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1.
Life Sci ; 273: 119286, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662429

RESUMO

AIMS: Hepatic ischemia/reperfusion (I/R) injury is a critical factor affecting the prognosis of liver surgery. The aim of this study is to explore the effects of SET8 on hepatic I/R injury and the putative mechanisms. MAIN METHODS: The expression of SET8 and MARK4 in I/R group and sham group were detected both in vivo and in vitro. In addition, mouse and RAW 264.7 cells were transfected with MARK4 siRNA and SET8 siRNA knockdown of MARK4 and SET8, respectively. The expression of SET8, MARK4 and NLRP3-associated proteins were detected after different treatments. The pathology of liver and the serologic detection were detected after different treatments. KEY FINDINGS: Our present study identified SET domain-containing protein 8 (SET8) as an efficient protein, which can negatively regulate hepatic I/R-mediated inflammatory response and ameliorate hepatic I/R injury by suppressing microtubule affinity-regulating kinase 4 (MARK4)/ NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway. The data showed that MARK4 deficiency inhibited hypoxia/reoxygenation (H/R)-induced NLRP3 inflammasome activation, while SET8 deficiency showed the opposite effect. We further demonstrated that SET8 restrained NLRP3 inflammasome activation by inhibiting MARK4. Moreover, we verified SET8 made protective effect on hepatic I/R injury. SIGNIFICANCE: SET8 plays an essential role in hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway. Our results may offer a new strategy to mitigate hepatic I/R injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Histona-Lisina N-Metiltransferase/metabolismo , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Histona-Lisina N-Metiltransferase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
2.
Life Sci ; 271: 119192, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577850

RESUMO

AIMS: GYY4137 [GYY, morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a novel and perfect hydrogen sulfide (H2S) donor that is stable in vivo and in vitro. H2S, along with CO and NO, has been recognized as the third physiological gas signaling molecule that plays an active role in fighting various lung infections. However, the mechanism by which GYY4137 affects cecal ligation and puncture (CLP)-induced acute lung injury (ALI) is not understood. This study aimed to investigate whether GYY4137 inhibits the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome by inhibiting the PDGFRß/Akt/NF-κB pathway. MAIN METHODS: The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 µg/g and 50 µg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs). KEY FINDINGS: GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRß, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB. SIGNIFICANCE: These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Morfolinas/uso terapêutico , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos Organotiofosforados/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organotiofosforados/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sepse/complicações , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
4.
Immunopharmacol Immunotoxicol ; 43(1): 37-50, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33406943

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has infected millions of individuals and has claimed hundreds of thousands of human lives worldwide. Patients with underlying cardiovascular conditions are at high risk for SARS-CoV-2 infection, and COVID-19 patients have high incidence of cardiovascular complications such as acute cardiac injury, arrhythmias, heart failure, and thromboembolism. The disease has no approved proven effective therapy and hence repurposing of existing approved drugs has been considered as the fastest treatment approach. Statins have been shown to exhibit lipid lowering dependent and independent cardiovascular protective effects as well as favorable effects in various other pathophysiological states. These beneficial properties of statins are a result of their multiple pleotropic effects that include, anti-inflammatory, immunomodulatory, antithrombotic and antimicrobial properties. In this review, we provide a comprehensive description of the mechanisms of the pleotropic effects of statins, the relevant pre-clinical and clinical data pertinent to their role in infections and acute lung injury, the possible cardiovascular benefits of statins in COVID-19, and the implications of the therapeutic potential of statins in COVID-19 disease. We conclude with the rationale for conducting randomized controlled trials of statins in COVID-19 disease.


