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1.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823870

RESUMO

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Reposicionamento de Medicamentos , Hipóxia/tratamento farmacológico , Adhatoda , Pulmão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pneumonia/prevenção & controle , Fibrose Pulmonar/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Bleomicina , /virologia , Ceco/microbiologia , Ceco/cirurgia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/metabolismo , Adhatoda/química , Ligadura , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/microbiologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/microbiologia , Transcriptoma
3.
Nat Commun ; 12(1): 1386, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654090

RESUMO

The COVID-19 pandemic is a global health crisis that poses a great challenge to the public health system of affected countries. Safe and effective vaccines are needed to overcome this crisis. Here, we develop and assess the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine in rhesus macaques. Twenty macaques were divided into four groups of five animals each. One group was administered a placebo, while three groups were immunized with three different vaccine candidates of BBV152 at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which exhibited interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. This vaccine candidate BBV152 has completed Phase I/II (NCT04471519) clinical trials in India and is presently in phase III, data of this study substantiates the immunogenicity and protective efficacy of the vaccine candidates.


Assuntos
/uso terapêutico , /patogenicidade , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Linfócitos/imunologia , Linfócitos/metabolismo , Macaca mulatta , Masculino , Pneumonia/imunologia , Pneumonia/metabolismo
4.
Nat Immunol ; 22(2): 118-127, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462453

RESUMO

Macrophages have long been considered as particularly plastic cells. However, recent work combining fate mapping, single-cell transcriptomics and epigenetics has undermined the macrophage plasticity dogma. Here, we discuss recent studies that have carefully dissected the response of individual macrophage subsets to pulmonary insults and call for an adjustment of the macrophage plasticity concept. We hypothesize that prolonged tissue residency shuts down much of the plasticity of macrophages and propose that the restricted plasticity of resident macrophages has been favored by evolution to safeguard tissue homeostasis. Recruited monocytes are more plastic and their differentiation into resident macrophages during inflammation can result in a dual imprinting from both the ongoing inflammation and the macrophage niche. This results in inflammation-imprinted resident macrophages, and we speculate that rewired niche circuits could maintain this inflammatory state. We believe that this revisited plasticity model offers opportunities to reset the macrophage pool after a severe inflammatory episode.


Assuntos
Plasticidade Celular , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia/imunologia , Animais , Microambiente Celular , Epigênese Genética , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Fenótipo , Pneumonia/genética , Pneumonia/metabolismo , Transdução de Sinais
5.
Nat Immunol ; 22(3): 279-286, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495652

RESUMO

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.


Assuntos
Anticorpos/metabolismo , Bactérias/metabolismo , Cresóis/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiologia , Pulmão/metabolismo , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Ésteres do Ácido Sulfúrico/metabolismo , Tirosina/metabolismo , Administração Oral , Alérgenos , Animais , Anticorpos/imunologia , Diversidade de Anticorpos , Bactérias/imunologia , Células Cultivadas , Quimiocina CCL20/metabolismo , Técnicas de Cocultura , Cresóis/administração & dosagem , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Injeções Intravenosas , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/microbiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/microbiologia , Transdução de Sinais , Ésteres do Ácido Sulfúrico/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Tirosina/administração & dosagem
6.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33300070

RESUMO

Pneumonia accounts for ~1.3 million mortalities in children per year worldwide. MicroRNAs are implicated in several diseases, including cancer and pneumonia; however, the role of let7f­5p in pneumonia is not completely understood. In the present study, lipopolysaccharide (LPS) was used to establish an in vitro pneumonia model in A549 and WI­38 cells. The reverse transcription­quantitative PCR (RT­qPCR) and western blotting results demonstrated that let7f­5p expression levels were significantly decreased, whereas MAPK6 expression levels were significantly increased in the peripheral venous blood of patients with pneumonia and in LPS­induced A549 and WI­38 cells compared with healthy volunteers and control cells, respectively. Furthermore, the dual­luciferase reporter assay demonstrated that let7f­5p targeted the 3'­untranslated region of MAPK6. The ELISA and RT­qPCR results demonstrated that let7f­5p mimic ameliorated LPS­induced inflammatory injury in A549 and WI­38 cells, as demonstrated by decreased expression levels of proinflammatory cytokines, including TNF­α and IL­6. In addition, the Cell Counting Kit­8 assay results indicated that let7f­5p mimic ameliorated LPS­induced reductions in cell viability, and the western blotting results demonstrated that let7f­5p mimic reversed LPS­induced activation of the STAT3 signaling pathway. Notably, the aforementioned let7f­5p­mediated effects were reversed by MAPK6 overexpression. Collectively, the results of the present study suggested that let7f­5p inhibited inflammation by targeting MAPK6 in the in vitro pneumonia model, thus let7f­5p may serve as a potential novel therapeutic target for pneumonia.


