to evaluate the prognostic values of ΔEVLWI and ΔAng-2 on the prognosis, and the Kaplan-Meier survival curve was plotted. RESULTS: 115 patients were enrolled in the final analysis, 72 survived in 28 days, 43 died, and the mortality rate was 37.4%. The APACHE II and ISS scores of the non-survival group were significantly higher than those of the survival group [APACHE II score: 25.7±2.7 vs. 20.6±2.2, ISS score: 22.1±3.1 vs. 18.1±2.1, both P < 0.05]. EVLWI and Ang-2 showed a gradual downwards tendency with the prolongation of the length of ICU stay in the survival group, but no significant change was found in the non-survival group. Parallel contour test showed that both P < 0.05, indicating that the curves between the two groups had different tendencies and were not parallel. The levels of EVLWI, Ang-2 and PaO2/FiO2 showed no statistical differences from 0 hour to 24 hours between the two groups, but EVLWI and Ang-2 in the non-survival group were significantly higher than those in the survival group from 48 hours on [EVLWI (mL/kg): 15.5±4.2 vs. 10.8±3.2, Ang-2 (ng/L): 352.7±51.2 vs. 237.9±42.8, both P < 0.05], and PaO2/FiO2 was significantly decreased [mmHg (1 mmHg = 0.133 kPa): 126.1±43.7 vs. 211.2±33.8, P < 0.05]. The ΔEVLWI and ΔAng-2 in the non-survival group were significantly lower than those in the survival group [ΔEVLWI (mL/kg): -0.9±6.1 vs. 3.1±6.4, ΔAng-2 (ng/L): -45.3±32.1 vs. 79.8±58.2, both P < 0.05], but ΔPaO2/FiO2 showed no significant difference as compared with the survival group (mmHg: 23.2±24.2 vs. -22.1±22.8, P > 0.05). Multivariate Logistic regression analysis demonstrated that ΔEVLWI [odds ratio (OR) = 2.811, 95% confidence interval (95%CI) = 1.232-3.161, P = 0.001], ΔAng-2 (OR = 2.204, 95%CI = 1.012-3.179, P = 0.001) and APACHE II (OR = 1.206, 95%CI = 1.102-1.683, P = 0.002) were independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS. ROC curve analysis showed that the area under ROC curve (AUC) of ΔEVLWI for predicting 28-day prognosis of severe multiple trauma patients with ARDS was 0.832, which was higher than ΔAng-2 (AUC = 0.790) and APACHE II (AUC = 0.735). When the cut-off value of ΔEVLWI was 2.3 mL/kg, the sensitivity was 79.1%, and the specificity was 81.9%. Kaplan-Meier survival curve showed that the patients with ΔEVLWI > 2.3 mL/kg had a significantly higher 28-day cumulative survival rate as compared with the patients with ΔEVLWI ≤ 2.3 mL/kg (log-rank test: χ2 = 23.385, P = 0.000). CONCLUSIONS: ΔEVLWI and ΔAng-2 can be used as independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS, and the predictive value of ΔEVLWI was better than Ang-2 and APACHE II. Dynamic observation of EVLWI could improve the accuracy of death forecasting for severe multiple trauma patients with ARDS.


Assuntos
Angiopoietina-2/metabolismo , Água Extravascular Pulmonar/metabolismo , Traumatismo Múltiplo/terapia , Síndrome do Desconforto Respiratório do Adulto/terapia , Humanos , Traumatismo Múltiplo/metabolismo , Prognóstico , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Índices de Gravidade do Trauma
8.
Biomed Res Int ; 2019: 2121357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080811

