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1.
Biomed Pharmacother ; 119: 109412, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31514069

RESUMO

Acute pulmonary injury, or acute respiratory distress syndrome, has a high incidence in elderly individuals and high mortality in its most severe degree, becoming a challenge to public health due to pathophysiological complications and increased economic burden. Acute pulmonary injury can develop from sepsis, septic shock, and pancreatitis causing reduction of alveolar airspace due to hyperinflammatory response. Oxidative stress acts directly on the maintenance of inflammation, resulting in tissue injury, as well as inducing DNA damages. Once the DNA is damaged, enzymatic DNA repair mechanisms act on lesions in order to maintain genomic stability and, consequently, contribute to cell viability and homeostasis. Although palliative treatment based on mechanical ventilation and antibiotic using have a kind of efficacy, therapies based on modulation of DNA repair and genomic stability could be effective for improving repair and recovery of lung tissue in patients with acute pulmonary injury.


Assuntos
Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Reparo do DNA/genética , Instabilidade Genômica , Pulmão/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Estresse Oxidativo
2.
Biomed Pharmacother ; 118: 109363, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545277

RESUMO

OBJECTIVE: Alveolar epithelial barrier dysfunction in response to inflammatory reaction contributes to pulmonary edema in acute lung injury(ALI).Irisin,a newly-found myokine,exerts the anti-inflammatory effects. This study aims to investigate the protective effects of irisin on lipopolysaccharide (LPS)-induced ALIin vivo and in vitro, and to explore its underlying mechanism. METHODS: Male SD rats and A549 cells were divided into 4 groups: control group, LPS group, Irisin pretreated group, and Irisin/Compound C(a special inhibitor of AMPK)-treated group. The ALI model was established by intravenous injection of LPS in rats, and LPS challenge in A549 cells. Pulmonary specimens were harvested for microscopic examination of the pathological changes, and the expression of AMPK,SIRT1,NF-κB, p66Shc and caspase-3 in lung tissues. The pulmonary permeability were examined by wet/dry lung weight ratio(W/D) and lung permeability index(LPI). The apoptotic index, and the expression of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), monocyte chemoattractant activating protein-1 (MCP-1), tight junctions (occludin,ZO-1) were determined both in lung tissue and A549 cells. RESULTS: Irisin alleviated lung histological changes and decreased pulmonary microvascular permeability in LPS-induced rats. Irisin up-regulated the expression of occludin, ZO-1,AMPK,SIRT1, down-regulated the expression of TNF-α,IL-1ß,MCP-1,NF-κB, p66Shc caspase-3, and decreased the apoptotic index in LPS-induced rats and A549 cells. All these protective effects of irisin could be reversed by Compound C. CONCLUSION: Irisin improved LPS-induced alveolar epithelial barrier dysfunction via suppressing inflammation and apoptosis, and this protective effect might be mediated by activating AMPK/SIRT1 pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Epitélio/fisiopatologia , Fibronectinas/uso terapêutico , Pulmão/fisiopatologia , Transdução de Sinais , Sirtuína 1/metabolismo , Células A549 , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Epitélio/ultraestrutura , Fibronectinas/farmacologia , Humanos , Inflamação/patologia , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Permeabilidade , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Inhal Toxicol ; 31(3): 107-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31039646

