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1.
Nat Immunol ; 21(2): 135-144, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932813

RESUMO

The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.


Assuntos
Ritmo Circadiano/imunologia , Inflamação/metabolismo , Neutrófilos/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Animais , Degranulação Celular/imunologia , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/metabolismo , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/imunologia , Camundongos , Neutrófilos/imunologia , Pneumonia/complicações , Pneumonia/imunologia , Proteoma/imunologia , Proteoma/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia
2.
Immunology ; 159(2): 156-166, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31631335

RESUMO

Host-microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture-dependent and -independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung.


Assuntos
Disbiose , Pulmão/microbiologia , Microbiota , Pneumonia/microbiologia , Imunidade Adaptativa , Animais , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Pulmão/imunologia , Pulmão/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo
3.
Immunology ; 159(1): 121-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606895

RESUMO

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of the response and function of myeloid cells in hypoxic and inflammatory microenvironments. To define the role of HIF-1α in tuberculosis, the progression of aerosol Mycobacterium tuberculosis infection was analysed in mice deficient in HIF-1α in the myeloid lineage (mHIF-1α-/- ). We show that myeloid HIF-1α is not required for the containment of the infection, as both wild-type (WT) and mHIF-1α-/- mice mounted normal Th1 responses and maintained control of bacterial growth throughout infection. However, during chronic infection mHIF-1α-/- mice developed extensive lymphocytic inflammatory involvement of the interstitial lung tissue and died earlier than WT mice. These data support the hypothesis that HIF-1α activity coordinates the response of myeloid cells during M. tuberculosis infection to prevent excessive leucocyte recruitment and immunopathological consequences to the host.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células Mieloides/metabolismo , Pneumonia/metabolismo , Tuberculose Pulmonar/metabolismo , Animais , Carga Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Interações Hospedeiro-Patógeno , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/microbiologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
4.
Immunity ; 51(5): 899-914.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31732166

RESUMO

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.


Assuntos
Suscetibilidade a Doenças , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Biomarcadores , Contagem de Células , Suscetibilidade a Doenças/imunologia , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Isquemia/etiologia , Isquemia/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Células Musculares/imunologia , Células Musculares/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/patologia
5.
Toxicol Lett ; 317: 59-67, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577921

RESUMO

Toluene-diisocyanate (TDI) is mainly used in the manufacturing process of polyurethane foams, and is a potent inducer of occupational asthma characterized by airway inflammation and airway hyperreactivity. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of asthma, and correlating with the differentiation of Th2 and Th17 cells. However, the role of TSLP in TDI-induced asthma remains unclear. In this study, 96 TDI-exposed workers as well as a mouse model of TDI-induced asthma were investigated. The air exposure assessment result of TDI in the workplace showed that workers were exposed to inhalation of a very high concentration of TDI, approximately 8 times the recommended level, leading to a decrease in pulmonary function and an increase in inflammatory cells, as well as TSLP and IgE levels in the supernatant of sputum obtained from exposed workers. In order to further investigate the role of TSLP in the pathogenesis of TDI-induced asthma, a mouse model of TDI-induced asthma was also employed. Histopathological analysis of mouse lung and bronchus showed an obvious infiltration of inflammatory cells around the bronchus. The levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in bronchoalveolar lavage fluid (BALF), the expression levels of TSLP protein and ROR-γt and IL-17 mRNA in mouse lung tissues were also significantly increased. However, after treatment with TSLP neutralizing antibody (TSLP-Ab), the degree of pulmonary and bronchial inflammation in mice was significantly alleviated, and the levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in BALF, and the expression levels of ROR-γt and IL-17 mRNA in lung tissue were significantly decreased. Our data shows that TSLP plays an important role in the pathogenesis of TDI-induced asthma, and that TSLP-Ab can effectively alleviate TDI-induced airway inflammation of asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos Neutralizantes/farmacologia , Asma/prevenção & controle , Citocinas/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pneumonia/prevenção & controle , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunoglobulina E/imunologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Exposição por Inalação/efeitos adversos , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Ecotoxicol Environ Saf ; 185: 109687, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561077