Assuntos
/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/etiologia
5.
J Appl Physiol (1985) ; 130(3): 877-891, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444117

RESUMO

The worldwide pandemic caused by the SARS-CoV-2 virus has resulted in over 84,407,000 cases, with over 1,800,000 deaths when this paper was submitted, with comorbidities such as gender, race, age, body mass, diabetes, and hypertension greatly exacerbating mortality. This review will analyze the rapidly increasing knowledge of COVID-19-induced lung pathophysiology. Although controversial, the acute respiratory distress syndrome (ARDS) associated with COVID-19 (CARDS) seems to present as two distinct phenotypes: type L and type H. The "L" refers to low elastance, ventilation/perfusion ratio, lung weight, and recruitability, and the "H" refers to high pulmonary elastance, shunt, edema, and recruitability. However, the LUNG-SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) and ESICM (European Society of Intensive Care Medicine) Trials Groups have shown that ∼13% of the mechanically ventilated non-COVID-19 ARDS patients have the type-L phenotype. Other studies have shown that CARDS and ARDS respiratory mechanics overlap and that standard ventilation strategies apply to these patients. The mechanisms causing alterations in pulmonary perfusion could be caused by some combination of 1) renin-angiotensin system dysregulation, 2) thrombosis caused by loss of endothelial barrier, 3) endothelial dysfunction causing loss of hypoxic pulmonary vasoconstriction perfusion control, and 4) hyperperfusion of collapsed lung tissue that has been directly measured and supported by a computational model. A flowchart has been constructed highlighting the need for personalized and adaptive ventilation strategies, such as the time-controlled adaptive ventilation method, to set and adjust the airway pressure release ventilation mode, which recently was shown to be effective at improving oxygenation and reducing inspiratory fraction of oxygen, vasopressors, and sedation in patients with COVID-19.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , /patologia , Lesão Pulmonar Aguda/virologia , Animais , Pressão Positiva Contínua nas Vias Aéreas/métodos , Humanos , Hipóxia/patologia , Hipóxia/virologia , Pulmão/patologia , Pulmão/virologia , /virologia , Vasoconstrição/fisiologia
6.
BMC Infect Dis ; 20(1): 823, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176722

RESUMO

BACKGROUND: The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model. METHODS: MSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1ß, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured. RESULTS: The administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1ß were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups. CONCLUSION: The administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/cirurgia , Virus da Influenza A Subtipo H5N1 , Transplante de Células-Tronco Mesenquimais , Infecções por Orthomyxoviridae/complicações , Pneumonia/etiologia , Pneumonia/cirurgia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Pneumonia/prevenção & controle , Pneumonia/virologia , Resultado do Tratamento
7.
J Toxicol Sci ; 45(10): 625-637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012731

RESUMO

NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P < 0.05), but not ASC (P > 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1ß, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P < 0.05), but not of anti-inflammatory IL-4 and IL-10 (all P > 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Inativação Gênica , Terapia Genética/métodos , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosgênio/envenenamento , RNA Interferente Pequeno/administração & dosagem , Lesão Pulmonar Aguda/diagnóstico , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Masculino , Ratos Sprague-Dawley
8.
J Card Surg ; 35(10): 2469-2476, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32789962

RESUMO

BACKGROUND: Pulmonary artery perfusion during cardiopulmonary bypass (CPB) is a known but rarely used technique in adult cardiac surgery. In this study, we aimed to investigate biochemical and histopathological effects of pulmonary artery perfusion during CPB on lung functions. METHODS: Between May 2014 and August 2014, all patients (n = 24) who gave informed consent for participating this study with inclusion criteria were included. Patients undergoing isolated coronary artery bypass grafting were sequentially randomized to conventional CPB (control group, n = 12) and conventional CPB with selective pulmonary artery perfusion (study group, n = 12). Lung functions were monitored using PF ratio, alveolar-arterial oxygen gradient, and lactate levels. A small sample tissue from the left lung was excised for histopathologic examination. Immunocytochemistry analysis was performed using anti-rabbit polyclonal vascular endothelial growth factor (VEGF), rabbit polyclonal inducible nitric oxide synthase (i-NOS), and BCL-2 antibodies. RESULTS: Postoperative course of the patients were uneventful without any clinical outcome differences in terms of cardiopulmonary complications, ventilation time and hospital stay. Pulmonary perfusion group had significantly better oxygenation values after extubation and at postoperative 24-hour. Electron microscopy examinations revealed better preservation of the alveolar wall integrity with pulmonary perfusion. The intensity of VEGF, i-NOS, and BCL-2 antibody expressions in bronchial epithelial cells were more prominent in the pulmonary perfusion group. CONCLUSIONS: Pulmonary artery perfusion during aortic cross-clamping provides better oxygenation and preservation of the wall alveolar integrity after coronary artery bypass grafting surgery. This technique can be used as a protective strategy to minimize CPB-induced lung injury in adult cardiac surgery.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Ponte Cardiopulmonar/efeitos adversos , Perfusão/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Artéria Pulmonar , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/patologia , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/sangue , Contagem de Células Sanguíneas , Proteína C-Reativa , Ponte de Artéria Coronária/métodos , Feminino , Hemoglobinas , Humanos , Inflamação , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/análise , Recuperação de Função Fisiológica , Esternotomia , Fator A de Crescimento do Endotélio Vascular/análise
9.
Pancreatology ; 20(7): 1258-1261, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32859545