RESUMO

Objective: To establish a rat model with respiratory and pulmonary responses caused by inhalation exposure to non-lethal concentrations of ammonia (NH3) that can be used for evaluation of new medical countermeasure strategies for NH3-induced acute lung injury (ALI). This is of great value since no specific antidotes of NH3-induced injuries exist and medical management relies on supportive and symptomatically relieving efforts. Methods: Female Sprague-Dawley rats (8-9 weeks old, 213g ± 2g) were exposed to NH3 using two different exposure regimens; nose-only inhalation or intratracheal instillation. The experiment was terminated 5 h, 24 h, 14 and 28 days post-exposure. Results: Nose-only inhalation of NH3 (9000-15 000 ppm) resulted in increased salivation and labored breathing directly post-exposure. Exposure did not increase inflammatory cells in bronchoalveolar lavage fluid but exposure to 12 000 ppm NH3 during 15 min reduced body weight and induced coagulation abnormalities by increasing serum fibrinogen levels. All animals were relatively recovered by 24 h. Intratracheal instillation of NH3 (1%) caused early symptoms of ALI including airway hyperresponsiveness, neutrophilic lung inflammation and altered levels of coagulation factors (increased fibrinogen and PAI-1) and early biomarkers of ALI (IL-18, MMP-9, TGFß) which was followed by increased deposition of newly produced collagen 14 days later. Histopathology analysis at 5 h revealed epithelial desquamation and that most lesions were healed after 14 days. Conclusions: This study demonstrates that intratracheal instillation can reproduce several early hallmarks of ALI. Our findings therefore support that the intratracheal instillation exposure regimen can be used for new medical countermeasure strategies for NH3-induced ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Amônia/administração & dosagem , Amônia/toxicidade , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Colágeno/metabolismo , Feminino , Fibrina/metabolismo , Fibrinogênio/análise , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Nariz , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Traqueia
4.
Ther Adv Respir Dis ; 13: 1753466619847901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068086

RESUMO

Smoke-inhalation-induced acute lung injury (SI-ALI) is a leading cause of morbidity and mortality in victims of fire tragedies. SI-ALI contributes to an estimated 30% of burn-caused patient deaths, and recently, more attention has been paid to the specific interventions for this devastating respiratory illness. In the last decade, much progress has been made in the understanding of SI-ALI patho-mechanisms and in the development of new therapeutic strategies in both preclinical and clinical studies. This article reviews the recent progress in the treatment of SI-ALI, based on pathophysiology, thermal damage, airway obstruction, the nuclear-factor kappa-B signaling pathway, and oxidative stress. Preclinical therapeutic strategies include use of mesenchymal stem cells, hydrogen sulfide, peroxynitrite decomposition catalysts, and proton-pump inhibitors. Clinical interventions include high-frequency percussive ventilation, perfluorohexane, inhaled anticoagulants, and nebulized epinephrine. The animal model, dose, clinical application, and pharmacology of these medications are summarized. Future directions and further needs for developing innovative therapies are discussed.


Assuntos
Lesão Pulmonar Aguda/terapia , Obstrução das Vias Respiratórias/terapia , Lesão por Inalação de Fumaça/terapia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Obstrução das Vias Respiratórias/etiologia , Animais , Modelos Animais de Doenças , Humanos , Estresse Oxidativo , Lesão por Inalação de Fumaça/complicações , Lesão por Inalação de Fumaça/fisiopatologia , Terapias em Estudo/métodos
5.
Ulus Travma Acil Cerrahi Derg ; 25(2): 198-201, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30892668

RESUMO

Lightning strike is an environmental electrical injury with high rates of morbidity and mortality. Lightning strike injuries are also considered to be high-voltage injuries. Respiratory injuries associated with lightning strikes include pulmonary edema, pulmonary contusion, acute respiratory distress syndrome, and pulmonary hemorrhage. In addition to direct damage, the affected patients are also exposed to secondary trauma; similarly, many other mechanisms associated with lightning injury have the same risk. It will therefore always be a rational approach to evaluate patients as multiple trauma patients. In this case report, a 19-year-old patient was admitted to the emergency department with amnesia, disorientation, shortness of breath, abdominal pain complaints and lung contusion, and myopathy signs as a result of a lightning strike in open terrain. The patient had a blood pressure of 80/50 mmHg, a heart rate of 110/min, and oxygen saturation of 85%. Bilateral lung contusion and pleural effusion were detected on the computerized tomography of the thorax. In addition, global cardiac hypokinesia and the 20%-25% ejection fraction were detected on echocardiography. The central nervous system and abdominal scans were normal. The patient was admitted to the intensive care unit and treated with supportive oxygen, intravenous hydration, antibiotics, systemic steroids, and invasive cardiac monitoring. On the 10th day of admission to the hospital, the patient was discharged with clinical and radiological improvement. On the 20th day after discharge, tomography scans showed no thoracic pathologic findings.


