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1.
Folia Histochem Cytobiol ; 57(4): 168-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825519

RESUMO

INTRODUCTION: Sepsis-induced acute lung injury (ALI) is an inflammatory process involved with simultaneous production of inflammatory cytokines and chemokines. In this study, we investigated the regulatory role of miR-539-5p in sepsis-induced ALI using a mouse model of cecal ligation puncture (CLP) and an in vitro model of primary murine pulmonary microvascular endothelial cells (MPVECs). MATERIAL AND METHODS: Adult male C57BL/6 mice were intravenously injected with or without miR-539-5p agomir or scrambled control one week before CLP operation. MPVECs were transfected with miR-539-5p mimics or control mimics, followed by lipopolysaccharide (LPS) stimulation. ROCK1 was predicted and confirmed as a direct target of miR-539-5p using dual-luciferase reporter assay. In rescue experiment, MPVECs were co-transfected with lentiviral vector expressing ROCK1 (or empty vector) and miR-539-5p mimics 24 h before LPS treatment. The transcriptional activity of caspase-3, the apoptosis ratio, the levels of miR-539-5p, interleukin-1b (IL-1b), interleukin-6 (IL-6), and ROCK1 were assessed. RESULTS: Compared to sham group, mice following CLP showed pulmonary morphological abnormalities, elevated production of IL-1b and IL-6, and increased caspase-3 activity and apoptosis ratio in the lung. In MPVECs, LPS stimulation resulted in a significant induction of inflammatory cytokine levels and apoptosis compared to untreated cells. The overexpression of miR-539-5p in septic mice alleviated sepsis-induced pulmonary injury, apoptosis, and inflammation. MiR-539-5p also demonstrated anti-apoptotic and anti-inflammatory effect in LPS-treated MPVECs. The upregulation of ROCK1 in MPVECs recovered miR-539-5p-suppressed caspase-3 activity and proinflammatory cytokine production. CONCLUSION: In conclusion, miR-539-5p alleviated sepsis-induced ALI via suppressing its downstream target ROCK1, suggesting a therapeutic potential of miR-539-5p for the management of sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/terapia , MicroRNAs/uso terapêutico , Quinases Associadas a rho/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Regulação para Baixo , Inflamação/terapia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Sepse/induzido quimicamente , Sepse/complicações , Transfecção
2.
Lancet ; 394(10214): 2073-2083, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31711629

RESUMO

BACKGROUND: An ongoing outbreak of lung injury associated with e-cigarettes or vaping (also known as E-VALI or VALI) started in March, 2019, in the USA. The cause, diagnosis, treatment, and course of this disease remains unknown. METHODS: In this multicentre, prospective, observational, cohort study, we collected data on all patients with lung injury associated with e-cigarettes or vaping seen in Intermountain Healthcare, an integrated health system based in Utah, USA, between June 27 and Oct 4, 2019. Telecritical care, based in Salt Lake City, UT, USA, was used as the central repository for case validation, public reporting, and system-wide dissemination of expertise, which included a proposed diagnosis and treatment guideline for lung injury associated with e-cigarettes or vaping. We extracted data on patient presentation, treatment, and short-term follow-up (2 weeks after discharge) from chart review and interviews with patients undertaken by the Utah Department of Health (Salt Lake City, UT, USA). FINDINGS: 60 patients presented with lung injury associated with e-cigarettes or vaping at 13 hospitals or outpatient clinics in the integrated health system. 33 (55%) of 60 were admitted to an intensive care unit (ICU). 53 (88%) of 60 patients presented with constitutional symptoms, 59 (98%) with respiratory symptoms, and 54 (90%) with gastrointestinal symptoms. 54 (90%) of 60 were given antibiotics and 57 (95%) were given steroids. Six (10%) of 60 patients were readmitted to an ICU or hospital within 2 weeks, three (50%) of whom had relapsed with vaping or e-cigarette use. Of 26 patients who were followed up within 2 weeks, despite clinical and radiographic improvement in all, many had residual abnormalities on chest radiographs (ten [67%] of 15) and pulmonary function tests (six [67%] of nine). Two patients died and lung injury associated with e-cigarettes or vaping was thought to be a contributing factor, but not the cause of death, for both. INTERPRETATION: Lung injury associated with e-cigarettes or vaping is an emerging illness associated with severe lung injury and constitutional and gastrointestinal symptoms. Increased awareness has led to identification of a broad spectrum of severity of illness in patients who were treated with antibiotics and steroids. Despite improvement, at short-term follow-up many patients had residual abnormalities. Lung injury associated with e-cigarettes or vaping remains a clinical diagnosis with symptoms that overlap infectious and other lung diseases. Maintaining a high index of suspicion for this disease is important as work continues in understanding the cause or causes, optimal therapy, and long-term outcomes of these patients. FUNDING: Intermountain Healthcare.


