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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 ; 275: 119391, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33774026

RESUMO

Sevoflurane (Sev) has protective effects in acute lung injury (ALI), but the relevant mechanisms are still not fully understood. The present study aimed to determine whether Sev exerts a protective effect on lipopolysaccharide (LPS)-induced ALI by regulating ferroptosis. In this study, we found that Sev could protect mice from lung injury caused by LPS stimulation, including extenuating lung histological damage, pulmonary edema and pulmonary vascular permeability, and the content of inflammatory factors in Bronchoalveolar lavage fluid (BALF), as well as improving the survival rate of ALI mice, which was in line with the effects of ferroptosis inhibitor ferrostatin-1. Simultaneously, Sev could eliminate the worsening effects of ferroptosis inducer Fe-citrate on LPS-induced ALI to a certain extent. Additionally, the administration of Sev could inhibit ferroptosis caused by LPS, which was manifested by reducing the accumulation of MDA and Fe2+, and increasing the levels of GSH and GPX4 in the lung tissues of ALI mice. It was also observed in BEAS-2B cells that the increased MDA and Fe2+ levels and the decreased GSH and GPX4 levels caused by LPS could be rescued by ferrostatin-1 and Sev. LPS stimulation compensatory up-regulated heme oxygenase-1 (HO-1) expression in mouse lung tissues and BEAS-2B cells, which could be enhanced by Sev. Moreover, HO-1 depletion could offset the inhibitory effect of Sev on LPS-induced ferroptosis and inflammation in BEAS-2B cells. Taken together, Sev inhibited ferroptosis by up-regulating HO-1 expression to reduce LPS-induced ALI, which may provide a possible mechanism for the application of Sev in clinical anesthesia.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Ferroptose/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Sevoflurano/farmacologia , Lesão Pulmonar Aguda/patologia , Animais , Western Blotting , Linhagem Celular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Sevoflurano/uso terapêutico
3.
Carbohydr Polym ; 255: 117392, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436221

RESUMO

Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) for the first time. Structure characterized using FT-IR, MALDI-TOF-MS, NMR, AFM, and TEM, indicated that PFOS was graminan-type fructan with a degree of polymerization ranging from 5 to 10. A murine model of lipopolysaccharide (LPS)-induced peritonitis was used to evaluate the in vivo anti-inflammatory and lung protective efficacy of PFOS. The result shown that pretreatment with PFOS (1.0 mg/mL) in peritonitis-induced mice could significantly inhibit the level of pro-inflammatory cytokines (TNF-α, IL-1ß) in serum (P < 0.001), increase mice survival rate from 12.5 % to 54 % (P < 0.05), and alleviated lung injury through ameliorating the damage of the pulmonary cellular architecture and reducing inflammatory monocyte accumulation in lung tissue. This effect of oligosaccharides could explain the traditional usage of P. cyrtonema as a tonic medicine for respiratory problems and it could be used as a potential natural ingredient with anti-inflammatory activity.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Pulmão/efeitos dos fármacos , Oligossacarídeos/farmacologia , Peritonite/tratamento farmacológico , Polygonatum/química , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/mortalidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Expressão Gênica , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/administração & dosagem , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Oligossacarídeos/química , Oligossacarídeos/isolamento & purificação , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/mortalidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Life Sci ; 267: 118941, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359748

RESUMO

AIMS: Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with complex pathology and pathogenesis. Since there is no specific treatment for ALI, it is important to study the mechanism of how ALI develop. Sestrin2 (Sesn2) plays a critical role in the regulation of cellular stress response and oxidant defense. However, the potential function of Sesn2 in ALI/ARDS and the associated mechanism remains unclear. MAIN METHODS: Lipopolysaccharide (LPS) induced ALI model was performed in the wild-type and Sesn2 knockout (Sesn2-/-) mice. The nod-like receptor protein 3 (NLRP3) inflammasome, cell pyroptosis and mitophagy were detected by western blots, immunofluorescent staining, flow cytometry. Lung injury were measured by histopathology and electron microscopy. KEY FINDINGS: Knockout of Sesn2 enhanced LPS-induced ALI. As detailed in Sesn2-/- mice, NLRP3 inflammasome and cell pyroptosis were increased in lungs; IL-1ß and IL-18 in serum and bronchoalveolar lavage fluid (BALF) were further promoted; In the isolated alveolar macrophages from Sesn2-/- mice, mitophagy induced by LPS was markedly inhibited, while reactive oxygen species (ROS), mitochondrial damage and cell pyroptosis were enhanced. Knocking down or overexpressing Sensn2 in J774.A1 cells demonstrated Sesn2 promoted Sequestosome1 (SQSTM1) expression and mitophagy by PTEN-induced putative kinase 1 (Pink1)/Parkin pathway. SIGNIFICANCE: Sesn2 protected ALI by promoting mitophagy that exerts protection of AMs pyroptosis and negative regulation of NLRP3 inflammasomes. These data indicated Sesn2 might be a potential target for ALI treatment.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Macrófagos Alveolares/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Peroxidases/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
5.
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
6.
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
7.
Rev Med Virol ; 30(5): e2134, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32618072
8.
Mol Med ; 26(1): 64, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600316