Assuntos
Lesão Pulmonar Aguda , Lesões por Ação do Raio/complicações , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Adulto , Humanos , Adulto Jovem
6.
Medicine (Baltimore) ; 98(11): e14830, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30882668

RESUMO

This study aims to explore the dynamic changes of pulmonary arterial pressure (PAP) and its clinical significance in prenatal neonates with pulmonary and extra-pulmonary acute lung injury/respiratory distress syndrome (ALI/ARDS).A prospective study was conducted in the Neonate Intensive Care Unit (NICU) between May 2015 and April 2017. A total of 78 prenatal neonates with ALI/ARDS were selected and divided into 2 groups: pulmonary group (n = 37) and extra-pulmonary group (n = 41). These neonates were further divided into 3 groups according to the OSI index: mild, moderate, and severe groups. The dynamic changes of PAP were observed in these neonates. In the moderate and severe groups, PAP was significantly higher in neonates with pulmonary ALI/ADDS (ALI/ARDSp) than in neonates with extrapulmonary ALI/ARDS(ALI/ARDSexp) (62.5 ±â€Š5.4 vs 68.0 ±â€Š6.5, 54.7 ±â€Š5.9 vs 64.2 ±â€Š4.9; t = 3.264, 3.123; P = .004,.039). Furthermore, PAP was higher in neonates with ALI/ADDSp in the severe group, compared with those in the moderate group (t = 2.420, P < .05). There was significant difference among the 3 subgroups of neonates with ALI/ADDSexp (F = 60.100, P = .000). PAP was positively correlated with the OSI index (r = 0.823). The overall dynamic PAP monitoring results revealed that PAP was higher in the pulmonary group than that in the extrapulmonary group, and this exhibited a gradually decreasing trend as the condition of the subject improved.PAP in perinatal neonates with ALI/ARDS increases in varying degrees, and its extent was related to the severity of the illness. PAP was significantly higher in neonates with ALI/ADDSp than in neonates with ALI/ADDSexp. This can be used as a monitoring indicator for the severity of illness.


Assuntos
Lesão Pulmonar Aguda , Hipertensão Pulmonar/diagnóstico , Artéria Pulmonar , Síndrome do Desconforto Respiratório do Recém-Nascido , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/fisiopatologia , Pressão Arterial , China , Correlação de Dados , Feminino , Humanos , Recém-Nascido , Masculino , Monitorização Fisiológica/métodos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Ultrassonografia Doppler em Cores/métodos
7.
Curr Opin Anaesthesiol ; 32(2): 150-155, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30817387

RESUMO

PURPOSE OF REVIEW: High-flow nasal cannula oxygen therapy (HFOT) is becoming an alternative to noninvasive ventilation (NIV) and standard oxygen in management of patients with acute respiratory failure. RECENT FINDINGS: Patients with de novo acute respiratory failure should be managed with HFOT rather than NIV. Indeed, the vast majority of patients with de novo respiratory failure meet the criteria for ARDS, and NIV does not seem protective, as patients generate overly high tidal volume that may worsen underlying lung injury. However, NIV remains the first-line oxygenation strategy in postoperative patients and those with acute hypercapnic respiratory failure when pH is equal to or below 7.35. During preoxygenation, NIV also seems to be more efficient than standard oxygen using valve-bag mask to prevent profound oxygen desaturation. In postoperative cardiothoracic patients, HFOT could be an alternative to NIV in the management of acute respiratory failure. SUMMARY: Recent recommendations for managing patients with acute respiratory failure have been established on the basis of studies comparing NIV with standard oxygen. Growing use of HFOT will lead to new studies comparing NIV versus HFOT in view of more precisely defining the appropriate indications for each treatment.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Cuidados Críticos/métodos , Ventilação não Invasiva/efeitos adversos , Oxigenoterapia/métodos , Síndrome do Desconforto Respiratório do Adulto/terapia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Cânula , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Ventilação não Invasiva/instrumentação , Ventilação não Invasiva/métodos , Nariz , Oxigenoterapia/efeitos adversos , Oxigenoterapia/instrumentação , Seleção de Pacientes , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Volume de Ventilação Pulmonar/fisiologia , Resultado do Tratamento
8.
Mil Med ; 184(Suppl 1): 273-281, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901433