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) presents with myriad extra-pulmonary manifestation and a high mortality in patients with comorbidities. Its effect on patients with pre-existing acute pancreatitis is not known. METHODS: We hereby, present 3 cases with severe acute pancreatitis with persistent respiratory failure who acquired nosocomial COVID-19 during their hospital stay after recovery from respiratory failure. Their clinical course is highlighted which reflects on pathophysiology of organ dysfunction in these 2 disease states. RESULTS: None of the 3 patients with severe acute pancreatitis who developed nosocomial COVID-19 redeveloped respiratory failure due to COVID-19 despite having recently recovered from pancreatitis induced acute hypoxemic respiratory failure. Only one patient developed SARS-CoV2 induced moderate pneumonia. CONCLUSION: These cases highlight that host responses and mechanisms of lung injury might be different in severe acute pancreatitis and COVID-19.


Assuntos
Lesão Pulmonar Aguda/etiologia , Infecções por Coronavirus/complicações , Infecção Hospitalar/complicações , Pancreatite/complicações , Pneumonia Viral/complicações , Lesão Pulmonar Aguda/patologia , Adulto , Infecções por Coronavirus/patologia , Infecção Hospitalar/patologia , Feminino , Humanos , Masculino , Pancreatite/etiologia , Pancreatite/patologia , Pandemias , Pneumonia Viral/patologia , Cobertura de Condição Pré-Existente , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Resultado do Tratamento
10.
Life Sci ; 260: 118309, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841664

RESUMO

AIMS: Oral cavity pathogens play an important systemic role, modulating the development of several diseases. Periodontitis is a very common oral disease associated with dental biofilm. It is characterized by gum inflammation, periodontal ligament degeneration, dental cementum and alveolar bone loss. Studies point to the association between maternal periodontitis and adverse outcomes during pregnancy. However, they did not evaluate the impact of maternal periodontitis in the offspring. Thus, our objective was to investigate the effects of maternal periodontitis in the immune system of offspring. MATERIAL AND METHODS: For this evaluation we induced acute lung injury in rat pups. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after the birth, offspring was submitted to acute lung inflammation by administration of lipopolysaccharide (LPS, Salmonella abortus equi, 5 mg/kg, ip). KEY FINDINGS: Our results showed that maternal periodontitis increased myeloperoxidase activity, the levels of TNF-alpha and IL-17A in the bronchoalveolar fluid, the gene expression of TNF-alpha, IL-17A, and cyclooxygenases 1 and 2. In addition, maternal periodontitis did not alter the number of leukocytes migrated into the lung, tracheal responsiveness, expression of TLR4 and NF-KB translocation. SIGNIFICANCE: This study showed prenatal programming of the immune response induced by maternal periodontitis, and reinforces the importance of oral health care during pregnancy.