RESUMO

The ubiquiotous nuclear protein HMGB1 is extracellularly released by dying cells or activated innate immunity cells to promote inflammation. Extracellular HMGB1 plays a prominent role in the pathogenesis of acute lung injury of infectious as well as sterile origin including hyperoxia. Excessive amounts of systemic HMGB1 and HMGB1-partner molecule complexes can be retained in the pulmonary circulation indicated by a substantial reduction of HMGB1 plasma levels in arterial versus venous blood. The cholinergic antiinflammatory mechanism ameliorates pulmonary inflammation by inhibiting HMGB1 release and HMGB1 receptor expression. This comprehension was recently reinforced by results reported in Molecular Medicine by Sitapara and coworkers demonstrating that administration of an α7 nicotinic acetylcholine receptor agonist attenuated hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation. Activating the cholinergic antiinflammatory path might be considered to alleviate severe COVID-19 with or without concurrent oxygen-induced lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Proteína HMGB1/antagonistas & inibidores , Neuroimunomodulação/efeitos dos fármacos , Agonistas Nicotínicos/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia
9.
Gene ; 758: 144973, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707303

RESUMO

Renal ischemia-reperfusion (rI/R) is a risk factor for acute lung injury (ALI). Alveolar macrophages (AMs) activation mediated by rI/R-induced ALI is one of the pathogeneses associated with the development of ALI. In rI/R, α2-adrenergic receptor agonists have been indicated to be effective in decreasing urea nitrogen concentrations. In this study, we explored the underlying pathogenesis of the clinically obtainable α2-adrenergic receptor agonist dexmedetomidine (DEX) in protecting against rI/R -mediated AMs activation. We incubated AMs with the serum of sham and rI/R rats in the presence or absence of various concentrations of DEX. We used an enzyme-linked immunosorbent assay to detect the secretion levels of GSH, LDH, IL-18, IL-1ß, and HMGB1 in the culture supernatant. We employed real-time polymerase chain reaction to assess the expression of NOX-4 mRNA, and western blotting to observe the protein levels of NOX-4, the NLRP3 inflammasome, AMPK, and eNOS. In addition, we used immunofluorescence to analyze ROS and MMP activity. Incubation of AMs with DEX suppressed rI/R-mediated cellular LDH production and ROS release. DEX also abolished the rI/R-mediated decrease in the activity of GSH and increased the levels of the rI/R-related NADPH oxidase protein NOX-4. Furthermore, DEX reduced the amelioration of the mitochondrial potential induced by rI/R. Our study showed that DEX inhibits rI/R-mediated levels of the NLRP3 inflammasome proteins ASC, NLRP3, HMGB1 and p20, and ameliorates rI/R-mediated AMPK signaling inactivation. Therefore, DEX reduces the levels of two mediators that are activated by the NLRP3 inflammasome: IL-18 and IL-1ß. Finally, our study established that DEX mitigates the rI/R-mediated decrease in eNOS, demonstrating its protective functions against AMs activation. In conclusion, our study demonstrated that the protective action of DEX in AMs is induced through amelioration of HMGB1-NLRP3 inflammasome-AMPK signaling. Our results suggest that the anesthetic reagent DEX exerts beneficial effects to ameliorate rI/R-induced ALI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Proteína HMGB1/metabolismo , Isquemia/patologia , Macrófagos Alveolares/patologia , NADPH Oxidase 4/biossíntese , NADPH Oxidase 4/genética , Óxido Nítrico Sintase Tipo III/metabolismo , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real
10.
Rev Med Virol ; 30(5): e2119, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32584474

RESUMO

The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Receptores Virais/genética , Vitamina D/uso terapêutico , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Angiotensina I/genética , Angiotensina I/metabolismo , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
11.
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
12.
Diabetes Metab Syndr ; 14(5): 829-831, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32540737