RESUMO

Primary blast lung injury (PBLI) caused by exposure to high-intensity pressure waves is associated with parenchymal tissue injury and severe ventilation-perfusion mismatch. Although supportive ventilation is often required in patients with PBLI, maldistribution of gas flow in mechanically heterogeneous lungs may lead to further injury due to increased parenchymal strain and strain rate, which are difficult to predict in vivo. In this study, we developed a computational lung model with mechanical properties consistent with healthy and PBLI conditions. PBLI conditions were simulated with bilateral derecruitment and increased perihilar tissue stiffness. As a result of these tissue abnormalities, airway flow was heterogeneously distributed in the model under PBLI conditions, during both conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. PBLI conditions resulted in over three-fold higher parenchymal strains compared to the healthy condition during CMV, with flow distributed according to regional tissue stiffness. During high-frequency oscillatory ventilation, flow distribution became increasingly heterogeneous and frequency-dependent. We conclude that the distribution and rate of parenchymal distension during mechanical ventilation depend on PBLI severity as well as ventilatory modality. These simulations may allow realistic assessment of the risks associated with ventilator-induced lung injury following PBLI, and facilitate the development of alternative lung-protective ventilation modalities.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Traumatismos por Explosões/fisiopatologia , Simulação por Computador , Respiração Artificial/métodos , Lesão Pulmonar Aguda/terapia , Traumatismos por Explosões/terapia , Explosões , Humanos , Pulmão/fisiologia , Pulmão/fisiopatologia , Pressão/efeitos adversos , Respiração Artificial/tendências
9.
Med Sci Monit ; 25: 1828-1837, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30853709

RESUMO

Acute lung injury (ALI) is a life-threatening clinical syndrome in critically ill patients. The identification of novel biological markers for the early diagnosis of ALI and the development of more effective treatments are topics of current research. High mobility group box-1 protein (HMGB1) is a late inflammatory mediator associated with sepsis, malignancy, and immune disease. Levels of HMGB1 may reflect the severity of inflammation and tissue damage, indicating a potential role for HMGB1 as a prognostic biomarker in ALI, and a potential target for blocking inflammatory pathways. Several studies have shown that HMGB1 regulates autophagy. Autophagy, or type II programmed cell death, is an essential biological process that maintains cellular homeostasis. Studies have shown that HMGB1 and autophagy are involved in the pathogenesis of many lung diseases including ALI but the specific mechanisms underlying this association remain to be determined. This review aims to provide an update on the current status of the role of HMBG1 and autophagy in ALI.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Autofagia/fisiologia , Proteína HMGB1/fisiologia , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/metabolismo , Animais , Biomarcadores/sangue , Humanos , Inflamação , Pulmão , Prognóstico , Sepse
10.
Med Sci Monit ; 25: 827-835, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30734722

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS), which is characterized by severe hypoxemia (PaO2/FIO2 ≤300 mmHg), is usually companied by uncontrolled inflammation, oxidative injury, and the damage to the alveolar-capillary barrier. Severe ARDS is usually companied with acute lung injury that worsen the patients' condition. HIPK1 is a modulator of homeodomain-containing transcription factors and regulates multiple cellular biological process associated with inflammation and anti-stress responses. MATERIAL AND METHODS We used an LPS-induced mouse acute lung injury (ALI) model to investigate the possible role of HIPK1 in ALI pathophysiology. RESULTS We found the HIPK1 was elevated in ALI model mice while interference of HIPK1 by siRNA attenuated the inflammation and oxidative stress indicators (H2O2, O-2, and NO). Further research found HIPK1 interference enhanced the autophagy. CONCLUSIONS Decreased HIPK1 in ALI showed protective effects in attenuating inflammation and oxidative stress and enhancing autophagy, indicating HIPK1 as a possible target in ALI management.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Proteínas Quinases/metabolismo , Proteínas Quinases/fisiologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Autofagia/fisiologia , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-6 , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Proteínas Serina-Treonina Quinases , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Fator de Necrose Tumoral alfa
11.
Crit Care ; 23(1): 44, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760290