RESUMO

Background: cIAP2 is involved in necroptosis as a key upstream regulation factor. We aimed to investigate the role of cIAP2 in ARDS/ALI induced by H7N9 virus through regulating the RIPK1/3 necroptosis pathway. Methods: Lung tissues of 11 patients who died from ARDS-complicated H7N9 infection between 2013 and 2016 were obtained as the H7N9-ARDS group. Lung tissues near benign lung nodules were acquired as the control group. Histological changes were evaluated by H&E staining. Protein levels of cIAP2, RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL in the lung tissues were detected by Western Blot. The mRNA levels of cIAP2, RIPK1, and RIPK3 were detected by real-time PCR. Results: H7N9 virus infection had a high mortality, with ARDS being the leading cause of death. The protein level of cIAP2 in the experimental group was lower than that in the control group (P<0.05). However, the experimental group showed higher RIPK1, RIPK3, and p-RIPK3 protein levels than the control group (P<0.05), as well as the expression level of MLKL and p-MLKL protein, which is a key downstream protein in necroptosis (P<0.05). Conclusion: In tissues from patients with fatal H7N9, downregulation of cIAP2 and induction of necroptosis was observed. We could speculate that necroptosis of the pulmonary epithelium is associated with severe H7N9 infection leading to ARDS. Thus, necroptosis inhibition may be a novel therapy for H7N9 influenza virus.


Assuntos
Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/virologia , Adulto , Idoso , Animais , Células Cultivadas , Regulação para Baixo/fisiologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Pessoa de Meia-Idade , Necrose/metabolismo , Necrose/virologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia
9.
Biomed Res Int ; 2019: 8958069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111072

RESUMO

Background: Acute respiratory distress syndrome (ARDS) after living-donor liver transplantation (LDLT) is not uncommon, but it lacks the biomarkers for early detection. Club cell protein 16 (CC16), high-motility group box 1 protein (HMGB1), interleukin-1ß (IL-1ß), and IL-10 have been reported as relevant to the development of ARDS. However, they have not been investigated during LDLT. Methods: Seventy-three consecutive recipients undergoing LDLT were enrolled and received the same perioperative care plan. Perioperative serum CC16, HMGB1, IL-1ß, and IL-10 levels were measured at the pretransplant state, 30 minutes after reperfusion, postoperative day 1 (POD1), and POD3. ARDS was diagnosed according to the 2012 Berlin definition. Results: Of the 73 recipients, 13 developed ARDS with significantly longer durations of mechanical ventilation and intensive care unit stay. Serum CC16 levels on POD1 increased significantly from the pretransplant state in the ARDS group but not in the non-ARDS group. Pretransplant serum CC16 levels were also higher in the ARDS group. The area under the receiver operating characteristic curves for POD1 serum CC16 levels used to discriminate ARDS was 0.803 (95% confidence interval: 0.679 to 0.895; p < 0.001). By comparison, HMGB1, IL-1ß, and IL-10 were not associated with ARDS after LDLT. Conclusion: The higher pretransplant serum CC16 level and its increased level on POD1 were associated with the development of early ARDS after LDLT. This trial is registered with NCT01936545, 27 August 2013.


Assuntos
Biomarcadores/sangue , Transplante de Fígado , Doadores Vivos , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Uteroglobina/biossíntese , Adulto , Feminino , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Humanos , Unidades de Terapia Intensiva , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Taiwan , Uteroglobina/metabolismo
10.
Biochem Pharmacol ; 164: 64-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928674

RESUMO

As an organ system, the lung has unique advantages and disadvantages for localized drug delivery. Its direct contact with the external environment allows for the upper airways to be easily accessible to intrapulmonary delivery. However, its complex branching structure makes direct delivery to the peripheral airways challenging. This review will discus the utility of exogenous surfactant, a lipoprotein complex currently used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics to enhance the delivery of these drugs to the deeper regions of the lung. The focus is to provide an update on the many tools available to develop new surfactant-based therapeutics using computer modeling, in vitro approaches, and in vivo testing, which may ultimately lead to clinical trials. Two clinical conditions, Acute Respiratory Distress Syndrome and Bacterial Pneumonia are utilized throughout as prototypical examples of pulmonary conditions in which surfactant drug combination may be beneficial. Consequently, the pharmaceuticals discussed are primarily those with antimicrobial or anti-inflammatory activities.