RESUMO

BACKGROUND AND AIMS: People with type 2 diabetes mellitus (T2DM) have increased morbidity and mortality due to coronavirus disease-19(COVID-19). It has been speculated that use of pioglitazone might increase such risk. The aim of our brief commentary is to review the safety of pioglitazone in people with T2DM and mild/moderate COVID-19. METHODS: We searched PubMed database using specific keywords related to our aims till May 15, 2020. Full text of relevant articles published in English language were retrieved and reviewed. RESULTS: Medications, including pioglitazone, that upregulate tissue expression of angiotensin converting enzyme 2 (ACE2), might have a dual role in COVID-19; on the one hand they might increase risk of infection as SARS-CoV2 uses ACE2 as a coreceptor to enter alveolar cells, but on the other hand, by reducing angiotensin II levels, they can protect against acute lung injury. There is no evidence to date that pioglitazone upregulates ACE2 in the alveolar cells; rather, there is evidence from animal studies of upregulation of ACE2 in insulin sensitive tissues, which might have a protective effect on lung injury. Moreover by moderating the exaggerated host proinflammatory response, pioglitazone can potentially reduce SARS-CoV-2 driven hyperinflammation. CONCLUSIONS: Pioglitazone has more potential for benefit than harm, and can be continued in people with T2DM and mild/moderate COVID-19, unless there are specific contraindications for its use. There is an urgent need to assess clinically relevant outcomes in people with diabetes and COVID-19 based upon baseline antidiabetes therapy, in particular pioglitazone.


Assuntos
Infecções por Coronavirus/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pioglitazona/uso terapêutico , Pneumonia Viral/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Humanos , Inflamação/prevenção & controle , Inflamação/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pioglitazona/farmacologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Fatores de Risco
13.
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
14.
Acta Cir Bras ; 35(2): e202000205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428061

RESUMO

Purpose To investigate the effects of induction of selective liver hypothermia in a rodent model. Methods Seven male Wistar rats were subjected to 90 minutes of partial 70% liver ischemia and topic liver 26°C hypothermia (H group). Other seven male Wistar rats were subjected to 90 minutes of partial 70% normothermic liver ischemia (N group). Five additional rats underwent a midline incision and section of liver ligaments under normothermic conditions and without any liver ischemia (sham group). All animals were sacrificed 24-h after reperfusion, and livers were sampled for analyses. Pathology sections were scored for sinusoidal congestion, ballooning, hepatocelllular necrosis and the presence of neutrophilic infiltrates. Results At the end of the experiment, liver tissue expressions of TNF-ɑ, IL-1ß, iNOS and TNF-ɑ/IL-10 ratio were significantly reduced in the H group compared to N group, whereas IL-10 and eNOS were significantly increased in H group. Histopathological injury scores revealed a significant decrease in ischemia/reperfusion (I/R) injuries in H group. Conclusion Selective liver hypothermia prevented I/R injury by inhibiting the release of inflammatory cytokines, preserves microcirculation, prevents hepatocellular necrosis and leukocyte infiltration, allowing maintenance of the liver architecture.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Hipotermia Induzida/métodos , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Lesão Pulmonar Aguda/patologia , Animais , Temperatura Corporal , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Isquemia/patologia , Fígado/patologia , Masculino , Necrose/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa
15.
J Trauma Acute Care Surg ; 88(6): 809-815, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32453257

RESUMO

BACKGROUND: Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, which is released into the circulation after hemorrhagic shock (HS). Recently, we discovered that triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a new receptor of eCIRP to exaggerate inflammation. Here, we hypothesize that by inhibiting the interaction between eCIRP and TREM-1 with the use of a novel short peptide derived from human eCIRP known as M3, we can inhibit the inflammatory response and acute lung injury in HS. METHODS: Hemorrhagic shock was induced using C57BL/6 mice by cannulating both femoral arteries. One femoral artery was used for removal of blood while the other was used for continuous monitoring of mean arterial blood pressure. The mean arterial pressure of 25 mm Hg to 30 mm Hg was maintained for 90 minutes, followed by a resuscitation phase of 30 minutes with 1 mL of normal saline. The treatment group was given 10 mg/kg of M3 during the resuscitation phase. Four hours after resuscitation, serum and lungs were collected and analyzed for various injury and inflammatory markers by using colorimetry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS: There was an increase in the serum levels of tissue injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as cytokines (TNF-α and IL-6) when comparing the vehicle group versus the sham group. This increase was significantly inhibited in the M3-treated group. The mRNA expression of proinflammatory cytokines TNF-α, IL-6, and IL-1ß and the chemokines MIP-2 and KC in lungs was significantly increased in the vehicle-treated HS mice, while their expression was significantly decreased in M3-treated HS mice. Finally, M3 treatment significantly decreased the lung injury score compared with vehicle-treated HS mice. CONCLUSION: The novel eCIRP-derived TREM-1 antagonist (M3) can be a potential therapeutic adjunct in the management of hemorrhagic shock.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Choque Hemorrágico/tratamento farmacológico , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Alarminas/química , Alarminas/imunologia , Animais , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/sangue , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/imunologia , Choque Hemorrágico/sangue , Choque Hemorrágico/complicações , Choque Hemorrágico/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia
16.
Life Sci ; 256: 117851, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470454