Assuntos
Lesão Pulmonar Aguda/etiologia , Vaping/efeitos adversos , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/epidemiologia , Lesão Pulmonar Aguda/terapia , Adulto , Antibacterianos/uso terapêutico , Broncoscopia , Canabidiol/administração & dosagem , Estudos de Coortes , Surtos de Doenças , Dronabinol/administração & dosagem , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Glucocorticoides/uso terapêutico , Humanos , Tempo de Internação , Masculino , Nicotina/administração & dosagem , Ventilação não Invasiva , Oxigenoterapia , Estudos Prospectivos , Respiração Artificial , Tomografia Computadorizada por Raios X , Utah/epidemiologia , Adulto Jovem
3.
J Biol Regul Homeost Agents ; 33(4): 1063-1072, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31353880

RESUMO

Acute lung injury (ALI) is a disease with high incidence and no effective therapeutic treatments. miR- 145-5p has been reported to be aberrantly expressed in lung injury tissues, suggesting a potential role in the progression and development of ALI. To validate this hypothesis and explore the underlying mechanism, a mouse model of ALI was established using lipopolysaccharide (LPS). Hematoxylin and eosin (Hand E) staining verified the successful establishment of mouse model with ALI. Levels of interleukin (IL)-1ß, IL- 6, tumor necrosis factor α (TNF-α) and myeloperoxidase (MPO) were detected by both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Mouse type II alveolar epithelial cells (AT II) were isolated and treated with LPS. miR-145-5p was significantly down-regulated both in mice with acute lung injury and LPS-induced AT II cells. Dual luciferase assays confirmed miR-145-5p could target and regulate Toll Like Receptor 4 (TLR4). Further analysis showed that miR-145-5p overexpression decreased the expression levels of IL-1ß, IL-6 and TNF-α in LPS-induced AT II cells. miR-145-5p overexpression also blocked the LPS-induced activation of nuclear factor kappa B (NF-κB) pathway and reactive oxygen species (ROS) accumulation in AT II cells. Finally, in ALI mouse model, miR-145-5p overexpression alleviated lung tissue injury, decreased the expression levels of IL-1ß, IL-6 and TNF-α and reduced MPO activity. In conclusion, miR-145-5p participated in the progression and development of ALI by decreasing the production of pro-inflammatory cytokines, inhibiting NF-κB pathway and suppressing ROS accumulation, shedding light on miR-145-5p as a potential therapeutic target for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/terapia , MicroRNAs/genética , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , NF-kappa B/metabolismo , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Lipids Health Dis ; 18(1): 136, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174540

RESUMO

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are shown to attenuate lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in animal models. However, the molecular mechanism is largely unknown. MATERIALS AND METHODS: The animal model of ALI was induced by intratracheal instillation of purified LPS with 2.5 mg/ml/kg. The expression of microRNAs and ADAM15 in lung tissues and LPS-induced mouse pulmonary microvascular endothelial cells (MPMVECs) was determined by quantitative real-time PCR and western blot analysis. The target relationship between miR-10a/b-5p and ADAM15 was confirmed by luciferase reporter assay and RNA interference. The effect of EPCs on MPMVEC proliferation was detected by MTT assay. RESULTS: EPCs increased the expression of miR-10a/b-5p and reduced ADAM15 protein level in LPS-induced ALI lung tissues and MPMVECs (p < 0.05), and promoted LPS-induced MPMVEC proliferation (p < 0.05). ADAM15 was confirmed to be a downstream target of miR-10a/b-5p. Additionally, EPCs promoted LPS-induced MPMVEC proliferation and exerted the therapeutic effect of ALI via regulating miR-10a/b-5p/ADAM15 axis. CONCLUSION: EPC transplantation exerted its therapeutic effect of ALI via increasing miR-10a/b-5p and reducing ADAM15, thus providing a novel insight into the molecular mechanism of EPC transplantation in treating ALI.