RESUMO

BACKGROUND: The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. We previously found that endothelial progenitor cell (EPC) exosomes prevent endothelial dysfunction and lung injury in sepsis in part due to their encapsulation of miRNA-126. However, the effects of EPC exosomes in acute lung injury (ALI) remain unknown. METHODS: To determine if EPC exosomes would have beneficial effects in ALI, intratracheal administration of lipopolysaccharide (LPS) was used to induce ALI in mice. Lung permeability, inflammation, and the role of miRNA-126 in the alveolar-epithelial barrier function were examined. RESULTS: The intratracheal administration of EPC exosomes reduced lung injury following LPS-induced ALI at 24 and 48 h. Compared to placebo, intratracheal administration of EPC exosomes significantly reduced the cell number, protein concentration, and cytokines/chemokines in the bronchoalveolar lavage fluid (BALF), indicating a reduction in permeability and inflammation. Further, EPC exosomes reduced myeloperoxidase (MPO) activity, lung injury score, and pulmonary edema, demonstrating protection against lung injury. Murine fibroblast (NIH3T3) exosomes, which do not contain abundant miRNA-126, did not provide these beneficial effects. In human small airway epithelial cells (SAECs), we found that overexpression of miRNA-126-3p can target phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), while overexpression of miRNA-126-5p inhibits the inflammatory alarmin HMGB1 and permeability factor VEGFα. Interestingly, both miR-126-3p and 5p increase the expression of tight junction proteins suggesting a potential mechanism by which miRNA-126 may mitigate LPS-induced lung injury. CONCLUSIONS: Our data demonstrated that human EPC exosomes are beneficial in LPS-induced ALI mice, in part through the delivery of miRNA-126 into the injured alveolus.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Células Progenitoras Endoteliais/enzimologia , Inflamação/fisiopatologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Western Blotting/métodos , Exossomos/metabolismo , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Camundongos , MicroRNAs/fisiologia , Peroxidase/metabolismo , Peroxidase/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Índice de Gravidade de Doença , Traqueia/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Br J Anaesth ; 122(2): 277-285, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30686314

RESUMO

BACKGROUND: Tidal recruitment/derecruitment (R/D) of collapsed regions in lung injury has been presumed to cause respiratory oscillations in the partial pressure of arterial oxygen (PaO2). These phenomena have not yet been studied simultaneously. We examined the relationship between R/D and PaO2 oscillations by contemporaneous measurement of lung-density changes and PaO2. METHODS: Five anaesthetised pigs were studied after surfactant depletion via a saline-lavage model of R/D. The animals were ventilated with a mean fraction of inspired O2 (FiO2) of 0.7 and a tidal volume of 10 ml kg-1. Protocolised changes in pressure- and volume-controlled modes, inspiratory:expiratory ratio (I:E), and three types of breath-hold manoeuvres were undertaken. Lung collapse and PaO2 were recorded using dynamic computed tomography (dCT) and a rapid PaO2 sensor. RESULTS: During tidal ventilation, the expiratory lung collapse increased when I:E <1 [mean (standard deviation) lung collapse=15.7 (8.7)%; P<0.05], but the amplitude of respiratory PaO2 oscillations [2.2 (0.8) kPa] did not change during the respiratory cycle. The expected relationship between respiratory PaO2 oscillation amplitude and R/D was therefore not clear. Lung collapse increased during breath-hold manoeuvres at end-expiration and end-inspiration (14% vs 0.9-2.1%; P<0.0001). The mean change in PaO2 from beginning to end of breath-hold manoeuvres was significantly different with each type of breath-hold manoeuvre (P<0.0001). CONCLUSIONS: This study in a porcine model of collapse-prone lungs did not demonstrate the expected association between PaO2 oscillation amplitude and the degree of recruitment/derecruitment. The results suggest that changes in pulmonary ventilation are not the sole determinant of changes in PaO2 during mechanical ventilation in lung injury.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Consumo de Oxigênio , Recrutamento Neurofisiológico , Lesão Pulmonar Aguda/diagnóstico por imagem , Animais , Gasometria , Feminino , Masculino , Atelectasia Pulmonar/metabolismo , Atelectasia Pulmonar/fisiopatologia , Respiração Artificial , Mecânica Respiratória , Suínos , Irrigação Terapêutica , Volume de Ventilação Pulmonar , Tomografia Computadorizada por Raios X
13.
Int Immunopharmacol ; 68: 17-29, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30599444

