Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.805
Filtrar
1.
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
2.
Cancer Immunol Immunother ; 69(1): 15-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31745589

RESUMO

The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Doenças Pulmonares Intersticiais/complicações , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Incidência , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Pneumonia/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Fatores de Tempo
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.
Rev Med Chil ; 147(8): 983-992, 2019 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-31859962

RESUMO

BACKGROUND: C-reactive protein (CRP) is used to monitor patients' response during treatment of infectious diseases. Morbidity and mortality associated with community-acquired pneumonia (CAP) is high, particularly in hospitalized patients. Better risk prediction during hospitalization could improve management and ultimately reduce mortality rates. AIM: To evaluate CRP measured at admission and the third day of hospitalization as a predictor for adverse events in CAP. MATERIAL AND METHODS: A prospective cohort study of adult patients hospitalized with CAP at an academic hospital. Major adverse outcomes were admission to ICU, mechanical ventilation, prolonged hospital length of stay, hospital complications and 30-day mortality. Predictive associations between CRP (as absolute levels and relative decline at third day) and adverse events were analyzed. RESULTS: Eight hundred and twenty-three patients were assessed, 19% were admitted to ICU and 10.6% required mechanical ventilation. The average hospital stay was 8.8 ± 8.2 days, 42% had nosocomial complications and 8.1% died within 30 days. Ninety eight percent of patients had elevated serum CRP on admission to the hospital (18.1 ± 14.1 mg/dL). C-reactive protein measured at admission was associated with the risk of bacterial pneumonia, bacteremic pneumonia, septic shock and use of mechanical ventilation. Lack of CRP decline within three days of hospitalization was associated with high risk of complications, septic shock, mechanical ventilation and prolonged hospital stay. CONCLUSIONS: CRP responses at third day of hospital admission was a valuable predictor of adverse events in hospitalized CAP adult patients.


Assuntos
Proteína C-Reativa/análise , Infecções Comunitárias Adquiridas/sangue , Imunocompetência , Pneumonia/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/mortalidade , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Choque Séptico/sangue , Choque Séptico/mortalidade , Fatores de Tempo , Adulto Jovem
5.
Mol Immunol ; 116: 98-105, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31634816

RESUMO

Pseudomonas aeruginosa is a common nosocomial pathogen in burn patients, and rapidly acquires antibiotic resistance; thus, developing an effective therapeutic approach is the most promising strategy for combating infection. Type III secretion system (T3SS) translocates bacterial toxins into the cytosol of the targeted eukaryotic cells, which plays important roles in the virulence of P. aeruginosa infections in both acute pneumonia and burn wound models. The PcrV protein, a T3SS translocating protein, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targeting P. aeruginosa. In the present study, we evaluated the protective efficacy of chicken egg yolk antibodies (IgY) raised against recombinant PcrV (r-PcrV) in both acute pneumonia and burn wound models. R-PcrV protein was generated by expressing the pcrV gene (cloned in pET-28a vector) in E. coli BL-21. Anti-PcrV IgY was obtained by immunization of hen. Anti-PcrV IgY induced greater protection in P. aeruginosamurine acute pneumonia and burn wound models than control IgY (C-IgY) and PBS groups. Anti-PcrV IgY improved opsonophagocytic killing and inhibition of bacterial invasion of host cells. Taken together, our data provide evidence that anti-PcrV IgY can be a promising therapeutic candidate for combating P. aeruginosa infections.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Toxinas Bacterianas/imunologia , Queimaduras/imunologia , Imunoglobulinas/imunologia , Pneumonia/imunologia , Proteínas Citotóxicas Formadoras de Poros/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Animais , Queimaduras/microbiologia , Galinhas/imunologia , Galinhas/microbiologia , Modelos Animais de Doenças , Feminino , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/microbiologia , Vacinação/métodos , Virulência/imunologia
6.
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
7.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
8.
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
9.
Part Fibre Toxicol ; 16(1): 35, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533843

RESUMO

BACKGROUND: Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO2 (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1α, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1α as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays. RESULTS: By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO2, LiNiCoAlO2) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1α in the lung. Inhibition of HIF-1α with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1ß deficient mice, HIF-1α was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1α stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo. CONCLUSIONS: We conclude that HIF-1α, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1α in vitro can be used to predict the lung inflammatory potential of LIB particles.