Assuntos
Proteínas ADAM/genética , Lesão Pulmonar Aguda/terapia , Células Progenitoras Endoteliais/transplante , Proteínas de Membrana/genética , MicroRNAs/genética , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Pulmão/patologia , Camundongos
5.
Inhal Toxicol ; 31(2): 52-60, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31068039

RESUMO

Objective: We have previously found that mesenchymal stem cell (MSC) therapy can ameliorate phosgene-induced acute lung injury (ALI). Moreover, exosomes can be used as a cell-free alternative therapy. In the present study, we aimed to assess the effect of MSC-derived exosomes on phosgene-induced ALI. Methods: MSC-derived exosomes were isolated from MSCs through ultracentrifugation. Sprague-Dawley (SD) rats were exposed to phosgene at 8.33 g/m3 for 5 min. MSC-derived exosomes were intratracheally administered and rats were sacrificed at the time points of 6, 24 and 48 h. Results: Compared with the phosgene group, MSC-derived exosomes reversed respiratory function alterations, showing increased levels of TV, PIF, PEF and EF50 as well as decreased levels of RI and EEP. Furthermore, MSC-derived exosomes improved pathological alterations and reduced wet-to-dry ratio and total protein content in BALF. MSC-derived exosomes reduced the levels of TNF-α, IL-1ß and IL-6 and increased the IL-10 level in BALF and plasma. MSC-derived exosomes suppressed the MMP-9 level and increased the SP-C level. Conclusions: MSC-derived exosomes exerted beneficial effects on phosgene-induced ALI via modulating inflammation, inhibiting MMP-9 synthesis and elevating SP-C level.


Assuntos
Lesão Pulmonar Aguda/terapia , Substâncias para a Guerra Química/toxicidade , Exossomos/transplante , Pulmão/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Fosgênio/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Peptídeos/genética , Ratos Sprague-Dawley , Testes de Função Respiratória , Regulação para Cima
6.
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
7.
Regen Med ; 14(3): 165-177, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30994416

RESUMO

Aim: To determine the efficiency of mesenchymal stem cells (MSCs) of different sources on airway epithelial cells regeneration and track where and to what extent transplanted MSCs home to injured tissues. Materials & methods: We performed DiO-labeled human bone marrow-derived MSCs (hBMSCs) or human chorionic villi-derived MSCs transplantation studies using naphthalene-induced airway injury animal models. Results: Compared with human chorionic villi-derived MSCs, hBMSCs facilitated airway epithelium regeneration faster and better from day 5 after transplantation; moreover, more transplanted hBMSCs distributed in injured lung tissues at the early stage of postinjury, which was mediated by C-X-C motif chemokine ligand 12. Conclusion: hBMSCs possessed better potential of migration to the damaged lung and promoting the repair of the injured airway epithelium.


Assuntos
Lesão Pulmonar Aguda/terapia , Medula Óssea/crescimento & desenvolvimento , Terapia Baseada em Transplante de Células e Tecidos/métodos , Vilosidades Coriônicas/crescimento & desenvolvimento , Modelos Animais de Doenças , Células-Tronco Mesenquimais/citologia , Animais , Células Cultivadas , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL
8.
Med Sci Monit ; 25: 2623-2632, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967525

RESUMO

BACKGROUND Mesenchymal stem cells (MSCs) show anti-oxidative and anti-inflammatory effects that have prompted further research into their potential applications in treating paraquat (PQ) poisoning cases in emergency rooms. We assessed the protective effects, underlying mechanisms, and secondary inflammatory responses of MSCs on PQ-induced acute lung injury. MATERIAL AND METHODS Sprague-Dawley rats were injected intraperitoneally with PQ (20 µg per gram of body weight). MSCs were injected through the caudal vein 1 h after PQ treatment. The severity of lung injury and oxidative stress and levels of inflammatory mediators were examined with and without MSC grafting. Expression levels of TLR4, NF-kappaB, p65, Nrf2, HO-1, and activated caspase-3 protein were determined by Western blotting. RESULTS Administration of MSCs significantly decreased the levels of TNF-alpha, IL-1ß, and IL-6 and polymorphonuclear neutrophil (PMN) count in the bronchoalveolar lavage fluid (BALF) of rats with PQ-induced ALI. In addition, MSC also effectively reduced the wet-to-dry lung weight ratio, lung injury score, and the levels of MDA and 8-OHdG. Conversely, MSC increased SOD and GSH-PX activity in the lung tissue. Moreover, MSC significantly upregulated HO-1, Nrf-2 protein expression in the lung tissue. In contrast, the levels of TLR4, NF-kappaB p65 and activated caspase-3 protein were decreased in MSC-treated rats (P<0.05). CONCLUSIONS Treatment with MSCs overexpressed Nrf2 gene and activated downstream antioxidant HO-1, leading to inhibit oxidative stress, cell apoptosis and inflammatory response in lung tissue, thereby significantly improving PQ-induced acute lung injury in rats.