RESUMO

Chronic inflammation has been shown to play a vital role in lung tumorigenesis. Recently, we have successfully developed a C57BL/6 mouse model of inflammation-related lung tumorigenesis induced by benzo(a)pyrene [B(a)p] and lipopolysaccharide (LPS), which will contribute to better understand the association between pulmonary inflammation and cancer. In this study, we aim to explore the role of NLRP3 and NLRP6 inflammasome in lung tumorigenesis in the animal model that we set up previously. Levels of NLRP3, NLRP6, interleukin-1ß (IL-1ß) and IL-18 protein in lung tissues were detected by using immunohistochemistry. The co-localization of NLRP3 or NLRP6 with caspase-1 was examined using immunofluorescence and confocal. Western blotting was used to evaluate the levels of caspase-1 p10 and cleaved-IL-1ß protein. The expression of IL-18 in bronchoalveolar lavage fluid (BALF) was measured using ELISA kit. The expression of NLRP3, NLRP6 and IL-18 protein in the lung tissues of mice exposed to B(a)p plus LPS was upregulated significantly compared with those in Vehicle control group. Immunofluorescent results indicated the co-localization of NLRP3 with caspase-1 was increased in the lung tissues of LPS-, B(a)p- or B(a)p plus LPS-exposed mice than that in Vehicle control group, but no co-localization of NLRP6 with caspase-1. Additionally, caspase-1 activation was induced, cleaved-IL-1ß in lung tissues and IL-18 protein in BALF were increased in B(a)p plus LPS-exposed mice compared with those in B(a)p group. In conclusion, our results from this study demonstrate that NLRP3 inflammasome, not NLRP6 inflammasome, activation is involved in B(a)p plus LPS-induced inflammation-related lung tumorigenesis in mice, but the mechanisms of NLRP6 participate in the development of lung cancer should be further investigated.


Assuntos
Benzo(a)pireno/toxicidade , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Neoplasias Pulmonares/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/imunologia , Receptores de Superfície Celular/metabolismo , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo
7.
Nutrients ; 11(9)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470503

RESUMO

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Isoflavonas/farmacologia , Pulmão/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumaça , Produtos do Tabaco , beta-Glucanas/farmacologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais
8.
Ulus Travma Acil Cerrahi Derg ; 25(5): 433-439, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31475327

RESUMO

BACKGROUND: Pulmonary contusion (PC) is an important life-threatening clinical condition characterized by lung injury and inflammation. Caffeic acid phenethyl ester (CAPE) is a biological agent with potent antioxidant and anti-inflammatory effects. This study aimed to investigate the potential effects of CAPE on tissue damage, nuclear factor kappa-beta (Nf-κß) activity, inducible nitric oxide synthase (iNOS) synthesis, and pulmonary apoptosis in an experimental PC model. METHODS: Forty adult Wistar albino rats were used in this study and divided into four groups as follows: control, PC, PC + CAPE, and CAPE. CAPE was administered intraperitoneally for seven days following PC formation (10 µmol/kg, dissolved in dimethyl sulfoxide). Wet/dry weight ratio in lung tissue was determined. The pulmonary tissue was examined using hematoxylin-eosin and Masson's trichrome histochemical staining and also by scanning electron microscopy. Nf-κß and iNOS activities in the lungs were determined by the indirect immunohistochemical method. Pulmonary apoptosis was detected by the TUNEL method. RESULTS: Increased leukocyte infiltration score, pulmonary edema, alveolar damage, and increased Nf-κß and iNOS activities were determined in the PC group. CAPE administration inhibited Nf-κß and iNOS activities and pulmonary apoptosis. CONCLUSION: In this study, the findings showed that CAPE inhibited tissue damage by suppressing inflammatory mediators of Nf-κß and iNOS activities. Also, CAPE was found to be protective in the lung tissue and could be used as a therapeutic agent.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Lesão Pulmonar/metabolismo , NF-kappa B/metabolismo , Álcool Feniletílico/análogos & derivados , Pneumonia/metabolismo , Animais , Álcool Feniletílico/farmacologia , Ratos , Ratos Wistar
9.
Mediators Inflamm ; 2019: 3427053, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379467

