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1.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198751

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Itália , Leucócitos Mononucleares/virologia , Lopinavir/uso terapêutico , Pulmão/citologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/terapia , Prognóstico , Estudos Prospectivos , Respiração Artificial/métodos , Ritonavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Taxa de Sobrevida , Vírion/metabolismo , Vírion/ultraestrutura
2.
Mol Med ; 26(1): 98, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126860

RESUMO

BACKGROUND: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.


Assuntos
Compostos de Benzilideno/farmacologia , Hiperóxia/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Piridinas/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Hiperóxia/dietoterapia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pseudomonas aeruginosa , Células RAW 264.7
3.
J Toxicol Sci ; 45(10): 651-660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012733

RESUMO

Inhalation of silica particles leads to pulmonary inflammatory responses. Clara cell protein 16 (CC16) has been reported to played a protective role in inflammatory lung diseases. However, its role on silica particles-induced inflammation has not been fully clarified. In this study, THP-1 macrophages were exposed to 75 µg/cm2 silica particles with or without 2 µg/mL exogenous CC16 (recombinant CC16, rCC16) for 24 hr. The production of inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6, in the cell supernatants of different groups was detected through ELISA kits and real-time RT-PCR, respectively. The nuclear translocation of nuclear factor (NF)-κB, protein levels of pro-IL-1ß, the nucleotide-binding domain-like receptor protein 3 (NLRP3) and caspase-1 were evaluated via immunofluorescence or western blot. Results showed that, at 75 µg/cm2 silica particle concentration, the treatment of rCC16 significantly decreased IL-1ß, TNF-α and IL-6 protein release and mRNA levels in THP-1 macrophages. Compared to those only exposed to silica particles, THP-1 macrophages exposed to both silica particles and rCC16 showed significantly lower nuclear levels and higher cytosol levels of NF-κB p65, as well as lower co-localization coefficients through immunofluorescence. Additionally, the administration of rCC16 significantly attenuated the increase of pro-IL-1ß, NLRP3 and caspase-1 levels induced by silica particle exposure. Our results suggested that exogenous CC16 could inhibit silica particles-induced inflammation in THP-1 macrophages, mainly through suppressing NF-κB pathway and caspase-1 activation.


Assuntos
Caspase 1/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Macrófagos Alveolares/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , Dióxido de Silício/toxicidade , Caspase 1/genética , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Humanos , NF-kappa B/genética , Tamanho da Partícula , Proteínas Recombinantes/farmacologia , Células THP-1 , Uteroglobina/farmacologia
4.
Life Sci ; 258: 118166, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739471

RESUMO

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , /fisiopatologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Imunidade Inata , Inflamação/etiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/terapia , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Ativação de Neutrófilo , Pandemias , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , /imunologia , Trombofilia/etiologia , Trombofilia/imunologia , Trombofilia/fisiopatologia , Trombofilia/terapia
5.
Ecotoxicol Environ Saf ; 205: 111186, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853868

RESUMO

Exposure to ambient air particulate matter (PM) is associated with increased cardiorespiratory morbidity and mortality. In this context, alveolar macrophages exhibit proinflammatory and oxidative responses as a result of the clearance of particles, thus contributing to lung injury. However, the mechanisms linking these pathways are not completely clarified. Therefore, the oxinflammation phenomenon was studied in RAW 264.7 macrophages exposed to Residual Oil Fly Ash (ROFA), a PM surrogate rich in transition metals. While cell viability was not compromised under the experimental conditions, a proinflammatory phenotype was observed in cells incubated with ROFA 100 µg/mL, characterized by increased levels of TNF-α and NO production, together with PM uptake. This inflammatory response seems to precede alterations in redox metabolism, characterized by augmented levels of H2O2, diminished GSH/GSSG ratio, and increased SOD activity. This scenario resulted in increased oxidative damage to phospholipids. Moreover, alterations in mitochondrial respiration were observed following ROFA incubation, such as diminished coupling efficiency and spare respiratory capacity, together with augmented proton leak. These findings were accompanied by a decrease in mitochondrial membrane potential. Finally, NADPH oxidase (NOX) and mitochondria were identified as the main sources of superoxide anion () in our model. These results indicate that PM exposure induces direct activation of macrophages, leading to inflammation and increased reactive oxygen species production through NOX and mitochondria, which impairs antioxidant defense and may cause mitochondrial dysfunction.