RESUMO

AIMS: The aim of this study was to explore the role of miR-122-5p in acute lung injury. MATERIALS AND METHODS: Mice were subjected to intratracheal injection of lipopolysaccharide to establish an acute lung injury model. The mice also received miR-122-5p antagonist and mimic via injection to inhibit or overexpress miR-122-5p in the lung tissue, respectively. In an in vitro experiment, we isolated primary mouse lung microvascular endothelial cells and established a cell injury model via lipopolysaccharide treatment. KEY FINDINGS: Mice injected with an miR-122-5p antagonist exhibited reduced lung injury, inflammation and oxidative stress, while mice injected with a miR-122-5p mimic exhibited exaggerated lung injury, inflammation and oxidative stress. In an in vitro experiment, we found that the miR-122-5p antagonist suppressed lipopolysaccharide-induced inflammation, apoptosis and oxidative stress. Moreover, miR-122-5p regulated the promoter activity of DUSP4, which negatively regulated ERK1/2 signaling. The use of DUSP4 siRNA counteracted the effects of the miR-122-5p antagonist. SIGNIFICANCE: Taken together, these results show that miR-122-5p protected against acute lung injury via regulation of DUSP4/ERK signaling in pulmonary microvascular endothelial cells. MiR-122-5p antagonism may be a promising treatment method for acute lung injury.


Assuntos
Lesão Pulmonar Aguda/genética , Apoptose/genética , Inflamação/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Tirosina Fosfatases/genética , Transdução de Sinais/genética
17.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(2): 130-137, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32314710

RESUMO

Objective To investigate the effects on acute lung injury (ALI) of CD226 conditional knockout (CD226 CKO) in vascular endothelial cells were investigated in mice with hemorrhagic shock (HS) and its mechanism. Methods Male wild type (WT) and CD226 CKO mice were randomly divided into sham and HS groups: in the sham group, a heart puncture was performed but blood was not drawn; in the HS group, the heart was punctured and 30% of the total blood volume was drawn. To assess lung injury, lung lesions were observed by HE staining. Immunofluorescence histochemical staining was used to detect the expression and distribution of CD31, CD226 in lung tissue and CD3 and CD226 in spleen. In addition, a RNA interering (RNAi) was used to knockdown CD226 in human umbilical vein endothelial cells and a hypoxia model was established. Protein expression of Bcl2 in lung tissue and vascular endothelial cells was detected by Western blotting. Early apoptosis was detected by JC-1 mitochondrial membrane potential staining. Results In the HS groups, CD226 CKO mice showed significantly less ALI than WT mice, and the protein expression of Bcl2 in their lung tissues increased. Furthermore, in vitro cytological models revealed that protein expression of Bcl2 increased and apoptosis decreased in the siCD226 group relative to the siNC group under hypoxia. Conclusion CD226 CKO in vascular endothelial cells reduces ALI in mice with HS, and this effect is associated with increased expression of Bcl2 and decreased apoptosis.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Antígenos de Diferenciação de Linfócitos T/genética , Choque Hemorrágico/complicações , Lesão Pulmonar Aguda/etiologia , Animais , Apoptose , Células Endoteliais da Veia Umbilical Humana , Humanos , Pulmão , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória
18.
Int J Mol Sci ; 21(3)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32024151

RESUMO

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, p < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The i.p. administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O2 significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, p < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, p < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Antioxidantes/administração & dosagem , Suplementos Nutricionais , Proteína HMGB1/metabolismo , Hiperóxia/complicações , Macrófagos/metabolismo , Pneumonia/prevenção & controle , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Proteína HMGB1/genética , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/patologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo
19.
Mol Med Rep ; 21(3): 1233-1241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016469