Assuntos
Cobalto/toxicidade , Células Epiteliais/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/efeitos dos fármacos , Óxidos/toxicidade , Pneumonia/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Técnicas de Cultura de Células , Linhagem Celular , Citocinas/análise , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Exposição por Inalação , Íons , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pneumonia/imunologia , Pneumonia/patologia
10.
Mol Immunol ; 114: 395-409, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476634

RESUMO

Inflammation is a response to injury and infection. Although protective under physiological conditions, excessive and persistent inflammation is linked to numerous diseases. As the lungs are continuously exposed to the external environment, the respiratory system is particularly liable to damage from inflammation. RelB is a member of the non-canonical NF-κB pathway that may control lung inflammation caused by cigarette smoke (CS), a leading cause of morbidity and mortality worldwide. Our lab has previously shown that RelB protects against CS-induced inflammation in vitro, leading us to hypothesize that RelB would protect against acute CS-induced pulmonary inflammation in vivo. We exposed wild-type (Relb+/+) and RelB-deficient mice (Relb-/-) mice to room air or to CS and found that CS exposure caused a sustained decrease in pulmonary granulocytes in Relb-/- mice that was predominated by a decrease in neutrophils. Pulmonary inflammation caused by other irritants, including chlorine, ovalbumin (OVA; to mimic features of asthma) and lipopolysaccharide (LPS) was not controlled by RelB. Differential cytokine analysis suggests that alterations in chemotactic cytokines do not fully account for the CS-specific decrease in neutrophils in Relb-/- mice. Flow cytometric analysis of the bronchoalveolar lavage and bone marrow cells also reveal that it is unlikely that the sustained decrease is caused by excessive cell death or decreased hematopoiesis from the bone marrow. Overall, our results indicate that RelB regulates acute CS-induced pulmonary inflammation. Understanding how RelB regulates CS-induced inflammation may potentiate the discovery of new therapeutic strategies for many of the inflammatory diseases caused by CS.


Assuntos
Pulmão/imunologia , NF-kappa B/imunologia , Neutrófilos/imunologia , Pneumonia/imunologia , Fumaça/efeitos adversos , Tabaco/imunologia , Fator de Transcrição RelB/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doença Pulmonar Obstrutiva Crônica/imunologia , Transdução de Sinais/imunologia , Fumar/efeitos adversos , Fumar/imunologia , Tabaco/efeitos adversos
11.
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
12.
Gastroenterology ; 157(6): 1530-1543.e4, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31445037

RESUMO

BACKGROUND & AIMS: Dysregulation of the microbiome has been associated with development of complex diseases, such as obesity and diabetes. However, no method has been developed to control disease-associated commensal microbes. We investigated whether immunization with microbial antigens, using CpG oligodeoxynucleotides and/or curdlan as adjuvants, induces systemic antigen-specific IgA and IgG production and affects development of diseases in mice. METHODS: C57BL/6 mice were given intramuscular injections of antigens (ovalbumin, cholera toxin B-subunit, or pneumococcal surface protein A) combined with CpG oligodeoxynucleotides and/or curdlan. Blood and fecal samples were collected weekly and antigen-specific IgG and IgA titers were measured. Lymph nodes and spleens were collected and analyzed by enzyme-linked immunosorbent assay for antigen-specific splenic T-helper 1 cells, T-helper 17 cells, and memory B cells. Six weeks after primary immunization, mice were given a oral, nasal, or vaginal boost of ovalbumin; intestinal lamina propria, bronchial lavage, and vaginal swab samples were collected and antibodies and cytokines were measured. Some mice were also given oral cholera toxin or intranasal Streptococcus pneumoniae and the severity of diarrhea or pneumonia was analyzed. Gnotobiotic mice were gavaged with fecal material from obese individuals, which had a high abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes), and were placed on a high-fat diet 2 weeks after immunization with C ramosum. Intestinal tissues were collected and analyzed by quantitative real-time polymerase chain reaction. RESULTS: Serum and fecal samples from mice given injections of antigens in combination with CpG oligodeoxynucleotides and curdlan for 3 weeks contained antigen-specific IgA and IgG, and splenocytes produced interferon-gamma and interleukin 17A. Lamina propria, bronchial, and vaginal samples contained antigen-specific IgA after the ovalbumin boost. This immunization regimen prevented development of diarrhea after injection of cholera toxin, and inhibited lung colonization by S pneumoniae. In gnotobiotic mice colonized with C ramosum and placed on a high-fat diet, the mice that had been immunized with C ramosum became less obese than the nonimmunized mice. CONCLUSIONS: Injection of mice with microbial antigens and adjuvant induces antigen-specific mucosal and systemic immune responses. Immunization with S pneumoniae antigen prevented lung infection by this bacteria, and immunization with C ramosum reduced obesity in mice colonized with this microbe and placed on a high-fat diet. This immunization approach might be used to protect against microbe-associated disorders of intestine.