Assuntos
Macrófagos Alveolares/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Superóxidos/metabolismo , Poluentes Atmosféricos/toxicidade , Animais , Antioxidantes/metabolismo , Cinza de Carvão/toxicidade , Peróxido de Hidrogênio/metabolismo , Inflamação , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo/imunologia , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
6.
Toxicol Lett ; 333: 115-129, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758513

RESUMO

Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury, the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as well as its maintenance, resolution, and repair. Importantly, macrophages can serve as either pro-inflammatory or anti-inflammatory populations depending on the present conditions at any pathological stage. Different characteristics of macrophages, including their differentiation, phenotypic, and functional properties, as well as interactions with other cell populations determine the outcomes of lung diseases and the extent of long- or short-term pulmonary damage induced by SM. In this paper, we summarize the current state of knowledge regarding the role of alveolar macrophages and their mediators in the pathogenesis of SM in pulmonary injury. Investigating the specific cells and mechanisms involved in SM-lung injury may be useful in finding new target opportunities for treatment of this injury.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Imunidade Inata/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Gás de Mostarda/toxicidade , Animais , Humanos , Pulmão/imunologia , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia
8.
Front Immunol ; 11: 1625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719685

RESUMO

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus , Sistemas de Liberação de Medicamentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Pandemias , Pneumonia Viral , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
10.
Arch Virol ; 165(10): 2259-2277, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32699981

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is a widely disseminated, macrophage-tropic arterivirus that exhibits profound genetic and pathogenic heterogeneity. The present study was conducted to determine the complete genome sequences of two novel Korean lineage 1 PRRSV-2 strains, KNU-1901 and KNU-1902, which were isolated from vaccinated pig farms experiencing unusually high morbidity and mortality. Both isolates contained notable discontinuous 423-nucleotide deletions (DELs) within the genes encoding nonstructural protein 2 (nsp2) and GP3 when compared with the prototype strain VR-2332. In particular, the nsp2 DEL viruses had unique quadripartite discontinuous DEL signatures (111-1-19-9) in nsp2; this is an expanded version of the tripartite 111-1-19 DEL previously identified in virulent lineage 1 PRRSV-2 strains. Phylogenetic analysis revealed that both novel nsp2 DEL viruses belong to the Korean clade (KOR C) of lineage 1 isolates based on ORF5 but cluster with lineage KOR A strains based on the nsp2 or complete genome sequence. Recombination detection analysis suggested that both novel isolates are recombinants and may have evolved via natural inter-lineage recombination between circulating KOR A and KOR C strains. Interestingly, compared with the prototype VR-2332 virus, the novel nsp2 DEL variants were less efficient at promoting the expression of immune response genes in porcine alveolar macrophage culture. Taken together, we conclude that KNU-1901 and KNU-1902 are recently evolved recombinant variants of the virulent lineage 1 family that caused the regional severe PRRS outbreaks.


Assuntos
Citocinas/genética , Genoma Viral , Filogenia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Proteínas não Estruturais Virais/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular Transformada , Citocinas/imunologia , Evolução Molecular , Expressão Gênica , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Fases de Leitura Aberta , Síndrome Respiratória e Reprodutiva Suína/epidemiologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/classificação , Vírus da Síndrome Respiratória e Reprodutiva Suína/isolamento & purificação , Recombinação Genética , República da Coreia/epidemiologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Suínos , Virulência
11.
Rev Med Virol ; 30(5): e2140, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32686248