RESUMO

Occupational exposure to crystalline silica (CS) results in a persistent pulmonary inflammatory response that eventually leads to abnormal tissue repair, disability, and death. The inflammatory-immune responses occur in the early stages of CS exposure, and both innate and adaptive immunity are involved. CD4+ T cells play a pivotal role in the pathogenesis of CS-induced pulmonary disease, which has no proven curative therapy. Dihydrotanshinone I (DHI), a natural product isolated from Salvia miltiorrhiza Bunge (Danshen), has anti-inflammatory and immunomodulatory properties. However, whether DHI has a protective effect on CS-induced lung disease, how it influences the Th immune response, and the potential underlying molecular mechanism(s) have not been fully clarified. In this study, DHI treatment of CS-exposed mice reduced the expression of proinflammatory cytokines and the infiltration of immune cells. It significantly ameliorated CS-induced pulmonary inflammation by attenuating T helper (Th)1 and Th17 responses, which were tightly related to the inhibition of STAT1 and STAT3. DHI significantly altered Th2 cytokines but not the Th2 nuclear transcription factor. Furthermore, our study found that DHI treatment also affected regulatory T cell activity in CS-injured mice. Taken together, our findings indicated that DHI could modulate Th responses and alleviate CS-induced pulmonary inflammation, suggesting a novel application of DHI in CS-induced pulmonary disease.


Assuntos
Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Dióxido de Silício/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Feminino , Citometria de Fluxo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo
10.
Med Sci Monit ; 25: 6193-9203, 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31422413

RESUMO

BACKGROUND Recent studies have proved that autophagy dysfunction in proinflammatory cells is involved in tissue damage and an excessive inflammatory response in sepsis. In the present study, we identified that the human antimicrobial peptide LL-37 facilitates resistance to DNase II-induced mitochondrial DNA (mtDNA) degradation and subsequent autophagy. MATERIAL AND METHODS We found higher serum levels of LL-37 in patients with severe sepsis compared to that in patients with mild sepsis. Neutrophils isolated from mice with sepsis after treatment with Cramp-mtDNA produced an excess of proinflammatory cytokines, including IL-1ß, IL-6, IL-8, MMP-8, and TNF-alpha. Cramp-mtDNA in the lung samples from model animals with sepsis was detected by immunohistochemical staining. RESULTS Exogenous delivery of Cramp-mtDNA complex significantly exacerbated lung inflammation but the antibody against Cramp-mtDNA attenuated the excessive inflammatory response in LPS-induced acute lung injury. The expression of proinflammatory cytokines in lungs was upregulated and downregulated after treatment with the complex and antibody, respectively. LC-3 expression in 16HBE cells increased after LPS induction, irrespective of stimulation with LL-37. CONCLUSIONS These data show that LL-37 treatment worsens local inflammation in sepsis-induced acute lung injury by preventing mtDNA degradation-induced autophagy.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Peptídeos Catiônicos Antimicrobianos/sangue , DNA Mitocondrial/farmacologia , Sepse/sangue , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Autofagia , Pré-Escolar , Citocinas/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/isolamento & purificação , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Inflamação/sangue , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Pneumonia/metabolismo , Sepse/patologia
11.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426531

RESUMO

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.


Assuntos
Apoptose , Células Epiteliais/metabolismo , Gefitinibe/efeitos adversos , Lesão Pulmonar/metabolismo , Pneumonia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Receptores ErbB/metabolismo , Gefitinibe/uso terapêutico , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Animais , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Crescimento Transformador alfa , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
PLoS Pathog ; 15(8): e1007989, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412088

RESUMO

Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Interleucina-2/metabolismo , Infecções por Orthomyxoviridae/imunologia , Pneumonia/imunologia , Animais , Feminino , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Pneumonia/metabolismo , Pneumonia/virologia
13.
Ecotoxicol Environ Saf ; 183: 109500, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450033