Assuntos
Anti-Inflamatórios/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Surfactantes Pulmonares/administração & dosagem , Tensoativos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Humanos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/metabolismo
11.
Nutrients ; 11(4)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013737

RESUMO

The innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS). Glutamine (Gln) decreases lung inflammation in experimental ARDS, but its impact on the formation of extracellular traps (ETs) in the lung is unknown. In a mouse model of endotoxin-induced pulmonary ARDS, the effects of Gln treatment on leukocyte counts and ET content in bronchoalveolar lavage fluid (BALF), inflammatory profile in lung tissue, and lung morphofunction were evaluated in vivo. Furthermore, ET formation, reactive oxygen species (ROS) production, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were tested in vitro. Our in vivo results demonstrated that Gln treatment reduced ET release (as indicated by cell-free-DNA content and myeloperoxidase activity), decreased lung inflammation (reductions in interferon-γ and increases in interleukin-10 levels), and improved lung morpho-function (decreased static lung elastance and alveolar collapse) in comparison with ARDS animals treated with saline. Moreover, Gln reduced ET and ROS formation in BALF cells stimulated with lipopolysaccharide in vitro, but it did not alter GPx or GR activity. In this model of endotoxin-induced pulmonary ARDS, treatment with Gln reduced pulmonary functional and morphological impairment, inflammation, and ET release in the lung.


Assuntos
Armadilhas Extracelulares/metabolismo , Glutamina/uso terapêutico , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Animais , DNA , Modelos Animais de Doenças , Endotoxinas , Feminino , Glutamina/farmacologia , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Inflamação/etiologia , Interferon gama/metabolismo , Interleucina-10/metabolismo , Contagem de Leucócitos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Pneumonia/etiologia , Alvéolos Pulmonares , Espécies Reativas de Oxigênio/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/patologia
12.
PLoS One ; 14(4): e0202456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943189

RESUMO

Many lung diseases, such as the acute respiratory distress syndrome (ARDS), display significant regional heterogeneity with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDS's regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions and precludes many regenerative medicine studies since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be relatively mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies in current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used days later to track the location and extent of where the initial injury occurred. Furthermore, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves lung regions undamaged. Collectively, these attributes of CICSLI will allow investigators to better study how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other heterogenous lung diseases.


Assuntos
Modelos Animais de Doenças , Lesão Pulmonar , Pulmão , Síndrome do Desconforto Respiratório do Adulto , Animais , Cateteres/efeitos adversos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Camundongos , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia
13.
Exp Eye Res ; 184: 152-161, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31022399

RESUMO

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute lung failure in critically sick patients, which severely compromises the function of multiple organs, including the brain. Although, the optic nerve and the retina are a part of the central nervous system, the effects of ARDS on these ocular structures are completely unknown. Thus, the major goal of this study was to test the hypothesis that ARDS affects vascular function in the eye. ARDS was induced in anesthetized pigs by intratracheal injection of lipopolysaccharide (LPS). Sham-treated animals served as controls. Pigs were monitored for 8 h and then sacrificed. Subsequently, retinal arterioles and short posterior ciliary arteries were isolated and cannulated with micropipettes to measure vascular responses by videomicroscopy. Levels of reactive oxygen species (ROS) were quantified in isolated vessels using dihydroethidium (DHE). Messenger RNA expression of hypoxic, inflammatory, prooxidative, and antioxidative genes was assessed by real-time PCR. When group-dependent differences in mRNA expression levels were found for a particular gene, immunostainings were conducted. Strikingly, responses to the endothelium-dependent vasodilator, bradykinin, were markedly impaired in retinal arterioles of LPS-treated pigs, but no differences were seen between ciliary arteries of LPS- and sham-treated animals. ROS levels were increased in retinal arterioles but not in ciliary arteries of LPS-treated pigs. Messenger RNA levels for HIF-1α, VEGF-A and NOX2 were markedly increased in retinal arterioles of LPS-treated pigs, whereas ciliary arteries had only negligible mRNA level changes. Pronounced immunoreactivity for HIF-1α, VEGF-A and NOX2 was seen in the endothelium of retinal arterioles from LPS-treated pigs. Histologically, massive edema was seen especially in the retinal nerve fiber layer of pigs treated with LPS. Our study provides the first evidence that ARDS induced by intratracheal LPS application evokes endothelial dysfunction in porcine retinal arterioles together with retinal edema, indicative of vascular leakage. In contrast, ciliary arteries appear to be resistant to intratracheal LPS application.