Assuntos
Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Paraquat/envenenamento , Pneumonia/complicações , Pneumonia/terapia , Animais , Apoptose , Separação Celular , Edema/complicações , Edema/patologia , Proteínas de Fluorescência Verde/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Necrose , Estresse Oxidativo , Ratos Sprague-Dawley
9.
Cell Physiol Biochem ; 52(4): 935-950, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964610

RESUMO

BACKGROUND/AIMS: Although mesenchymal stem cells (MSCs) provide effective therapy for liver fibrosis, there are conflicting data regarding their marginal therapeutic effects. This study aimed to enhance the potential of hepatocyte regeneration in human adipose mesenchymal stem cells (ASCs) and investigate whether they have robust therapeutic efficacy in experimental liver fibrosis. METHODS: ASCs were cultured with four cytokines (ASC-C), the expression of hepatogenic factors was detected by microarray, and the effects of conditioned medium (CM) from ASC-C on the activation of hepatic stellate cells were analyzed. The therapeutic effects and mechanism of liver fibrosis induced by thioacetamide (TAA) were determined after cell transplantation. RESULTS: ASC-C exhibited high levels of hepatogenic (HGF, G-CSF), anti-apoptotic (IGFBP-2), and chemokine (IL-8) genes and increased expression of hepatocyte specific proteins. ASC-C CM inhibited the activation of hepatic stellate cells in vitro, and injection of ASC-C significantly delayed TAA-induced liver fibrosis and improved liver function and regeneration in vivo. In addition, human albumin-expressing ASC-C were observed in the livers of recipient animals. High levels of expression of HGF and its downstream signaling molecules, including p-38, were detected in the ASC-C-injected livers. Transplantation of ASC-C exerts anti-fibrotic effects and accelerates liver regeneration. CONCLUSION: Thus, ASC-C may be a novel candidate for the enhanced treatment of liver cirrhosis in clinical settings.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Adipócitos/metabolismo , Fator de Crescimento de Hepatócito/biossíntese , Sistema de Sinalização das MAP Quinases , Transplante de Células-Tronco , Células-Tronco/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Adipócitos/patologia , Animais , Linhagem Celular , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco/patologia
10.
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
11.
Int Immunopharmacol ; 71: 68-75, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877876

RESUMO

Acute lung injury (ALI), a persistent lung inflammatory response syndrome, may evolve into acute respiratory distress syndrome (ARDS). Characterized by rapid onset, critical features, and a complex etiology, ALI remains a challenging critical respiratory disease. Recently, mesenchymal stem cells (MSCs) have provided a new solution for the treatment of ALI. We built a lipopolysaccharide (LPS)-induced ALI model in mice. After treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs), FTY720, or a combination of hUC-MSCs and FTY207, the lung inflammatory response was apparently attenuated. To understand the mechanism underlying MSCs treatment of ALI at the genetic level, significant differentially expressed long non-coding RNAs (lncRNAs) between the treatment and model groups were analyzed using microarray technology. Moreover, genetic gene prediction, gene ontology (GO) analysis, pathway analysis, and transcription factor (TF) prediction were carried out. The results showed that a total of 66 lncRNAs were differentially expressed in all three treatment groups, including 8 up-regulated and 58 down-regulated lncRNAs. LncRNA A_30_P01029806 and A_30_P01029194, which were down-regulated, were involved in the signaling pathways closely related to ALI. Through further TF analysis, we identified several significant TFs which lay a foundation for revealing the mechanism underlying lncRNAs treatment of ALI. LncRNA A_30_P01029806 and A_30_P01029194 may serve as candidate biomarkers in the diagnosis and treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/terapia , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Pulmão/fisiologia , Células-Tronco Mesenquimais/fisiologia , Pneumonia/terapia , RNA Longo não Codificante/genética , Animais , Terapia Combinada , Modelos Animais de Doenças , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Lipopolissacarídeos/imunologia , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Transdução de Sinais/genética , Cordão Umbilical/patologia
12.
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
13.
PLoS One ; 14(1): e0210172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653512