Assuntos
Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Proteínas de Bactérias/imunologia , Toxina da Cólera/imunologia , Diarreia/diagnóstico , Diarreia/imunologia , Diarreia/microbiologia , Modelos Animais de Doenças , Disbiose/microbiologia , Feminino , Vida Livre de Germes , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Pneumonia/diagnóstico , Pneumonia/imunologia , Pneumonia/microbiologia , Índice de Gravidade de Doença
13.
Nat Immunol ; 20(9): 1138-1149, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427775

RESUMO

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.


Assuntos
Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Proteína Acessória do Receptor de Interleucina-1/antagonistas & inibidores , Peritonite/imunologia , Pneumonia/imunologia , Psoríase/imunologia , Células A549 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Imiquimode/toxicidade , Inflamação/patologia , Interleucina-1/imunologia , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1beta/imunologia , Interleucina-33/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Peritonite/tratamento farmacológico , Peritonite/patologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Psoríase/tratamento farmacológico , Psoríase/patologia , Transdução de Sinais/imunologia , Ácido Úrico/toxicidade
14.
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
15.
Part Fibre Toxicol ; 16(1): 28, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277695

RESUMO

BACKGROUND: Copper oxide (CuO) nanomaterials are used in a wide range of industrial and commercial applications. These materials can be hazardous, especially if they are inhaled. As a result, the pulmonary effects of CuO nanomaterials have been studied in healthy subjects but limited knowledge exists today about their effects on lungs with allergic airway inflammation (AAI). The objective of this study was to investigate how pristine CuO modulates allergic lung inflammation and whether surface modifications can influence its reactivity. CuO and its carboxylated (CuO COOH), methylaminated (CuO NH3) and PEGylated (CuO PEG) derivatives were administered here on four consecutive days via oropharyngeal aspiration in a mouse model of AAI. Standard genome-wide gene expression profiling as well as conventional histopathological and immunological methods were used to investigate the modulatory effects of the nanomaterials on both healthy and compromised immune system. RESULTS: Our data demonstrates that although CuO materials did not considerably influence hallmarks of allergic airway inflammation, the materials exacerbated the existing lung inflammation by eliciting dramatic pulmonary neutrophilia. Transcriptomic analysis showed that CuO, CuO COOH and CuO NH3 commonly enriched neutrophil-related biological processes, especially in healthy mice. In sharp contrast, CuO PEG had a significantly lower potential in triggering changes in lungs of healthy and allergic mice revealing that surface PEGylation suppresses the effects triggered by the pristine material. CONCLUSIONS: CuO as well as its functionalized forms worsen allergic airway inflammation by causing neutrophilia in the lungs, however, our results also show that surface PEGylation can be a promising approach for inhibiting the effects of pristine CuO. Our study provides information for health and safety assessment of modified CuO materials, and it can be useful in the development of nanomedical applications.


Assuntos
Cobre/toxicidade , Nanopartículas/toxicidade , Infiltração de Neutrófilos/efeitos dos fármacos , Pneumonia/induzido quimicamente , Polietilenoglicóis/química , Transcriptoma/efeitos dos fármacos , Animais , Cobre/química , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Camundongos Endogâmicos BALB C , Nanopartículas/química , Ovalbumina/imunologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/patologia , Propriedades de Superfície
16.
Environ Toxicol ; 34(10): 1137-1148, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31318498

RESUMO

The substances associated with PM2.5-induced inflammatory response were investigated using an elimination method. PM2.5 were heated at temperatures of 120, 250, and 360°C. The results demonstrated microbial substances such as LPS and b-glucan, and chemicals including BaP, 1,2-NQ, and 9,10-PQ were reduced drastically in PM2.5 heated at 120°C. On the other hand, DBA, 7,12-BAQ, and BaP-1,6-Q were not noticeably reduced. Most of these substances had disappeared in PM2.5 heated at 250°C and 360°C. Metals (eg, Fe, Cu, Cr, Ni) in PM2.5 exhibited a slight thermo-dependent increase. RAW264.7 macrophages with or without NAC were exposed to unheated PM2.5, oxidative stress-related and unrelated inflammatory responses were induced. PM2.5-induced lung inflammation in mice is caused mainly by thermo-sensitive substances (LPS, b-glucan, BaP, 1,2-NQ, 9,10-PQ, etc.). Also, a slight involvement of thermo-resistant substances (DBA, 7,12-BAQ, BaP-1,6-Q, etc.) and transition metals was observed. The thermal decomposition method could assist to evaluate the PM2.5-induded lung inflammation.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/química , Material Particulado/efeitos adversos , Material Particulado/química , Pneumonia/etiologia , Pneumonia/imunologia , Animais , Temperatura Alta , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pneumonia/genética
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(6): 684-688, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31315723