Assuntos
Lesão Pulmonar/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Pneumonia/metabolismo , Células A549 , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Inflamação , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Masculino , MicroRNAs/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Pneumonia/genética , Pneumonia/patologia
7.
Nanotoxicology ; 15(2): 238-256, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33332178

RESUMO

Inhalation of multi-walled carbon nanotubes (MWCNTs) induces lung inflammation. Depending on industrial applications, CNTs with different physicochemical characteristics are produced and workers can potentially be exposed. This raises concerns about the long-term health effects of these nanomaterials. Because of the wide variety of MWCNTs, it is essential to study the toxicological effects of CNTs of various shapes and to better understand the impact physical and chemical properties have on their toxicity. In this study, rats were exposed by nose-only to two pristine MWCNTs with different morphologies: the long and thick NM-401 or the short and thin NM-403. After four weeks of inhalation, animals were euthanized at four different times during the recovery period: three days (short-term), 30 and 90 days (intermediate-term) and 180 days (long-term). Analyses of the transcriptome in the whole lung and the proteome in the bronchoalveolar lavage fluid of exposed animals were performed to understand the MWCNT underlying mechanisms of toxicity. Following inhalation of NM-401, we observed a dose-dependent increase in the number of differentially expressed genes and proteins, whereas there is no clear difference between the two concentrations of NM-403. After NM-403 inhalation, the number of differentially expressed genes and proteins varied less between the four post-exposure times compared to NM-401, which supports the postulation of a persistent effect of this type of CNT. Our toxicogenomics approaches give insights into the different toxicological profile following MWCNT exposure.


Assuntos
Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Pneumonia/induzido quimicamente , Proteoma/metabolismo , Transcriptoma/efeitos dos fármacos , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Nanotubos de Carbono/química , Pneumonia/metabolismo , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Toxicogenética
8.
Molecules ; 25(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371364

RESUMO

Diesel exhaust particulates (DEP) have adverse effects on the respiratory system. Endoplasmic reticulum (ER) abnormalities contribute to lung inflammation. However, the relationship between DEP exposure and ER stress in the respiratory immune system and especially the alveolar macrophages (AM) is poorly understood. Here, we examined ER stress and inflammatory responses using both in vivo and in vitro study. For in vivo study, mice were intratracheally instilled with 25, 50, and 100 µg DEP and in vitro AM were stimulated with DEP at 1, 2, and 3 mg/mL. DEP increased lung weight and the number of inflammatory cells, especially neutrophils, and inflammatory cytokines in bronchoalveolar lavage fluid of mice. DEP also increased the number of DEP-pigmented AM and ER stress markers including bound immunoglobulin protein (BiP) and CCAAT/enhancer binding protein-homologous protein (CHOP) were upregulated in the lungs of DEP-treated mice. In an in vitro study, DEP caused cell damage, increased intracellular reactive oxygen species, and upregulated inflammatory genes and ER stress-related BiP, CHOP, splicing X-box binding protein 1, and activating transcription factor 4 expressions in AM. Furthermore, DEP released the C-X-C Motif Chemokine Ligand 1 (CXCL1/KC) in AM. In conclusion, DEP may contribute to neutrophilic lung inflammation pathogenesis by modulating ER stress-mediated CXCL1/KC expression in AM.