RESUMO

Experimental acute lung injury models are often used to increase our knowledge on the acute respiratory distress syndrome (ARDS), however, existing animal models often do not take into account the impact of specific fluid strategies on the development of lung injury. In contrast, the current literature strongly suggests that fluid management strategies have a significant impact on clinical outcome of patients with ARDS. Thus, it is important to characterize the role of fluid management strategies in experimental models of lung injury. In this study we investigated the effect of two different fluid strategies on commonly used outcome variables in a short-term model of acute lung injury, in relation to age. Infant (2-3 weeks) and adult (3-4 months) Wistar rats received intratracheal instillations of lipopolysaccharide and 24 hours later were mechanically ventilated for 6 hours. During mechanical ventilation, rats from both age groups were randomized to either a standard or conservative intravenous fluid strategy. We found that the hemodynamic response in infant and adult rats was similar in both fluid strategies. Lung wet-to-dry ratios were lower in adult, but not in infant rats receiving the conservative fluid strategy as compared to the standard fluid strategy. There were age-related differences in markers of alveolar capillary barrier disruption and alveolar fluid clearance, yet these were unaffected by fluid strategy. Finally, we found significantly higher IL-1ß and TNF-α concentrations in the adult rats treated with the conservative as compared to the standard fluid regimen. In conclusion, the choice of fluid strategy in mechanically ventilated rats with experimental LPS-induced acute lung injury has a significant effect on pulmonary extravascular water, an important and well-recognized lung injury marker, and on the local pro-inflammatory cytokine profiles. We advocate the use of a more uniform, conservative, fluid strategy regimen in experimental models of acute lung injury.


Assuntos
Lesão Pulmonar Aguda/terapia , Tratamento Conservador/métodos , Hidratação/métodos , Edema Pulmonar/terapia , Respiração Artificial , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Água Extravascular Pulmonar/metabolismo , Feminino , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Pulmão/patologia , Masculino , Edema Pulmonar/etiologia , Edema Pulmonar/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Organismos Livres de Patógenos Específicos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
14.
Clin Toxicol (Phila) ; 57(2): 77-98, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30672349