Assuntos
Lesão Pulmonar Aguda/imunologia , Reprogramação Celular , Periodontite/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Animais Recém-Nascidos , Feminino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , NF-kappa B/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
11.
Gene ; 759: 144969, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32712064

RESUMO

Sepsis-induced acute lung injury (ALI) remains one of the most common disorders in hospitals. The aim of this research was to explore the underlying characteristics and mechanisms of artesunate (AS) in protecting rat lungs from sepsis. The sepsis-induced ALI model was generated in SD rats by the intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg) for 24 h. The rats were randomly assigned into 4 groups: Sham, LPS, LPS + AS, and LPS + AS + LY294002. Pathological evaluation of the lungs was conducted by HE staining, immunofluorescence, and TUNEL assay, and the MPO activity and the W/D ratio of each group were evaluated. The levels of inflammatory mediators (TNF-α and IL-6) were measured by immunoblotting, immunofluorescence and real-time PCR. Western blotting was used to determine the protein levels of PI3K, cleaved Caspase-3, p-mTOR, mTOR, p-Akt, and Akt in the lungs. The MPO activity, W/D ratio and lung injury score were obviously elevated after induction of ALI by LPS. Nevertheless, these alterations could be inhibited by AS. In addition, sepsis decreased the levels of p-mTOR, p-Akt, and PI3K and elevated the expression of cl-caspase-3, TNF-α, and IL-6 in the lungs. After AS administration, these alterations were obviously decreased, but treatment with the PI3K antagonist LY294002 inhibited the function of AS. AS could partially protect against LPS-induced ALI by inhibiting apoptosis and inflammatory mediator production, and this function is perhaps associated with the regulation of the mTOR/AKT/PI3K axis. These findings suggest that AS may possess certain beneficial characteristics in protecting the lungs from sepsis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Artesunato/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/complicações , Serina-Treonina Quinases TOR/metabolismo , Lesão Pulmonar Aguda/etiologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Artesunato/farmacologia , Interleucina-6/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
15.
Emerg Med Pract ; 22(7): 1-20, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559026

RESUMO

There are a variety of ventilator options available to the emergency clinician, and decisions on choosing optimal settings will depend on the clinical circumstances. Understanding the latest literature in ventilator management can improve patient outcomes by ensuring optimal oxygenation and ventilation and reducing the potential for ventilator-induced lung injury. This article reviews the most appropriate ventilator settings for a variety of conditions in intubated adult patients presenting to the emergency department, and gives recommendations on monitoring the ventilated patient and making ventilator adjustments. An update on managing COVID-19-associated acute respiratory distress syndrome is also included.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Infecções por Coronavirus/terapia , Serviço Hospitalar de Emergência/organização & administração , Monitorização Fisiológica/métodos , Pneumonia Viral/terapia , Respiração Artificial/instrumentação , /terapia , Lesão Pulmonar Aguda/etiologia , Adulto , Infecções por Coronavirus/epidemiologia , Segurança de Equipamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Respiração Artificial/efeitos adversos , Medição de Risco , Resultado do Tratamento , Ventiladores Mecânicos
16.
Thorax ; 75(7): 556-567, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32546573

RESUMO

INTRODUCTION: Mesenchymal stromal cell (MSC) therapy mitigates lung injury and improves survival in murine models of sepsis. Precise mechanisms of therapeutic benefit remain poorly understood. OBJECTIVES: To identify host-derived regulatory elements that may contribute to the therapeutic effects of MSCs, we profiled the microRNAome (miRNAome) and transcriptome of lungs from mice randomised to experimental polymicrobial sepsis-induced lung injury treated with either placebo or MSCs. METHODS AND RESULTS: A total of 11 997 genes and 357 microRNAs (miRNAs) expressed in lungs were used to generate a statistical estimate of association between miRNAs and their putative mRNA targets; 1395 miRNA:mRNA significant association pairs were found to be differentially expressed (false discovery rate ≤0.05). MSC administration resulted in the downregulation of miR-27a-5p and upregulation of its putative target gene VAV3 (adjusted p=1.272E-161) in septic lungs. In human pulmonary microvascular endothelial cells, miR-27a-5p expression levels were increased while VAV3 was decreased following lipopolysaccharide (LPS) or tumour necrosis factor (TNF) stimulation. Transfection of miR-27a-5p mimic or inhibitor resulted in increased or decreased VAV3 message, respectively. Luciferase reporter assay demonstrated specific binding of miR-27a-5p to the 3'UTR of VAV3. miR27a-5p inhibition mitigated TNF-induced (1) delayed wound closure, increased (2) adhesion and (3) transendothelial migration but did not alter permeability. In vivo, cell infiltration was attenuated by intratracheal coinstillation of the miR-27a-5p inhibitor, but this did not protect against endotoxin-induced oedema formation. CONCLUSIONS: Our data support involvement of miR-27a-5p and VAV3 in cellular adhesion and infiltration during acute lung injury and a potential role for miR-27a-based therapeutics for acute respiratory distress syndrome.