RESUMO

Previous studies demonstrated that triptolide (PG490) has many anti-inflammatory and immunosuppressive effects. However, little is known about the effect of PG490-88 (a water-soluble derivative of triptolide) on ischemia/reperfusion (I/R)-induced acute lung injury. We assessed the effects of PG490-88 on I/R-induced acute lung injury in rats and on hypoxia/reoxygenation (H/R) in a line of murine epithelial cells. Isolated perfused rat lungs were subjected to 40 min of ischemia, followed by 60 min of reperfusion to induce I/R injury. Induction of I/R led to lung edema, elevated pulmonary arterial pressure, histological evidence of lung inflammation, oxidative stress, and increased levels of TNF-α and CINC-1 in bronchoalveolar lavage fluid. PG490-88 significantly suppressed all of these responses. Additionally, induction of I/R reduced the expression of claudin-4, occludin, and ZO-1, and increased apoptosis in lung tissue. PG490-88 also significantly suppressed these effects. I/R reduced the levels of IκB-α and MKP-1, and increased the levels of nuclear NF-κB and mitogen-activated protein kinase in lung tissue, and PG490-88 suppressed these effects. In vitro studies using mouse lung alveolar epithelial cells indicated that H/R increased the levels of phosphorylated p65 and MIP-2, but decreased the level of IκB-α. PG490-88 also suppressed these effects. In I/R damaged lungs, PG490-88 suppresses the inflammatory response, disruption of tight junction structure, and apoptosis. PG490-88 has the potential as a prophylactic agent to prevent I/R-induced lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Diterpenos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Linhagem Celular , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos
14.
Acta Pharmacol Sin ; 40(5): 630-641, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30022154

RESUMO

The integrity of the endothelial barrier is a determinant of the prognosis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated whether and how Sirtuin 1 (SIRT1) maintained the vascular integrity during ALI. An experimental model of ALI was established in mice through intratracheal administration of LPS (10 mg/kg). LPS stimulation significantly increased the pulmonary permeability and decreased the expression of SIRT1 and tight junction proteins (TJs), including occludin, claudin-5, tight junction protein 1 and tight junction protein 2. Morphological studies showed that LPS induced obvious lung injury with inflammatory cell infiltration in the interstitial and alveolar space, hemorrhage, edema, and the thickened alveolar wall compared to the control mice. Intratracheal administration of the selective SIRT1 activator SRT1720 (6.25 mg/kg) significantly attenuated LPS-induced lung injury, lung hyper-permeability and increased TJs expression, whereas intratracheal administration of the selective SIRT1 inhibitor EX527 (6.25 mg/kg) aggravated LPS-induced ALI. Similar protective effects of SIRT1 on pulmonary cellular permeability were observed in primary human pulmonary microvascular endothelial cells treated with LPS (2 mg/mL) in vitro. We further demonstrated that the RhoA/ROCK signaling pathway was activated in SIRT1 regulation of tight junction permeability. The RhoA/ROCK inhibitor Y-27632 (10 µM) increased the expression of TJs and reversed LPS- or EX527-induced hyper-permeability. In conclusion, SIRT1 ameliorates LPS-induced lung injury via decreasing endothelial tight junction permeability, possibly via RhoA/ROCK signaling pathway. This finding may contribute to the development of new therapeutic approaches for lung injury.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Permeabilidade da Membrana Celular/fisiologia , Células Endoteliais/metabolismo , Sirtuína 1/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Administração por Inalação , Amidas/farmacologia , Animais , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores
15.
Thorax ; 74(1): 43-50, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30076187