RESUMO

INTRODUCTION: Chlorine exposure can lead to pulmonary obstruction, reactive airway dysfunction syndrome, acute respiratory distress syndrome and, rarely, death. OBJECTIVE: We performed a systematic review of published animal and human data regarding the management of chlorine exposure. METHODS: Three databases were searched from 2007 to 2017 using the following keywords "("chlorine gas" OR "chlorine-induced" OR" chlorine-exposed") AND ("therapy" OR "treatment" OR "post-exposure")". Forty-five relevant papers were found: 22 animal studies, 6 reviews, 19 case reports and 1 human randomized controlled study. General management: Once the casualty has been removed from the source of exposure and adequately decontaminated, chlorine-exposed patients should receive supportive care. Humidified oxygen: If dyspnea and hypoxemia are present, humidified oxygen should be administered. Inhaled bronchodilators: The use of nebulized or inhaled bronchodilators to counteract bronchoconstriction is standard therapy, and the combination of ipratropium bromide with beta2-agonists effectively reversed bronchoconstriction, airway irritation and increased airway resistance in experimental studies. Inhaled sodium bicarbonate: In a randomized controlled trial, humidified oxygen, intravenous prednisolone and inhaled salbutamol were compared with nebulized sodium bicarbonate. The only additional benefit of sodium bicarbonate was to increase the forced expiratory volume in one second, 2 and 4 h after administration. Corticosteroids: Dexamethasone 100 mg/kg intraperitoneally (IP) reduced lung edema when given within 1 h of chlorine inhalation and when administered within 6 h significantly decreased (p < 0.01) the leukocyte count in the bronchoalveolar lavage (BAL). As corticosteroids were never given alone in clinical studies, it is impossible to assess whether they had an additional beneficial effect. Antioxidants: An ascorbic acid/deferoxamine combination (equivalent to 100 mg/kg and 15 mg/kg, respectively) was administered intramuscularly 1 h after chlorine exposure, then every 12 h up to 60 h, then as an aerosol, and produced a significant reduction (p < 0.05) in BAL leukocytes and a significant reduction (p < 0.007) in mortality at 72 h. The single clinical case reported was uninterpretable. Sodium nitrite: Sodium nitrite 10 mg/kg intramuscularly (IM), 30 min post-chlorine exposure in mice and rabbits significantly reduced (p < 0.01) the number of leukocytes and the protein concentration in BAL and completely reversed mortality in rabbits and decreased mortality by about 50% in mice. No clinical studies have reported the use of sodium nitrite. Dimethylthiourea: Dimethylthiourea 100 mg/kg IP significantly decreased (p < 0.05) lymphocytes and neutrophils in BAL fluid 24 h after chlorine exposure in experimental studies. No clinical studies have been undertaken. AEOL 10150: Administration of AEOL10150 5 mg/kg IP at 1 h and 9 h post-chlorine exposure reduced significantly the neutrophil (p < 0.001) and macrophage (p < 0.05) bronchoalveolar cell counts. Transient receptor potential vanilloid 4 (TRPV4): IM or IP TRPV4 reduced significantly (p < 0.001) bronchoalveolar neutrophil and macrophage counts to baseline at 24 h. No clinical studies have been performed. Reparixin and triptolide: In experimental studies, triptolide 100-1000 µg/kg IP 1 h post-exposure caused a significant decrease (p < 0.001) in bronchoalveolar neutrophils, whereas reparixin 15 mg/kg IP 1 h post-exposure produced no benefit. Rolipram: Nanoemulsion formulated rolipram administered intramuscularly returned airway resistance to baseline. Rolipram (40%)/poly(lactic-co-glycolic acid) (60%) 0.36 mg/mouse given intramuscularly 1 h post-exposure significantly reduced (p < 0.05) extravascular lung water by 20% at t + 6 h. Prophylactic antibiotics: Studies in patients have failed to demonstrate benefit. Sevoflurane: Sevoflurane has been used in one intubated patient in addition to beta2-agonists. Although the peak inspiratory pressure was decreased after 60 min, the role of sevofluorine is not known. CONCLUSIONS: Various therapies seem promising based on animal studies or case reports. However, these recommendations are based on low-level quality data. A systematic list of outcomes to monitor and improve may help to design optimal therapeutic protocols to manage chlorine-exposed patients.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Cloro/toxicidade , Exposição por Inalação/efeitos adversos , Lesão Pulmonar Aguda/terapia , Animais , Serviços Médicos de Emergência/métodos , Humanos
15.
Curr Opin Pulm Med ; 25(2): 211-216, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30608256

RESUMO

PURPOSE OF REVIEW: Acute toxic inhalation exposures affect thousands of individuals worldwide each year. The acute evaluation of these inhaled exposures is often fraught with difficulty in identifying a specific agent, may involve multiple compounds, and a wide variety of responses are seen depending on the physical properties of the specific toxicant, the length of time of inhalation, and the concentration of the exposure. Recognizing key aspects of the most common acute toxic inhalations is useful in developing a diagnosis and treatment strategy. RECENT FINDINGS: Use of sequential observations with flexible bronchoscopy has been the standard of care for assessing airway injury, and virtual bronchoscopy using computed tomographic images in a three-dimensional reconstructed image can now better identify airway narrowing. Use of [F]-fluorodeoxyglucose uptake, as measured by PET, has the potential for early recognition of delayed acute lung injury in toxic inhalation exposures. Development of a standardized respiratory injury grading system is ongoing with a recent multicenter trial nearly complete, allowing for more accurate estimates of eventual outcomes and guide levels of intensity of care for patients with acute inhalation injury. Removal from the source of exposure and airway support remain the first critical aspect of treatment, and additional therapies have been studied recently that focus on altering molecular mechanisms of acute cellular injury, expanding potential treatments beyond other pharmacotherapeutic strategies utilized previously such as mucolytics, bronchodilators, and inhaled anticoagulants. SUMMARY: Although a prevalent source of airway injury, exposure to acute toxic inhalants is often difficult to assess and prognosticate, and challenging to treat.


Assuntos
Lesão Pulmonar Aguda , Poluentes Atmosféricos/toxicidade , Broncoscopia/métodos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/terapia , Manuseio das Vias Aéreas/métodos , Humanos , Exposição por Inalação , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências
16.
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
17.
Inflammation ; 42(1): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30187337

RESUMO

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.