RESUMO

A knowledge-based cybernetic framework model representing the dynamics of SARS-CoV-2 inside the human body has been studied analytically and in silico to explore the pathophysiologic regulations. The following modeling methodology was developed as a platform to introduce a predictive tool supporting a therapeutic approach to Covid-19 disease. A time-dependent nonlinear system of ordinary differential equations model was constructed involving type-I cells, type-II cells, SARS-CoV-2 virus, inflammatory mediators, interleukins along with host pulmonary gas exchange rate, thermostat control, and mean pressure difference. This formalism introduced about 17 unknown parameters. Estimating these unknown parameters requires a mathematical association with the in vivo sparse data and the dynamic sensitivities of the model. The cybernetic model can simulate a dynamic response to the reduced pulmonary alveolar gas exchange rate, thermostat control, and mean pressure difference under a very critical condition based on equilibrium (steady state) values of the inflammatory mediators and system parameters. In silico analysis of the current cybernetical approach with system dynamical modeling can provide an intellectual framework to help experimentalists identify more active therapeutic approaches.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Pulmão/imunologia , Dinâmica não Linear , Pneumonia Viral/imunologia , Proteínas da Fase Aguda/antagonistas & inibidores , Proteínas da Fase Aguda/genética , Proteínas da Fase Aguda/imunologia , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Temperatura Corporal , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/virologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Troca Gasosa Pulmonar/imunologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
12.
PLoS Pathog ; 16(7): e1008655, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673357

RESUMO

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.


Assuntos
Modelos Animais de Doenças , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/virologia , Animais , Macrófagos Alveolares/imunologia , Camundongos
13.
Expert Opin Pharmacother ; 21(11): 1359-1366, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32511020

RESUMO

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a heterogeneous group of rare diseases characterized by the abnormal production and impaired degradation of pulmonary surfactant as a result of malfunctioning of alveolar macrophages. This is due to the downstream dysregulation of the GM-CSF pathway, which can be caused by specific autoantibodies (autoimmune, aPAP formerly known as idiopathic iPAP), direct injury to alveolar macrophages (e.g. by toxic inhaled agents.), or by genetic defects (hereditary or congenital PAP). Few pharmacotherapy options are currently available to treat this disease. AREA COVERED: The authors discuss the exogenous administration of GM-CSF, rituximab, and the potential role of cholesterol lowering medications in this review. The authors, furthermore, provide their opinion on the available pharmacotherapeutic options and give their future perspectives. EXPERT OPINION: Inhaled GM-CSF remains the most commonly used therapy in patients with iPAP but other inhaled therapies such as PPARγ activators should be considered, especially in patients who are partially responsive or unresponsive to traditional treatments.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Rituximab/uso terapêutico , Administração por Inalação , Animais , Autoanticorpos/imunologia , Ensaios Clínicos como Assunto , Terapia Genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Injeções Subcutâneas , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos
14.
Nanotoxicology ; 14(7): 929-946, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32538272

RESUMO

Multi-walled carbon nanotubes (MWCNTs) are known to induce pulmonary inflammatory effects through stimulating pro-inflammatory cytokine secretion from alveolar macrophages. Despite extensive studies on MWCNTs' pro-inflammatory reactivity, the understanding of molecular mechanisms involved is still incomplete. In this study, we investigated hemichannel's involvement in MWCNTs-induced macrophage IL-1ß release. Our results showed that the unmodified and COOH MWCNTs could induce ATP release and ATP-P2X7R axis-dependent IL-1ß secretion from THP-1 macrophages. By using various inhibitors, we confirmed that the MWCNTs-induced ATP release was primarily through hemichannels. EtBr dye uptake assay detected significant hemichannels opening in MWCNTs exposed THP-1 macrophages. Inhibition of hemichannels by CBX, 43Gap27, or 10Panx1 pretreatment results in decreased ATP and IL-1ß release. The addition of ATP restored the reduced IL-1ß secretion level from hemichannel inhibition. We also confirmed with five other types of MWCNTs that the induction of hemichannels by MWCNTs strongly correlates with their capacity to induce IL-1ß secretion. Taken together, we conclude that hemichannels-mediated ATP release and subsequent NLRP3 inflammasome activation through P2X7R may be one mechanism by which MWCNTs induce macrophage IL-1ß secretion. Our findings may provide a novel molecular mechanism for MWCNTs induced IL-1ß secretion.


