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1.
Int J Mol Sci ; 21(21)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138181

RESUMO

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.


Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Vasoconstrição/fisiologia , Betacoronavirus , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Sistema Calicreína-Cinina/fisiologia , Pandemias , Sistema Renina-Angiotensina/fisiologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos
2.
Front Immunol ; 11: 584514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101314

RESUMO

Physical trauma can be considered an unrecognized "pandemic" because it can occur anywhere and affect anyone and represents a global burden. Following severe tissue trauma, patients frequently develop acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) despite modern surgical and intensive care concepts. The underlying complex pathophysiology of life-threatening ALI/ARDS has been intensively studied in experimental and clinical settings. However, currently, the coronavirus family has become the focus of ALI/ARDS research because it represents an emerging global public health threat. The clinical presentation of the infection is highly heterogeneous, varying from a lack of symptoms to multiple organ dysfunction and mortality. In a particular subset of patients, the primary infection progresses rapidly to ALI and ARDS. The pathophysiological mechanisms triggering and driving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ALI/ARDS are still poorly understood. Although it is also generally unknown whether insights from trauma-induced ARDS may be readily translated to SARS-CoV-2-associated ARDS, it was still recommended to treat coronavirus-positive patients with ALI/ARDS with standard protocols for ALI/ARDS. However, this strategy was questioned by clinical scientists, because it was documented that some severely hypoxic SARS-CoV-2-infected patients exhibited a normal respiratory system compliance, a phenomenon rarely observed in ARDS patients with another underlying etiology. Therefore, coronavirus-induced ARDS was defined as a specific ARDS phenotype, which accordingly requires an adjusted therapeutic approach. These suggestions reflect previous attempts of classifying ARDS into different phenotypes that might overall facilitate ARDS diagnosis and treatment. Based on the clinical data from ARDS patients, two major phenotypes have been proposed: hyper- and hypo-inflammatory. Here, we provide a comparative review of the pathophysiological pathway of trauma-/hemorrhagic shock-induced ARDS and coronavirus-induced ARDS, with an emphasis on the crucial key points in the pathogenesis of both these ARDS forms. Therefore, the manifold available data on trauma-/hemorrhagic shock-induced ARDS may help to better understand coronavirus-induced ARDS.


Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Trombose/patologia , Lesão Pulmonar Aguda/virologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Citocinas/sangue , Humanos , Imunidade Inata/imunologia , Inflamação/patologia , Inflamação/virologia , Pulmão/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Trombose/virologia
3.
Mol Immunol ; 126: 111-119, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32818819

RESUMO

Here, we aimed to investigate the role of long noncoding RNA (lncRNA) THRIL in septic-induced acute lung injury. C57BL/6 mice were injected with Adenoviruses (Ad)-shTHRIL or negative control (NC) before caecal ligation and puncture (CLP) operation. MPVECs were transfected with Ad-shTHRIL or NC, followed by lipopolysaccharide (LPS) treatment. MiR-424 and Rho-associated kinase 2 (ROCK2) were predicted and verified as direct targets of THRIL and miR-424, respectively, by using dual-luciferase reporter assay. ROCK2 overexpression vector and shTHRIL were co-transfected into mouse pulmonary microvascular endothelial cells for 24 h before LPS treatment. Our results showed that THRIL was highly expressed in the lung of sepsis mice. CLP triggered severe lung injury and apoptosis in mice, which was abolished by THRIL knockdown. Moreover, CLP treatment visibly increased protein concentration, the number of total cell of neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). Besides, elevated protein levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were observed in both lung and BALF. However, inhibition of THRIL reduced the number of inflammatory cells and the production of pro-inflammatory cytokines in sepsis mouse model. The effect of THRIL on inflammatory response and apoptosis in the lung was confirmed in sepsis cell model. Moreover, mechanistic studies have shown that THRIL up-regulated ROCK2 level through sponging miR-424. Furthermore, ROCK2 overexpression reversed the inhibitory effects of THRIL knockdown on LPS-induced inflammatory response and apoptosis. Overall, in vivo and in vitro results suggested that THRIL accelerates sepsis-induced lung injury by sponging miR-424 and further restoring ROCK2.