Assuntos
Quimiocina CXCL1/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Material Particulado/efeitos adversos , Pneumonia/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Feminino , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Pneumonia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Fator de Transcrição CHOP/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/ética , Emissões de Veículos
9.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33352854

RESUMO

Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 µg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants.


Assuntos
Fumarato de Dimetilo/farmacologia , Estresse Oxidativo , Pneumonia/etiologia , Pneumonia/metabolismo , Emissões de Veículos , Poluentes Atmosféricos/efeitos adversos , Animais , Biomarcadores , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , NF-kappa B/metabolismo , Oxirredução , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Emissões de Veículos/toxicidade
10.
PLoS One ; 15(11): e0241663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147270

RESUMO

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.


Assuntos
Infecções por Coronavirus/patologia , Doenças do Sistema Digestório/patologia , Doenças do Sistema Digestório/virologia , Hepatopatias/patologia , Hepatopatias/virologia , Pneumonia Viral/patologia , Pneumonia/patologia , Pneumonia/virologia , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , Doenças do Sistema Digestório/metabolismo , Feminino , Seguimentos , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença
11.
J Pharmacol Sci ; 144(4): 189-196, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070837

RESUMO

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.


Assuntos
Diterpenos/administração & dosagem , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fitoterapia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Poli I-C/efeitos adversos , Animais , Citocinas/sangue , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia Viral/tratamento farmacológico
12.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913008

RESUMO

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.


Assuntos
Antivirais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Vimentina/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Regulação para Baixo , Descoberta de Drogas/métodos , Humanos , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptores Virais , Replicação Viral/fisiologia
13.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
14.
Mol Immunol ; 125: 24-31, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32623292

RESUMO

Toll-like receptor 9 (TLR9) has been reported to mediate airway inflammation, however, the underlying mechanism is poorly understood. In the present study, our objective was to reveal whether TLR9 regulates NLRP3 inflammasome and oxidative stress in murine allergic airway inflammation and Raw264.7 cells. Female wild type(WT)and TLR9-/-mice on C57BL/6 background were used to induce allergic airway inflammation by challenge of OVA, and Raw264.7 cells with or without TLR9 knockdown by small interfering RNA (siRNA) were stimulated by S.aureus. The results demonstrated that deletion of TLR9 effectively attenuated OVA-induced allergic airway inflammation including inflammatory cells infiltration and goblet cell hyperplasia. Meanwhile, OVA-induced protein expression of NLRP3, caspase-1(p20) and mature IL-1ß, as well as secretion of IL-1ß and IL-18 in wild type mice (WT) was obviously suppressed by TLR9 deficiency. Concomitantly, the expression of oxidative markers 8-OhDG and nitrotyrosine was increased in OVA-challenged WT mice, while TLR9 deficiency significantly inhibited such increase. Similarly, in the in vitro study, we found that knockdown of TLR9 markedly suppressed S.aureus-induced activation of NLRP3 inflammasome and oxidative stress in Raw264.7 cells. Collectively, our findings indicated that TLR9 may mediate allergic airway inflammation via activating NLRP3 inflammasome and oxidative stress.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Estresse Oxidativo/fisiologia , Receptor Toll-Like 9/imunologia , Animais , Asma/metabolismo , Hipersensibilidade/metabolismo , Hipersensibilidade/fisiopatologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Células RAW 264.7 , Receptor Toll-Like 9/metabolismo
15.
Mol Carcinog ; 59(9): 1088-1099, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673443