Assuntos
Artérias Ciliares/fisiologia , Endotélio Vascular/patologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Artéria Retiniana/fisiologia , Animais , Arteríolas/fisiologia , Catalase/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Glutationa Peroxidase/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Interleucinas/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Microscopia de Vídeo , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Suínos
14.
Am J Respir Crit Care Med ; 200(2): 235-246, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849228

RESUMO

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , Subunidade alfa de Receptor de Interleucina-4/imunologia , Interleucina-4/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Subunidade alfa de Receptor de Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Camundongos , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores de Superfície Celular/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
15.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(3): 281-287, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30914086

RESUMO

OBJECTIVE: To investigate the effects of Hippo signaling pathway on lung injury repair of mesenchymal stem cells (MSC) in acute respiratory distress syndrome (ARDS) and its mechanism. METHODS: Mouse bone marrow-derived MSC (mMSCs) cell lines with low expression of large tumor suppressor 2 (LATS2) were constructed by lentiviral vector transfection. Male C57BL/6 mice aging 6-8 weeks old were divided into four groups according to random number table (n = 36). The ARDS animal model (ARDS group) was reproduced by intratracheally injection of 2 g/L lipopolysaccharide (LPS) 50 µL, the normal saline (NS) control group was injected with an equal volume of NS. After 4 hours of model reproduction, 5×104 mMSCs transfected with blank lentivirus vector (MSC-shcontrol group) or shLATS2 lentivirus vector (MSC-shLATS2 group) were transplanted intratracheally, while NS control group and ARDS group were injected with equal volume of phosphate buffered saline (PBS). Mice were sacrificed at 3, 7, and 14 days after modeling, and lung tissue and bronchoalveolar lavage fluid (BALF) were harvested. Near-infrared fluorescence imaging, immunofluorescence staining and Western Blot were used to track mMSCs in lung tissue. Retension and proportion of mMSC differentiation into type II alveolar epithelial cells (AEC II) were evaluated. Lung tissue wet weight/body weight ratio (LWW/BW) and total protein (TP) and albumin (ALB) in BALF were determined to reflect pulmonary edema. The expression of Occludin protein in lung epithelium was tested by Western Blot to reflect permeability of epithelium. The levels of interleukins (IL-1ß, IL-6, IL-10) in BALF were assessed by enzyme-linked immunosorbent assay (ELISA) to reflect lung inflammation. Hematoxylin-eosin (HE) staining and modified Masson staining were carried out, and the scores were assessed to reflect lung injury and evaluate pulmonary fibrosis. RESULTS: The signal intensity of isolated lung fluorescence images at 3 days in the MSC-shLATS2 group was significantly higher than that in the MSC-shcontrol group (fluorescence intensity: 0.039±0.005 vs. 0.017±0.002, P < 0.05), the number of green fluorescent protein (GFP)-positive cells in lung tissue was also significantly higher than that in the MSC-shcontrol group (cells/HP: 29.65±6.98 vs. 17.50±4.58, P < 0.05), but they all decreased with time; and the proportion of mMSCs differentiated into AEC II was significantly increased [(64.12±15.29)% vs. (19.64±3.71)%, P < 0.05]. Compared with the NS control group, the levels of surface active protein C (SPC) and Occludin protein in the ARDS group were significantly decreased, LWW/BW ratio and TP, ALB and inflammatory factors levels in BALF were significantly increased; extensive alveolar and interstitial edema, hemorrhage and diffuse inflammatory cell infiltration were found in lung tissue, and the lung injury score was significantly increased; collagen fibers were deposited in alveolar septum and alveolar cavity, and pulmonary fibrosis score was also increased significantly. Compared with the ARDS group, the expression levels of SPC and Occludin at 14 days in the MSC-shcontrol group and the MSC-shLATS2 group were significantly increased (SPC/ß-actin: 0.51±0.12, 0.68±0.10 vs. 0.27±0.08, Occludin/ß-actin: 0.49±0.19, 0.79±0.11 vs. 0.25±0.08, all P < 0.05), TP, ALB, IL-1ß, IL-6 levels in BALF at 3 days were significantly decreased [TP (g/L): 8.08±1.72, 5.12±0.87 vs. 12.55±2.09; ALB (g/L): 0.71±0.21, 0.44±0.18 vs. 1.18±0.29, IL-1ß (ng/L): 99.26±14.32, 60.11±8.58 vs. 161.86±25.17, IL-6 (ng/L): 145.54±13.29, 101.74±11.55 vs. 258.79±27.88, all P < 0.05], and IL-10 was significantly increased (ng/L: 190.83±22.61, 316.65±37.88, both P < 0.05). Furthermore, all the above parameters in the MSC-shLATS2 group were significantly improved as compared with those in the MSC-shcontrol group (all P < 0.05). LWW/BW ratio in the MSC-shLATS2 group was significantly lower than that in the ARDS group and the MSC-shcontrol group (mg/g: 9.85±1.51 vs. 16.78±1.92, 14.88±1.74, both P < 0.05). CONCLUSIONS: Inhibiting Hippo signaling pathway by low expression of LATS2 could promote the retention of mMSCs in lung tissue and differentiation into AEC II cells of ARDS mice, improve pulmonary edema and alveolar epithelial permeability, regulate pulmonary inflammatory response, and alleviate pathological damage and fibrosis of lung tissue.