RESUMO

Exposure to diesel engine exhaust (DEE) impairs lung function. But the underlying mechanisms are still not fully understood. The aim of this study was to investigate the effects of long-term DEE exposure on lung inflammation and the underlying mechanisms. Sprague-Dawley male rats were exposed to DEE with 3 mg/m3 of diesel exhaust particles (DEP) for 12 weeks. Then urine, blood, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for the determination of biochemistry indexes, DNA methylation status, and histological changes in the lung. The results showed that the metabolites of polycyclic aromatic hydrocarbons (PAHs) 2-hydroxyphenanthrene (2-OHPh) and 9-OHPh, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) level were higher in urine of DEE-exposed rats than control group. The level of proinflammatory cytokines IL-8, IL-6, and TNF-α was significantly higher in serum (1.8, 3.5, and nearly 1.0-fold increase, respectively), BALF (2.2, 3.8, and 2.0-fold increase, respectively) and lung tissues (3.5, 4.3, and 2.4-fold increase, respectively) of DEE-exposed rats than control group. While the level of clara cell secretory protein (CC16) and pulmonary surfactant protein D (SP-D) with anti-inflammatory property was obviously lower in serum (reduction of 29% and 38%, respectively), BALF (reduction of 50% and 46%, respectively) and lung tissues (reduction of 50% and 55%, respectively) of DEE-exposed rats than control group. Exposure to DEE also resulted in significant increases in total white blood cell (WBC), neutrophil, eosinophil, and lymphocyte number in BALF. Airway inflammation and remolding were apparent in DEE group. The methylation level of CCAAT/enhancer-binding protein alpha (C/EBPα) promoter was markedly increased (about 3.2-fold increase), and its mRNA and protein expression were significantly decreased (about 62% and 68% decrease, respectively) in the lungs of DEE-exposed rats compared with the group. Further, cell experiments were performed to investigate the relationship between C/EBPα and CC16, and CC16 function under DEP conditions. The results showed that DEP inhibited CC16 expression via methylation of C/EBPα promoter, and the increase of CC16 level significantly relieved the proinflammatory effects caused by DEP exposure. In conclusion, our data indicated that long-term exposure to DEE can cause lung inflammation, at least in part via methylation of C/EBPα promoter, and inhibition of CC16 expression.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Exposição por Inalação/efeitos adversos , Pneumonia/induzido quimicamente , Emissões de Veículos/toxicidade , Animais , Citocinas/metabolismo , Metilação de DNA/efeitos dos fármacos , Masculino , Pneumonia/metabolismo , Pneumonia/patologia , Hidrocarbonetos Policíclicos Aromáticos/urina , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Uteroglobina/genética , Uteroglobina/metabolismo
14.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 827-831, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441404

RESUMO

OBJECTIVE: To evaluate the predictive value of neutrophil to lymphocyte ratio (NLR) on 28-day mortality of patients with severe pneumonia. METHODS: The clinical data of 214 severe pneumonia patients admitted to the department of emergency medicine of the First Affiliated Hospital of Xi'an Jiao Tong University from January 2015 to December 2018 were retrospectively analyzed. The clinical parameters, such as gender, age, underlying diseases, and blood routine, procalcitonin (PCT), liver and kidney function, blood lactic acid (Lac), arterial partial pressure of oxygen (PaO2) at admission or within 24 hours after admission were reviewed. NLR, oxygenation index (PaO2/FiO2) and acute physiology and chronic health evaluation II (APACHE II) were calculated, and the change tendency of each index within 3 days after admission were observed. The patients were divided into survival group and death group according to 28-day outcomes. Multivariate Logistic regression analysis was used to screen the high risk factors of 28-day mortality in patients with severe pneumonia. Receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of NLR for 28-day mortality risk in patients with severe pneumonia. RESULTS: 214 patients were enrolled in the analysis, 132 survived in 28 days and 82 died. Compared with survival group, the white blood cell (WBC), neutrophil (NEU), NLR, PCT, Lac and APACHE II scores were significantly increased, and lymphocyte (LYM) was significantly decreased in the death group. There was no significant difference in gender, age, basic diseases, platelet count (PLT), liver and kidney function parameters, or PaO2/FiO2 between the two groups. The NLR, PCT, Lac and APACHE II score in the death group were increased gradually within 3 days after admission, PaO2/FiO2 was decreased gradually, which showed significant differences as compared with survival group at 3 days after admission [NLR: 27.15±7.61 vs. 14.66±4.83, PCT (µg/L): 13.52±3.22 vs. 6.41±4.22, Lac (mmol/L): 6.78±1.70 vs. 2.74±1.15, APACHE II score: 37.76±5.30 vs. 22.11±4.94, PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 114.12±20.16 vs. 186.49±13.95, all P < 0.05]. Multiple Logistic regression analysis showed that NLR [odds ratio (OR) = 1.163, 95% confidence interval (95%CI) = 1.007-1.343, P = 0.040], PCT (OR = 1.210, 95%CI = 1.098-1.333, P = 0.001), Lac (OR = 1.263, 95%CI = 1.011-1.579, P = 0.040) and APACHE II score (OR = 1.103, 95%CI = 1.032-1.179, P = 0.004) were the independent risk factors of 28-day mortality in the patients with severe pneumonia. ROC curve analysis showed that compared with the traditional indicators including PCT, Lac, and APACHE II score, NLR showed a good predictive value for 28-day mortality in the patients with severe pneumonia [area under ROC curve (AUC): 0.791 vs. 0.707, 0.690, 0.720]. When the optimal cut-off value of NLR was 14.92, the sensitivity was 71.95% and the specificity was 73.48%, meanwhile, the positive likelihood ratio was 2.713 and the negative likelihood ratio was 0.382. CONCLUSIONS: The increased NLR at admission is a high risk factor of 28-day mortality in patients with severe pneumonia, which is useful for predicting prognosis of patients with severe pneumonia.