Assuntos
Lesão Pulmonar Aguda/imunologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Sepse/complicações , Quinases Associadas a rho/genética , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/genética , Apoptose/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais , Endotélio Vascular/citologia , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/imunologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Microvasos/citologia , Sepse/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia
4.
Nat Commun ; 11(1): 3852, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737308

RESUMO

Acute critical illness is often preceded by deterioration of routinely measured clinical parameters, e.g., blood pressure and heart rate. Early clinical prediction is typically based on manually calculated screening metrics that simply weigh these parameters, such as early warning scores (EWS). The predictive performance of EWSs yields a tradeoff between sensitivity and specificity that can lead to negative outcomes for the patient. Previous work on electronic health records (EHR) trained artificial intelligence (AI) systems offers promising results with high levels of predictive performance in relation to the early, real-time prediction of acute critical illness. However, without insight into the complex decisions by such system, clinical translation is hindered. Here, we present an explainable AI early warning score (xAI-EWS) system for early detection of acute critical illness. xAI-EWS potentiates clinical translation by accompanying a prediction with information on the EHR data explaining it.


Assuntos
Lesão Renal Aguda/diagnóstico , Lesão Pulmonar Aguda/diagnóstico , Inteligência Artificial , Registros Eletrônicos de Saúde/estatística & dados numéricos , Sepse/diagnóstico , Doença Aguda , Lesão Renal Aguda/sangue , Lesão Renal Aguda/patologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Área Sob a Curva , Pressão Sanguínea , Estado Terminal , Diagnóstico Precoce , Frequência Cardíaca , Humanos , Prognóstico , Curva ROC , Sepse/sangue , Sepse/patologia
5.
J Toxicol Sci ; 45(8): 423-434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741895

RESUMO

Paraquat (PQ) as a non-selective heterocyclic herbicide, has been applied worldwide for over a few decades. But PQ is very harmful to humans and rodents. The lung is the main target organ of PQ poisoning. It is an important event that lung epithelial cells are injured during PQ-induced acute lung injury and pulmonary fibrosis. As a regulator of mRNA expression, microRNA (miRNA) may play an important role in the progress. Our study was to investigate the mechanisms of PQ-induced injury of pulmonary epithelial cells through analyzing the profiling of miRNAs and their target genes. As a result, 11 differentially expressed miRNAs were screened, including 1 upregulated miRNA and 10 downregulated miRNAs in PQ-treated murine lung alveolar epithelial cells (MLE-12 cells). The bioinformatic analyses suggested that the target genes of these miRNAs were involved in mitochondrial apoptosis pathway and DNA methylation, and participated in the regulation of PI3K-Akt, mTOR, RAS, TNF, MAPK and other signal pathways which related to oxidative stress and apoptosis. This indicated that miRNAs were an important regulator of oxidative stress and apoptosis during PQ-induced injury of murine lung alveolar epithelial cells. The findings would deepen our understanding of the mechanisms of PQ-induced pulmonary injury and might provide new treatment targets for this disease.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Apoptose/genética , Células Epiteliais/efeitos dos fármacos , Perfilação da Expressão Gênica , Expressão Gênica , Herbicidas/toxicidade , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Paraquat/toxicidade , Alvéolos Pulmonares/citologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Metilação de DNA/genética , Camundongos , MicroRNAs/fisiologia , Mitocôndrias/patologia
6.
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
7.
Nat Commun ; 11(1): 4311, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855420

RESUMO

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.


Assuntos
Lesão Pulmonar Aguda/complicações , Aneurisma da Aorta Abdominal/patologia , Proteína HMGB1/metabolismo , Macrófagos/metabolismo , Remodelação Vascular , Lesão Pulmonar Aguda/patologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Humanos , Macrófagos/citologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estudos Retrospectivos , Regulação para Cima
8.
Life Sci ; 260: 118308, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32828942