Assuntos
Lesão Pulmonar/prevenção & controle , Células-Tronco Mesenquimais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Transdução de Sinais , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
16.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769918

RESUMO

The main function of the lungs is oxygen transport from the atmosphere into the blood circulation, while it is necessary to keep the pulmonary tissue relatively free of pathogens. This is a difficult task because the respiratory system is constantly exposed to harmful substances entering the lungs by inhalation or via the blood stream. Individual types of lung cells are equipped with the mechanisms that maintain pulmonary homeostasis. Because of the clinical significance of acute respiratory distress syndrome (ARDS) the article refers to the physiological role of alveolar epithelial cells type I and II, endothelial cells, alveolar macrophages, and fibroblasts. However, all these cells can be damaged by lipopolysaccharide (LPS) which can reach the airspaces as the major component of the outer membrane of Gram-negative bacteria, and lead to local and systemic inflammation and toxicity. We also highlight a negative effect of LPS on lung cells related to alveolar-capillary barrier and their response to LPS exposure. Additionally, we describe the molecular mechanism of LPS signal transduction pathway in lung cells.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Capilares/efeitos dos fármacos , Capilares/patologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Oxigênio/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Síndrome do Desconforto Respiratório do Adulto/patologia , Transdução de Sinais/genética
17.
Thorax ; 74(3): 219-228, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30636196

RESUMO

BACKGROUND: In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), leading to a decline of the alveolar CO2 concentration [CO2]iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. METHODS: In isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+]cyt or [Ca2+]mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. RESULTS: Low [CO2]iA decreased [Ca2+]cyt and increased [Ca2+]mito in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses. CONCLUSIONS: Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+]cyt reduces surfactant secretion and thus regional ventilation in lung regions with high VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.


Assuntos
Hipocapnia/etiologia , Mitocôndrias/fisiologia , Surfactantes Pulmonares/metabolismo , Síndrome do Desconforto Respiratório do Adulto/etiologia , Volume de Ventilação Pulmonar/fisiologia , Animais , Modelos Animais de Doenças , Alvéolos Pulmonares/irrigação sanguínea , Ratos , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia
18.
Clin Sci (Lond) ; 133(2): 321-334, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30622219

RESUMO

Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production in vitro These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward.