Assuntos
Neutrófilos , Pneumonia/mortalidade , APACHE , Humanos , Linfócitos , Pneumonia/metabolismo , Prognóstico , Curva ROC , Estudos Retrospectivos
15.
Mol Med Rep ; 20(4): 3347-3354, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432172

RESUMO

Ulinastatin, a urinary trypsin inhibitor (UTI) is commonly used to treat patients with acute inflammatory disease. However, the underlying mechanisms of its anti­inflammatory effect in acute lung injury (ALI) are not fully understood. The present study aimed to investigate the protective effect of UTI and explore its potential mechanisms by using a rat model of lipopolysaccharide (LPS)­induced ALI. Rats were treated with 5 mg/kg LPS by intratracheal instillation. The histological changes in LPS­induced ALI was evaluated using hematoxylin and eosin staining and the myeloperoxidase (MPO) activity was determined using ELISA. The wet/dry ratio (W/D ratio) of the lungs was used to assess the severity of pulmonary edema and Evans blue dye was used to evaluate the severity of lung vascular leakage. The results demonstrated that LPS administration induced histological changes and significantly increased the lung W/D ratio, MPO activity and Evans blue dye extravasation compared with the control group. However, treatment with UTI attenuated LPS­induced ALI in rats by modifying histological changes and reducing the lung W/D ratio, MPO activity and Evans blue dye extravasation. In addition, LPS induced the secretion of numerous pro­inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor­α, interleukin (IL)­6, IL­1ß and interferon­Î³; however, these cytokines were strongly reduced following treatment with UTI. In addition, UTI was able to reduce cellular counts in BALF, including neutrophils and leukocytes. Western blotting demonstrated that UTI significantly blocked the LPS­stimulated MAPK and NF­κB signaling pathways. The results of the present study indicated that UTI could exert an anti­inflammatory effect on LPS­induced ALI by inhibiting the MAPK and NF­κB signaling pathways, which suggested that UTI may be considered as an effective drug in the treatment of ALI.


Assuntos
Glicoproteínas/farmacologia , Lipopolissacarídeos/toxicidade , Lesão Pulmonar , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pneumonia , Animais , Citocinas/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , NF-kappa B/metabolismo , Peroxidase/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Ratos , Ratos Sprague-Dawley
16.
J Pharmacol Sci ; 140(3): 228-235, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31358372

RESUMO

Acute lung injury (ALI) results from various factors including uncontrolled pulmonary inflammation, oxidative damage and the over-activated complement with high mortality rates. Jaceosidin was a flavonoid compound with significant anti-complement activity. We aimed to investigate the therapeutic effects of Jaceosidin on ALI induced by lipopolysaccharide (LPS). Mice were orally administrated with Jaceosidin (15, 30 and 60 mg/kg) after LPS challenge. 24 h after LPS challenge, Jaceosidin could significantly decrease the lung wet-to-dry weight (W/D) ratio and the protein concentration in bronchoalveolar lavage fluid (BALF). Jaceosidin could down-regulate the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), together with up-regulation the levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) in BALF. Jaceosidin could significantly decrease the levels of myeloperoxidase (MPO), cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB), COX-2 mRNA and NF-κB p65 mRNA together with increasing the activity of catalase (CAT). Additionally, Jaceosidin attenuated lung histopathological changes, inhibited the expressions of COX-2 and NF-κB p65 and reduced complement deposition with decreasing the levels of complement 3 (C3) and complement 3c (C3c) in serum. These data suggest that Jaceocidin may dampen the inflammatory response and decrease the levels of complement together with the antioxidant activity following LPS-induced ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Flavonoides/farmacologia , Lipopolissacarídeos/farmacologia , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Ciclo-Oxigenase 2/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Peroxidase/metabolismo , Extratos Vegetais/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Oxid Med Cell Longev ; 2019: 7450151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281589

RESUMO

Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.