Assuntos
Lesão Pulmonar Aguda/genética , Regulação da Expressão Gênica , Transplante de Células-Tronco Mesenquimais/métodos , MicroRNAs/genética , RNA Mensageiro/genética , Sepse/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/terapia , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , RNA Mensageiro/metabolismo , Transdução de Sinais
17.
Thorac Surg Clin ; 30(3): 279-291, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32593361

RESUMO

The intraoperative anesthetic management for thoracic surgery can impact a patient's postoperative course, especially in patients with significant lung disease. One-lung ventilation poses an inherent risk to patients, including hypoxemia, acute lung injury, and right ventricular dysfunction. Patient-specific ventilator management strategies during one-lung ventilation can reduce postoperative morbidity.


Assuntos
Anestesia/métodos , Ventilação Monopulmonar/métodos , Procedimentos Cirúrgicos Torácicos , Lesão Pulmonar Aguda/etiologia , Hidratação , Humanos , Hipóxia/etiologia , Ventilação Monopulmonar/efeitos adversos , Ventilação Monopulmonar/instrumentação , Manejo da Dor , Complicações Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Torácicos/efeitos adversos
18.
Life Sci ; 256: 117907, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504751

RESUMO

Acute lung injury (ALI) and the subsequent multi-system organ failure is a serious health problem with devastating impacts on the health care systems. Indeed, the world has been facing an un-preceded situation in the past couple of months following COVID-19 infestation and the associated high-mortality rates mainly attributed to sepsis and the associated multiple organ failures of particular concern; acute respiratory distress syndrome post lung injury. The current study provides evidence on the ameliorative impact of nifuroxazide, and FDA approved antidiarrheal drug in attenuation of lipopolysaccharide (LPS)-induced ALI and myocarditis when administrated either in prophylactic or curative regimens. Nifuroxazide administration was associated with a significant improvement in lung and heart histopathological characteristics and architecture with retraction of LPS-induced inflammatory-infiltration. This was associated with retraction in serum biomarkers of cellular injury of which; LDH, CK-MB, and ALP. Nifuroxazide administration was associated with a significant improvement in both lung and heart oxidative status. Such positive outcomes were underlined by a significant inhibitory effect of nifuroxazide on lung and heart contents of toll-like receptor (4) (TLR4)/the inflammasome NALPR3/interleukin- 1ß (IL-1ß). In conclusion: Nifuroxazide attenuates LPS-induced ALI and myocardial injury via interruption of TLR4/NALPR3/IL-1ß signaling. Thus it can offer a potential approach for attenuation of sepsis in critically ill patients.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Infecções por Coronavirus/complicações , Hidroxibenzoatos/farmacologia , Miocardite/prevenção & controle , Nitrofuranos/farmacologia , Pneumonia Viral/complicações , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Animais , Infecções por Coronavirus/epidemiologia , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Miocardite/etiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
19.
Med Hypotheses ; 143: 109906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32505910

RESUMO

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Retroalimentação Fisiológica , Humanos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pandemias , Pneumonia Viral/imunologia
20.
J Clin Pharmacol ; 60(7): 815-825, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32441805

RESUMO

Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID-19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome-coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra-alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add-on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti-inflammatory and anti-viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add-on therapy in ALI related to COVID-19 infection.


Assuntos
Lesão Pulmonar Aguda/etiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Escina/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Quimioterapia Combinada , Escina/administração & dosagem , Escina/farmacologia , Humanos , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Pandemias , Pneumonia Viral/fisiopatologia
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