RESUMO

BACKGROUND: We previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in both Escherichia coli lipopolysaccharide and live bacteria-induced acute lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI. METHODS: In the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilled E. coli bacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy. RESULTS: After 6 hours, instillation of E. coli bacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours. CONCLUSIONS: In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Terapia Baseada em Transplante de Células e Tecidos , Micropartículas Derivadas de Células , Infecções por Escherichia coli/complicações , Células-Tronco Mesenquimais , Pneumonia Bacteriana/complicações , Proteínas/metabolismo , Alvéolos Pulmonares/metabolismo , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Adulto , Idoso , Pressão Arterial , Carga Bacteriana , Micropartículas Derivadas de Células/efeitos dos fármacos , Feminino , Humanos , Indutores de Interferon/farmacologia , Contagem de Leucócitos , Complacência Pulmonar , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Neutrófilos , Técnicas de Cultura de Órgãos , Oxigênio/metabolismo , Permeabilidade , Poli I-C/farmacologia , Alvéolos Pulmonares/microbiologia , Alvéolos Pulmonares/patologia , Artéria Pulmonar , Edema Pulmonar/microbiologia , Edema Pulmonar/terapia , Receptor 3 Toll-Like/agonistas , Fator de Necrose Tumoral alfa/metabolismo
16.
Life Sci ; 216: 156-167, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468833

RESUMO

AIMS: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D2 has been observed in CS-induced lung injury. Currently, no effective pharmacological therapies are available to treat ALI, and supportive therapies remain the mainstay of treatment. Therefore, we investigated the protective effect of CT­133, a newly discovered selective CRTH2 antagonist, on CS-induced ALI in vivo and in vitro. MAIN METHODS: CT­133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD2-stimulated RAW 264.7 macrophages were used to evaluate the protective effect of CT­133. KEY FINDINGS: CT­133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL­1ß, IL­6, TNF­α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT­133 not only reversed the uncontrolled secretion of IL­1ß, IL-6, TNF­α and KC from CSE- and PGD2-stimulated RAW 264.7 macrophages but also augmented IL-10 production in both in vivo and in vitro studies. Additionally, CT­133 alleviated in vitro neutrophil migration chemoattracted by PGD2. SIGNIFICANCE: Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Fumaça/efeitos adversos , Lesão Pulmonar Aguda/fisiopatologia , Animais , Líquido da Lavagem Broncoalveolar , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Peroxidase/metabolismo , Prostaglandina D2/metabolismo , Células RAW 264.7 , Tabaco/efeitos adversos
17.
Pulm Pharmacol Ther ; 54: 53-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528955

RESUMO

The main goal of this study was to evaluate the effects of arbutin (AR) on lipopolysaccharide (LPS)-induced lung injury. A lung injury rat model was established by intravenous LPS administration. We found that levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6) in both serum and lung tissue were significant increased after LPS challenge. In addition, pathological conditions were examined in rat lungs, and it was demonstrated that AR-pretreatment reduced LPS-induced malondialdehyde (MDA) levels and increased LPS-induced superoxide dismutase (SOD) activity. Moreover, the expression of sirtuin1 (SIRT1), nuclear erythroid factor 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) as well as the phosphorylation of NF-κBp65 and IκBα were increased with LPS-induced lung injury, and were significantly restored by AR treatment. Together, our results indicated that SIRT1 is a potential therapeutic target in LPS-induced lung injury, and that AR may be a novel therapeutic in patients with acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Arbutina/farmacologia , Sirtuína 1/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/toxicidade , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/metabolismo
18.
Acta Cir Bras ; 33(10): 896-903, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30484499