RESUMO

Lung injury is characterized by inflammatory processes demonstrated as loss of function of the pulmonary capillary endothelial and alveolar epithelial cells. Autophagy is an intracellular digestion system that work as an inducible adaptive response to lung injury which is a resultant of exposure to various stress agents like hypoxia, ischemia-reperfusion and xenobiotics which may be manifested as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic lung injury (CLI), bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), asthma, ventilator-induced lung injury (VILI), ventilator-associated lung injury (VALI), pulmonary fibrosis (PF), cystic fibrosis (CF) and radiation-induced lung injury (RILI). Numerous regulators like LC3B-II, Beclin 1, p62, HIF1/BNIP3 and mTOR play pivotal role in autophagy induction during lung injury possibly for progression/inhibition of the disease state. The present review focuses on the critical autophagic mediators and their potential cross talk with the lung injury pathophysiology thereby bringing to limelight the possible therapeutic interventions.


Assuntos
Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Biomarcadores/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Humanos
9.
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
10.
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
11.
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
12.
Front Immunol ; 11: 1626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714336

RESUMO

Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF, and IL-1ß increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine storm syndrome (CSS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.


Assuntos
Lesão Pulmonar Aguda/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Humanos , Pulmão/patologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/terapia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/terapia
13.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L218-L227, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32519893

RESUMO

Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.


Assuntos
Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Bacteriemia/patologia , Pulmão/patologia , Streptococcus pneumoniae/patogenicidade , Adulto , Bacteriemia/microbiologia , Epitélio/microbiologia , Epitélio/patologia , Feminino , Humanos , Pulmão/microbiologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Neutrófilos/patologia , Permeabilidade , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Alvéolos Pulmonares/microbiologia , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório do Adulto/microbiologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Mucosa Respiratória/microbiologia , Mucosa Respiratória/parasitologia
14.
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
16.
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
17.
Exp Biol Med (Maywood) ; 245(11): 970-976, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32460624

RESUMO

The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.


Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Pneumonia Viral/patologia , Lesão Pulmonar Aguda/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Humanos , Linfo-Histiocitose Hemofagocítica/patologia , Linfopenia/patologia , Pandemias , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia
18.
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
20.
Exp Mol Pathol ; 115: 104438, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32277959

RESUMO

BACKGROUND: Acute liver injury (ALI) is associated with the oxidative stress and apoptosis in liver. Recent studies have shown that miR-195, a critical member of miR-15 family, has modulated the apoptosis in various organic diseases. However, it is elusive whether miR-195 regulation exert a hepatic ameliorative effect on ALI by the suppression of apoptosis and oxidative stress levels. We aimed to explore the regulated role of miR-195 in acute liver injury via the current study. METHODS: C57BL/6 J mice (male, seven-week, 18-20 g) were administrated intraperitoneal injection with tetrachloromethane (CCl4) to induce ALI. miR-195 inhibitor or mimics loaded in lentivirus vectors (miR-195 INH or MMC) and Pim-1 loaded in Adeno-associated viral vectors (AAV-Pim-1) were respectively delivered into mouse tail intravenous to establish silence or overexpression of miR-195 and overexpression of Pim-1. Western blotting, Reverse Transcription-Polymerase Chain Reaction (RT-PCR), enzyme linked immunosorbent assay (ELISA) technique, Immunohistochemistry (IHC) and Hematoxylin-eosin (H&E) staining were conducted to measure miR-195 and Pim-1 expression, apoptosis and oxidative stress levels, histological and functional change. RESULTS: We found that the expression of miR-195 markedly increased in CCl4-induced ALI. Besides, we demonstrated that the silence of miR-195 attenuated the apoptosis and oxidative stress via up-regulating Pim-1 in CCl4-induced ALI. Moreover, the inhibition of miR-195 protected the integrity and function of liver tissue. CONCLUSIONS: The above results showed that the suppression of miR-195 ameliorated ALI through inhibiting apoptosis and oxidative stress via targeting Pim-1. Our research provided a novel scheme that the miR-195 modulation in process of ALI may be an effective therapy method and verifies a promising target for diagnostic and therapeutic strategy of miRNAs.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Apoptose , MicroRNAs/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Apoptose/genética , Sequência de Bases , Tetracloreto de Carbono , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Estresse Oxidativo/genética , Recuperação de Função Fisiológica
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