Assuntos
Material Particulado/toxicidade , Pneumonia/etiologia , Hipersensibilidade Respiratória/etiologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Acrilamidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oximas/farmacologia , Tamanho da Partícula , Pneumonia/metabolismo , Pneumonia/patologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese
18.
Psychiatr Prax ; 46(5): 287-289, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31269521

RESUMO

Systemic infections are known to alter the metabolism of various drugs via inhibition of the cytochrome P450 family. Here, we report the cases of two patients with schizophrenic psychosis and highly elevated clozapine levels during pulmonary systemic infection, however without experiencing side effects. After antibiotic treatment and temporary reduction of clozapine dosage blood levels of clozapine normalized within a few days. These cases show that clozapine levels may be highly elevated without necessarily causing side effects and that intensified pharmacovigilance should be considered by the clinician in patients with systemic infections.


Assuntos
Clozapina , Pneumonia/metabolismo , Antipsicóticos/farmacocinética , Clozapina/farmacocinética , Alemanha , Humanos , Transtornos Psicóticos/tratamento farmacológico
19.
Inflammation ; 42(5): 1886-1900, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359324

RESUMO

Chicken fat and fructose are added into food-processing to reduce costs and enhance acceptability; however, these additives turn food into unhealthy and hypercaloric meals. Herein we have hypothesized that chronic feeding with chicken fat and fructose, together or by separate, can cause pulmonary redox and inflammatory changes. These changes are particularly related to neutrophils and myeloperoxidase, with consequent changes in the organ histophysiology. To test this hypothesis, we fed mice for 16 weeks with either control food (low-fat diet, LFD) or control food supplemented with 22% chicken fat and with or without 10% fructose in the drinking water. At the end of the feeding regimen, we measured redox and inflammatory changes in the lung with particular emphasis on neutrophil accumulation/activation and molecular-histological markers of fibrosis. Our results suggest that a diet supplemented with chicken fat and fructose causes additive effects on pulmonary oxidative stress, inflammation, and a pro-fibrotic status. Neutrophilic inflammation may play a critical role in pulmonary pathology associated with metabolic syndrome.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fibrose/etiologia , Neutrófilos/patologia , Pneumonia/etiologia , Animais , Inflamação/etiologia , Pulmão/metabolismo , Camundongos , Oxirredução , Estresse Oxidativo , Pneumonia/metabolismo , Pneumonia/patologia
20.
Environ Pollut ; 253: 507-515, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330343

RESUMO

Black carbon (BC) can combine with organic matter and form secondary pollutants known as aged BC. BC and aged BC can cause respiratory system inflammation and induce lesions at relevant sites, but the underlying mechanism has remained unknown. To gain insight into the potential mechanisms, we focused on macrophages and transforming growth factor ß-activated kinase 1 (TAK1) which are a crucial factor in inflammation. Our research aims to determine the role of TAK1 in macrophages in pulmonary inflammation induced by particulate matter. In this study, BC and 1,4-naphthoquinone were mixed to model aged BC (1,4NQ-BC) in atmosphere. BC induced mice lung inflammation model, lung macrophage knock-down TAK1 animal model and primary macrophage knock-down TAK1 model were used to explore whether TAK1 in macrophage is a critical role in the process of inflammation. The results showed that the expressions of inflammatory cytokines (IL-1ß, IL-6, IL-33) mRNA were significantly increased and the phosphorylation of MAPK and NF-κB signaling pathway related proteins were enhanced in RAW 264.7 cell lines. In vivo studies revealed that the indicators of pulmonary inflammation (pathology, inflammatory cell numbers) and related cytokines (IL-1ß, IL-6, IL-33) mRNA expressions in CD11c-Map3k7-/- animals were significantly lower than wild-type animals after mice were instilled particles. In mice primary macrophages, the expressions of IL-6, IL-33 mRNA were inhibited after TAK1 gene was knock-down. These results unequivocally demonstrated that TAK1 plays a crucial role in BC induced lung inflammation in mice, and we can infer that BC and 1,4NQ-BC cause these inflammatory responses by stimulating pulmonary macrophages.


Assuntos
Poluentes Atmosféricos/toxicidade , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pneumonia/induzido quimicamente , Fuligem/toxicidade , Animais , Carbono/metabolismo , Citocinas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação , Pneumonia/metabolismo , Células RAW 264.7
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