Assuntos
Lesão Pulmonar Aguda/terapia , Pulmão/patologia , Células-Tronco Mesenquimais/fisiologia , Linfócitos T Reguladores/citologia , Células Th17/citologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Contagem de Células , Movimento Celular , Lipopolissacarídeos/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos
18.
Burns ; 45(2): 317-321, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30429074

RESUMO

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a complication that affects approximately 40% of burn patients and is associated with high mortality rates. Extracorporeal membrane oxygenation (ECMO) therapy is a management option for severe refractory hypoxemic respiratory failure; however, there is little literature reporting the effectiveness of this therapy in burns. Our study objective was to review patient outcomes in burns following severe ARDS treated with ECMO. METHODS: We retrospectively reviewed all patients treated with ECMO for ARDS who received their burn care at a single regional burn center between 9/1/2006 and 8/31/2016. Primary patient outcome examined was discharge disposition. RESULTS: We identified 8 patients who had ARDS secondary to burn who were placed onto ECMO during this 10-year period. The average APACHE score, SOFA score, and P/F ratio were 21±3, 9±2, and 59±8, respectively, at the time of decision for ECMO. No ECMO-related complications were identified. Out of the 8 patients reviewed, 1 died, 4 were discharged to acute rehabilitation or a long-term acute care facility, and 3 were discharged to home. CONCLUSION: Mortality in burn patients with ARDS who are managed with ECMO is extremely low. Careful selection and timely intervention with ECMO contributed to good clinical outcomes.


Assuntos
Lesão Pulmonar Aguda/terapia , Queimaduras/terapia , Oxigenação por Membrana Extracorpórea/métodos , Síndrome do Desconforto Respiratório do Adulto/terapia , APACHE , Lesão Pulmonar Aguda/etiologia , Adolescente , Queimaduras/complicações , Queimaduras por Inalação/complicações , Queimaduras por Inalação/terapia , Criança , Pré-Escolar , Intervenção Médica Precoce , Feminino , Humanos , Lactente , Masculino , Escores de Disfunção Orgânica , Seleção de Pacientes , Síndrome do Desconforto Respiratório do Adulto/etiologia , Estudos Retrospectivos , Terapia de Salvação , Índice de Gravidade de Doença , Taxa de Sobrevida , Adulto Jovem
19.
Pharmacol Res ; 139: 560-568, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30394320

RESUMO

BACKGROUND AND PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar damage and generally irreversible airflow limitation. Nuclear factor-κB (NF-κB) plays a critical role in COPD pathogenesis. Receptor-interacting protein 2 (Rip2), a 60 kDa adaptor protein, is a positive regulator of NF-κB pathway and also an inducible transcriptional product of NF-κB activation. We sought to investigate if Rip2 gene silencing could protect against cigarette smoke (CS)-induced acute lung injury. EXPERIMENTAL APPROACH: Gene silencing efficacy of Rip2 siRNA was characterized in mouse macrophage and mouse lung epithelial cell lines, and in a CS-induced acute lung injury mouse model. Bronchoalveolar lavage (BAL) fluid cell counts, levels of pro-inflammatory and oxidative damage markers, lung section inflammatory and epithelium thickness scorings, and nuclear NF-κB translocation were measured. KEY RESULTS: CS was found to upregulate Rip2 level in mouse lungs. Rip2 siRNA was able to suppress Rip2 levels in both macrophage and lung epithelial cell lines and in mouse lungs, block CS extract (CSE)-induced mediator release by the cultured cells, and abate neutrophil counts in BAL fluid from CS-challenged mice. Rip2 siRNA suppressed CS-induced inflammatory and oxidative damage markers, and nuclear p65 accumulation and transcriptional activation in lung tissues. Besides, Rip2 siRNA was able to disrupt CSE-induced NF-κB activation in a NF-κB reporter gene assay. CONCLUSIONS AND IMPLICATIONS: Taken together, we report for the first time that Rip2 gene silencing ameliorated CS-induced acute lung injury probably via disruption of the NF-κB activity, postulating that Rip2 may be a novel therapeutic target for COPD.


Assuntos
Lesão Pulmonar Aguda/terapia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Feminino , Inativação Gênica , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Doença Pulmonar Obstrutiva Crônica , RNA Interferente Pequeno
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