Assuntos
Permeabilidade Capilar , Células Endoteliais/metabolismo , Pulmão/irrigação sanguínea , Proteínas Mitocondriais/deficiência , Proteínas Nucleares/deficiência , Edema Pulmonar/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Vasculite/prevenção & controle , Animais , Adesão Celular , Técnicas de Cocultura , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Edema Pulmonar/genética , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/patologia , Transdução de Sinais , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vasculite/genética , Vasculite/metabolismo , Vasculite/patologia
19.
Am J Respir Crit Care Med ; 200(1): 42-50, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30645145

RESUMO

Rationale: Two biologic phenotypes of acute respiratory distress syndrome (ARDS) have been identified based on plasma protein markers in four previous studies. Objectives: To determine if blood leukocyte gene expression is different between the "reactive" and "uninflamed" phenotype. Methods: This is a new study adding blood leukocyte transcriptomics and bioinformatics analysis to an existing patient cohort of ARDS in patients with sepsis admitted to two ICUs during a 1.5-year period. Canonical pathway analysis was performed. Measurements and Main Results: A total of 210 patients with sepsis and ARDS were included, of whom 128 had a reactive and 82 an uninflamed phenotype. A total of 3,332/11,443 (29%) transcripts were significantly different between the phenotypes. Canonical pathway analysis showed upregulation of oxidative phosphorylation genes indicative of mitochondrial dysfunction (52% of genes in pathway). The uninflamed phenotype was characterized by upregulation of mitogen-activated protein kinase pathways. Conclusions: A third of genes are differentially expressed between biologic phenotypes of ARDS supporting the observation that the subgroups of ARDS are incomparable in terms of pathophysiology. These data provide additional support for biologic heterogeneity in patients with ARDS and suggests that a personalized approach to intervention focusing on oxidative phosphorylation is pivotal in this condition.


Assuntos
Inflamação/genética , Leucócitos/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Mitocôndrias/metabolismo , Síndrome do Desconforto Respiratório do Adulto/genética , Sepse/genética , Idoso , Estudos de Coortes , Biologia Computacional , Feminino , Perfilação da Expressão Gênica , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Fosforilação Oxidativa , Fenótipo , RNA Mensageiro/metabolismo , Síndrome do Desconforto Respiratório do Adulto/classificação , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Sepse/metabolismo , Transcriptoma , Regulação para Cima
20.
Int J Mol Med ; 43(3): 1241-1252, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628652

RESUMO

Mesenchymal stem cell (MSC)­mediated repair of injured alveolar epithelial cells is a promising potential cure for acute respiratory distress syndrome (ARDS); however, the repairing effect of MSCs is limited by poor homing and differentiation. Our previous study revealed that the inhibition of the Hippo signaling pathway promotes the proliferation, migration and differentiation of MSCs in vitro, leading to the hypothesis that MSCs with downregulated Hippo signaling could further ameliorate lipopolysaccharide (LPS)­induced ARDS in vivo. In the current study, mouse bone marrow­derived MSCs (mMSCs) with downregulated Hippo signaling were constructed by shRNA­mediated knockdown of large tumor suppressor kinase 1 (Lats1) and were intratracheally administered to LPS­induced mouse models of ARDS. The inhibition of Hippo signaling increased the retention of mMSC in ARDS lung tissue and their differentiation toward alveolar type II epithelial cells. Furthermore, mMSCs with downregulated Hippo signaling led to a decreased lung wet weight/body weight ratio, decreased total protein and albumin concentrations in bronchoalveolar lavage fluid, decreased levels of proinflammatory factors and increased levels of anti­inflammatory factors. Finally, mMSCs with downregulated Hippo signaling improved pathological changes and decreased pulmonary fibrosis in lungs of mice with ARDS. These results suggest that the inhibition of the Hippo signaling pathway in mouse mMSCs by knockdown of Lats1 could further improve the protective effects of mMSCs against epithelial damage and the therapeutic potential of mMSCs on mice with ARDS.


Assuntos
Lipopolissacarídeos/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Transdução de Sinais , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Diferenciação Celular , Permeabilidade da Membrana Celular , Modelos Animais de Doenças , Fibrose , Técnicas de Inativação de Genes , Vetores Genéticos/genética , Lentivirus/genética , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Proteínas Serina-Treonina Quinases/genética , Síndrome do Desconforto Respiratório do Adulto/patologia , Mucosa Respiratória/metabolismo
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