RESUMO

Manganese superoxide dismutase (SOD-2), an important primary antioxidant enzyme located in mitochondria, plays a critical role in tumor progression. Reportedly, the proinflammatory cytokine, tumor necrosis factor (TNF)-α, can increase SOD-2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF-α-mediated inflammation may regulate SOD-2 expression, which may be related to cancer promotion. Using a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mice model, we investigated whether and how TNF-α-mediated inflammation upregulated SOD-2 expression in lung adenocarcinoma. Our results showed that SOD-2 was mostly expressed on surfactant protein-C+ AT-II cells (alveolar type II cell) and tumor cells in IDLA mice, which were surrounded by CD68+ macrophages. Blocking TNF-α-dependent inflammation downregulated SOD-2 expression in inflamed lung tissues at the protumor stage and also inhibited SOD-2 expression in tumor cells in the IDLA model. In human lung adenocarcinoma, both the number of infiltrating CD68+ macrophages and TNF-α expression correlated positively with SOD-2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharide-activated phorbol myristate acetate-induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1-M1 upregulated SOD-2 by secreting TNF-α. Blocking SOD-2 expression significantly inhibited TNF-α-induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF-α-mediated lung inflammation can upregulate SOD-2 expression in lung adenocarcinoma, and macrophages contribute to SOD-2 upregulation by secreting TNF-α.


Assuntos
Adenocarcinoma de Pulmão/patologia , Proliferação de Células , Neoplasias Pulmonares/patologia , Pneumonia/complicações , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Uretana/toxicidade , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Apoptose , Carcinógenos/toxicidade , Citocinas , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Células Tumorais Cultivadas
16.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32584597

RESUMO

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Assuntos
Reação de Fase Aguda/imunologia , Proteínas de Transporte/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Proteínas de Membrana/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Hormônios Tireóideos/metabolismo , alfa 1-Antitripsina/imunologia , Reação de Fase Aguda/metabolismo , Adulto , Idoso , Betacoronavirus , Western Blotting , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Estado Terminal , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pandemias , Fosforilação , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Índice de Gravidade de Doença , alfa 1-Antitripsina/metabolismo
18.
Respir Res ; 21(1): 154, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552811

RESUMO

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.


Assuntos
Infecções por Coronavirus/epidemiologia , Sistemas Eletrônicos de Liberação de Nicotina , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia/metabolismo , Vaping/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Gasometria , Western Blotting , Líquido da Lavagem Broncoalveolar , Citocinas/análise , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pandemias , Pneumonia/fisiopatologia , Distribuição Aleatória , Valores de Referência , Papel (figurativo) , Síndrome Respiratória Aguda Grave/epidemiologia , Transdução de Sinais/genética
19.
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
20.
Toxicol Lett ; 331: 92-101, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32446815

RESUMO

Aflatoxin G1 (AFG1) is a member of the carcinogenic aflatoxin family. Our previous studies indicated that oral administration of AFG1 caused tumor necrosis factor (TNF)-α-dependent inflammation that enhanced oxidative DNA damage in alveolar epithelial cells, which may be related to AFG1-induced lung carcinogenesis. High mobility group box-1 (HMGB1) is a nuclear DNA-binding protein; the intracellular and extracellular roles of HMGB1 have been shown to contribute to DNA repair and sterile inflammation. The role of HMGB1 in DNA damage in an aflatoxin-induced lung inflammatory environment was investigated in this study. Upregulation of HMGB1, TLR2, and RAGE was observed in AFG1-induced lung inflamed tissues and adenocarcinoma. Blocking AFG1-induced inflammation by neutralization of TNF-α inhibited the upregulation of HMGB1 in mouse lung tissues, suggesting that AFG1-induced TNF-α-dependent inflammation regulated HMGB1 expression. In the in vitro human pulmonary epithelial cell line model, Beas-2b, AFG1 directly enhanced the cytosolic translocation of HMGB1 and its extracellular secretion. The addition of extracellular soluble HMGB1 protected AFG1-induced DNA damage through the TLR2/NF-κB pathway in Beas-2b cells. In addition, blockade of endogenous HMGB1 by siRNA significantly enhanced AFG1-induced damage. Thus, our findings showed that both extracellularly-released and nuclear and cytosolic HMGB1 could protect the cell from AFG1-induced cell damage in a TNF-α-dependent lung inflammatory environment.


Assuntos
Adenocarcinoma/patologia , Aflatoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Proteína HMGB1/metabolismo , Neoplasias Pulmonares/patologia , Pulmão/efeitos dos fármacos , Pneumonia/patologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Proteína HMGB1/genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , RNA Interferente Pequeno/genética
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