RESUMO

PURPOSE: To investigate the apoptotic mechanisms in rabbits with blast-induced acute lung injury (ALI). METHODS: A total of 40 rabbits were randomly divided into a blank control group (A, n=10) and an experimental group (EXP, n=30). Explosion-induced chest-ALI models were prepared and sampled at different time points (4, 12, and 24h after modeling, T1-T3) to test the lung dry weight/wet weight ratio (W/D) and arterial oxygen pressure (PaO2), apoptosis of lung tissue by the TUNEL assay, and Caspase-3, Bax, and Bcl-2 levels by immunohistochemical analysis. Furthermore, lung tissue was sampled to observe pathological morphology by microscopy. RESULTS: Under a light microscope, Group EXP exhibited obvious edema in the pulmonary interstitial substance and alveoli, a large number of red blood cells, inflammatory cells, and serous exudation in the alveolar cavity, as well as thickening of the pulmonary interstitial fluid. Compared to Group A, the W/D ratio was significantly increased in Group EXP (P<0.01), while PaO2 was significantly reduced (P<0.01). The apoptosis index was significantly increased (P<0.01), and caspase-3 and Bax/Bcl-2 levels were increased (P<0.01). CONCLUSION: Apoptosis plays an important role in the occurrence and development of acute lung injury in rabbits by participating in lung injury and promoting the progression of ALI.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Apoptose/fisiologia , Traumatismos por Explosões/fisiopatologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Animais , Traumatismos por Explosões/sangue , Traumatismos por Explosões/patologia , Caspase 3/sangue , Modelos Animais de Doenças , Feminino , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Alvéolos Pulmonares/patologia , Coelhos , Distribuição Aleatória , Proteína X Associada a bcl-2/sangue
19.
J Vis Exp ; (140)2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30417861

RESUMO

The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit patients. Despite treatment advances over the last decades, ARDS patients still suffer mortality rates between 35 and 40%. There is still a need for further research to improve the outcome of patients suffering from ARDS. One problem is that no single animal model can mimic the complex pathomechanism of the acute respiratory distress syndrome, but several models exist to study different parts of it. Oleic acid injection (OAI)-induced lung injury is a well-established model for studying ventilation strategies, lung mechanics and ventilation/perfusion distribution in animals. OAI leads to severely impaired gas exchange, deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The disadvantage of this model is the controversial mechanistic relevance of this model and the necessity for central venous access, which is challenging especially in smaller animal models. In summary, OAI-induced lung injury leads to reproducible results in small and large animals and hence represents a well-suited model for studying ARDS. Nevertheless, further research is necessary to find a model that mimics all parts of ARDS and lacks the problems associated with the different models existing today.


Assuntos
Ácido Oleico , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Animais , Modelos Animais de Doenças , Humanos , Ácido Oleico/administração & dosagem , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/terapia , Testes de Função Respiratória , Suínos
20.
BMC Pulm Med ; 18(1): 164, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30373540

RESUMO

BACKGROUND: Interleukin (IL)-3 amplifies inflammation. However, the effect of IL-3 in acute lung injury (ALI), an acute inflammatory disease, is unclear. The aim of this study was to test the hypothesis that IL-3 plays an important role in hyperoxia-induced ALI. METHODS: Hyperoxic ALI was induced in wild-type (WT) and IL-3 gene disrupted (IL-3-/-) mice by exposure to 100% O2 for 72 h. RESULTS: Hyperoxia increased IL-3 levels in plasma and lung tissues in WT mice. Pulmonary inflammation and edema were detected by histological assay in WT mice exposed to 100% O2 for 72 h. However, the hyperoxia-induced lung histological changes were improved in IL-3-/- mice. The hyperoxia-induced elevation of neutrophils in bronchoalveolar lavage fluids and circulation were reduced in IL-3-/- mice. Meanwhile, the levels of tumor necrosis factor-α and IL-6 were suppressed in IL-3-/- mice compared with WT mice. Moreover, the hyperoxia-induced the activation of IκBα kinase (IKK) ß, IκBα phosphorylation, and nuclear factor-κB translocation were inhibited in IL-3-/- mice compared with WT mice. CONCLUSIONS: Our results suggest IL-3 is a potential therapeutic target for hyperoxia-induced ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Hiperóxia/fisiopatologia , Interleucina-3/metabolismo , Pneumonia/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Quinase I-kappa B/metabolismo , Interleucina-3/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Oxigênio/administração & dosagem , Oxigênio/efeitos adversos , Pneumonia/patologia , Fator de Necrose Tumoral alfa/metabolismo
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