Assuntos
Trifosfato de Adenosina/metabolismo , Conexinas/metabolismo , Interleucina-1beta/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nanotubos de Carbono/química , Células THP-1
15.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544188

RESUMO

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Assuntos
Antígenos CD11/imunologia , Macrófagos Alveolares , Monócitos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Animais , Antígenos CD11/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium tuberculosis/genética , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/patologia
16.
Front Immunol ; 11: 1312, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582222

RESUMO

Respiratory, circulatory, and renal failure are among the gravest features of COVID-19 and are associated with a very high mortality rate. A common denominator of all affected organs is the expression of angiotensin-converting enzyme 2 (ACE2), a protease responsible for the conversion of Angiotensin 1-8 (Ang II) to Angiotensin 1-7 (Ang 1-7). Ang 1-7 acts on these tissues and in other target organs via Mas receptor (MasR), where it exerts beneficial effects, including vasodilation and suppression of inflammation and fibrosis, along an attenuation of cardiac and vascular remodeling. Unfortunately, ACE2 also serves as the binding receptor of SARS viral spike glycoprotein, enabling its attachment to host cells, with subsequent viral internalization and replication. Although numerous reports have linked the devastating organ injuries to viral homing and attachment to organ-specific cells widely expressing ACE2, little attention has been given to ACE-2 expressed by the immune system. Herein we outline potential adverse effects of SARS-CoV2 on macrophages and dendritic cells, key cells of the immune system expressing ACE2. Specifically, we propose a new hypothesis that, while macrophages play an important role in antiviral defense mechanisms, in the case of SARS-CoV, they may also serve as a Trojan horse, enabling viral anchoring specifically within the pulmonary parenchyma. It is tempting to assume that diverse expression of ACE2 in macrophages among individuals might govern the severity of SARS-CoV-2 infection. Moreover, reallocation of viral-containing macrophages migrating out of the lung to other tissues is theoretically plausible in the context of viral spread with the involvement of other organs.


Assuntos
Betacoronavirus/metabolismo , Células Dendríticas/metabolismo , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Peptidil Dipeptidase A/metabolismo , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Humanos , Pulmão/virologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Pandemias , Tecido Parenquimatoso/patologia , Tecido Parenquimatoso/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
17.
Nat Immunol ; 21(6): 636-648, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424365

RESUMO

Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.


Assuntos
Epigênese Genética , Inflamação/etiologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Biomarcadores , Reprogramação Celular , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Imunofenotipagem , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Alveolares/imunologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Fagocitose/imunologia , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
19.
Nature ; 583(7818): 830-833, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380511

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Pulmão/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Transgenes , Animais , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Brônquios/patologia , Brônquios/virologia , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Humanos , Imunoglobulina G/imunologia , Pulmão/imunologia , Pulmão/virologia , Linfócitos/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Masculino , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/imunologia , Receptores de Complemento 3d/genética , Receptores de Complemento 3d/metabolismo , Replicação Viral , Perda de Peso
20.
Scand J Immunol ; 92(1): e12889, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32299134

RESUMO

The analysis of tumour-associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan-macrophage markers (CD14 and CD68) as well as some suggested markers for tumour-promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non-small cell lung cancer (NSCLC). Tumour, non-cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan-macrophage marker although careful selection of antibody was found to be critical. The widely used anti-CD68 antibody clone KP-1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane marker such as CD14, CD163 or CD206. In flow cytometry, the commonly used combination of CD14 and HLA-DR was found to not be optimal because some TAMs do not express CD14. Instead, combined staining of CD68 and HLA-DR is preferable to gate all TAMs. Concerning macrophage phenotypic markers, the scavenger receptor CD163 was found to be expressed by a substantial fraction (50%-86%) of TAMs with a large patient-to-patient variation. Approximately 50% of TAMs were positive for CD206. Surprisingly, there was no clear overlap between CD163 and CD206 positivity, and three distinct TAM sub-populations were identified in NSCLC tumours: CD163+ CD206+ , CD163+ CD206- and CD163- CD206- . This work should help develop macrophage-based prognostic tools for cancer.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Receptores de Lipopolissacarídeos/análise , Neoplasias Pulmonares/diagnóstico , Macrófagos Alveolares/imunologia , Receptores de Superfície Celular/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/análise , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Lectinas Tipo C/análise , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Lectinas de Ligação a Manose/análise , Prognóstico , Receptores Depuradores Classe A/análise
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