RESUMO

The aim of the present study was to investigate the antioxidant mechanisms of dexmedetomidine against lung injury during intestinal ischemia reperfusion (IIR) in rats. The model of IIR­induced acute lung injury was established by occluding the superior mesenteric artery (SMA) for 1 h and reperfusing for 2 h using Sprague­Dawley rats. Pathological examination was used to assess the extent of the lung injury. Oxidative stress was evaluated by measuring malondialdehyde, myeloperoxidase and superoxide dismutase in the lung and plasma. The proinflammatory cytokines tumor necrosis factor­α and interleukin­6 were determined via an enzyme­linked immunosorbent assay. The mRNA and protein expression of nuclear factor­erythroid 2 related factor 2 (Nrf2) and heme oxygenase 1 (HO­1) were determined using a reverse transcription­quantitative polymerase chain reaction and western blotting. Pretreatment with dexmedetomidine significantly inhibited the oxidative stress response and proinflammatory factor release caused by IIR compared with the normal saline group (MDA and SOD in lung and plasma, P<0.05; MPO, IL­1ß and TNF­α in lung and plasma, P<0.05). Dexmedetomidine improved pulmonary pathological changes in IIR rats compared with the normal saline group. Investigations into the molecular mechanism revealed that dexmedetomidine increased the expression levels of Nrf2 and HO­1 via activating α2 adrenergic receptors compared with the normal saline group. The antagonism of α2 adrenergic receptors may reverse the protective effect of dexmedetomidine on lung injury during IIR, including decreasing the expression levels of Nrf2 and HO­1, elevating the oxidative stress response and increasing the proinflammatory factor release. In conclusion, pretreatment with dexmedetomidine demonstrated protective effects against lung injury during IIR via α2 adrenergic receptors. The Nrf2/HO­1 signaling pathway may serve a function in the protective effect of dexmedetomidine.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Antioxidantes/farmacologia , Dexmedetomidina/farmacologia , Heme Oxigenase-1/metabolismo , Fator de Transcrição NF-E2/metabolismo , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Heme Oxigenase-1/genética , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/análise , Fator de Transcrição NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/efeitos dos fármacos
20.
J Ethnopharmacol ; 252: 112633, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32001275

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pequi fruit are obtained from the pequi tree (Caryocar coriaceum), from which the pulp and nut are used in order to extract an oil that is commonly used in popular medicine as an antiinflammatory agent, particularly for the treatment of colds, bronchitis and bronchopulmonary infections. Making use of the fixed oil of Caryocar coriaceum (FOCC), an attractive alternative for the treatment of diseases caused by exposure to environmental tobacco smoke. AIM OF THE STUDY: To evaluate whether oral intake FOCC provides beneficial effects in the respiratory system of rats submitted to a short-term secondhand smoke (SHS) exposure model. MATERIALS AND METHODS: The experiments were performed on Wistar rats divided into 4 groups; in the SHS + O and SHS + T groups, the animals were pretreated orally with 0.5 mL of FOCC (SHS + O) or vehicle (Tween-80 [1%] solution) (SHS + T). Immediately after pretreatment, the animals were submitted to the SHS exposure protocol, for a total period of 14 days. Exposures were performed 6 times per day, with a duration of 40 min per exposure (5 cigarettes per exposure), followed by a 1-h interval between subsequent exposures. In the AA + O and AA + T groups, animals were submitted to daily oral pretreatment with 0.5 mL of FOCC (AA + O) or vehicle (AA + T). These animals were then subjected to the aforementioned exposure protocol, but using ambient air. After the exposure period, we investigated the effects of FOCC in respiratory mechanics in vivo (Newtonian resistance -RN, tissue elastance -H, tissue resistance -G, static compliance -CST, inspiratory capacity -IC, PV loop area) histopathology and lung parenchymal morphometry in vitro (polymorphonuclear cells -PMN, mean alveolar diameter -Lm, bronchoconstriction index -BCI), temporal evolution of subjects' masses, and percent composition of the FOCC. RESULTS: Regarding the body mass of the animals, the results demonstrated an average body mass gain of 10.5 g for the animals in the AA + T group, and 15.5 g for those in the AA + O group. On the other hand, the body mass of animals in the SHS + T and SHS + O suffered an average loss of 14.4 and 4.75 g, respectively. Regarding respiratory system analyzes, our results demonstrated significant changes in all respiratory mechanics variables and lung parenchyma morphometry analyzed for the SHS + T group when compared to the AA + T group (p < 0,05), confirming the establishment of pulmonary injury induced by SHS exposure. We also observed that rats pretreated orally with FOCC (SHS + O) showed improvement in all variables when compared to the SHS + T group (p < 0,05), thus demonstrating the effectiveness of FOCC in preventing lung damage induced by short-term SHS exposure. CONCLUSION: In conclusion, our results demonstrate that FOCC was able to prevent lung injury in rats submitted to short-term SHS exposure.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Ericales , Óleos Vegetais/uso terapêutico , Mecânica Respiratória/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Masculino , Ratos Wistar , Sementes
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