RESUMO

OBJECTIVE: To analyze the characteristics of cellular immune function and its prognostic risk factors in patients with community-acquired pneumonia (CAP). METHODS: The clinical data of patients diagnosed as CAP admitted to department of respiratory and critical care medicine of the Second Affiliated Hospital of Anhui Medical University from June 2018 to February 2019 were retrospectively analyzed. The patients were divided into survival group and death group according to the mortality at discharge and 28-day survival after hospital discharge; in addition, they were divided into bacterial group, fungi group and mixed infection group according to pathogen results at discharge. The differences of general clinical characteristics, arterial blood gas analysis indexes, plasma albumin, cellular immune function, inflammatory cytokines, the length of hospital stay among groups were analyzed. The correlation between the prognosis-related indicators in patients were analyzed by Pearson test or Spearman test, and Logistic regression model was used to analyze the risk factors of patients in non-survival group. RESULTS: 106 patients were finally enrolled, 69 of whom were survived, and 37 dead. Among 56 patients with pathogen results, 27 were diagnosed as bacterial infection, 11 as fungal infection, and 18 with mixed infection. Compared with the survival group, plasma albumin level, total T cell count, CD4+T cell count, CD8+T cell count were decreased in the death group, temperature, pH, acute physiology and chronic health evaluation II (APACHE II), procalcitonin (PCT), interleukin-6 (IL-6), C-reactive protein (CRP) were increased, and the length of hospital stay was significantly shortened. While there was no significant difference in gender, age, mean arterial pressure, arterial oxygen pressure, CD4+/CD8+, regulation T cell/effect T cell (TREG/TEF) between the two groups. Correlation analysis showed that plasma albumin, the length of hospital stay, APACHE II score, CD4+T cell count, CD8+T cell count, CD4+/CD8+, PCT, IL-6, CRP were correlated with death (r value was -0.480, -0.209, 0.203, -0.279, -0.270, 0.271, 0.247, 0.410, 0.329, all P < 0.05). Logistic regression analysis showed that plasma albumin, CD4+T cell count, CD8+T cell count, CD4+/CD8+decreased; APACHE II score, PCT, IL-6, and CRP increased; the length of hospital stay were correlated with death, and all were independent risk factors for death in CAP patients (all P < 0.05). Correlation analysis showed that the APACHE II score was negatively related to plasma albumin (r = -0.375, P < 0.05), positively related to CRP and IL-6 (r value was 0.363 and 0.333 respectively, both P < 0.05); negative correlation between plasma albumin and IL-6 (r = -0.372, P < 0.05), PCT and CD4+T cell count (r = -0.354, P < 0.05), CRP and the length of hospital stay (r = -0.356, P < 0.05). There were no significant correlations between the others. There was no significant difference in cellular immune function or inflammatory factor expression between different pathogenic infections. CONCLUSIONS: Cellular immune dysfunction, hypoproteinemia, APACHE II score and elevated inflammatory index are all influential factors for the death of CAP patients. Apart from conventional anti-infective treatment, the symptoms of hypoproteinemia and cellular immune function can predict the severity and prognosis of CAP patients.


Assuntos
Infecções Comunitárias Adquiridas/imunologia , Imunidade Celular/fisiologia , Pneumonia/imunologia , APACHE , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de Risco
18.
Curr Med Sci ; 39(3): 363-370, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209804

RESUMO

Respiratory syncytial virus (RSV) infection is the primary cause of respiratory disease in infants. The formalin-inactivated RSV (FI-RSV) vaccine resulted in an enhanced respiratory disease (ERD) in infants upon natural RSV infection, which is a major obstacle for development of safe and efficacious vaccines. Excessive and uncontrolled Th immune responses could be involved in the ERD. Agonists of TLRs are used as adjuvants to guide the type of immune response induced by vaccines. We evaluated the impact of lipopolysaccharide (LPS), the agonist of TLR4, on ERD as the adjuvant of FI-RSV. The results showed that LPS remarkably inhibited FI-RSV-enhanced lung inflammation, mucus production, airway inflammatory cell infiltration, and inflammatory cytokines following RSV challenge. Interestingly, LPS inhibited both Th2 and Th17 type cytokines in lungs of FI-RSV-immunized mice following RSV challenge, without an increase in the Th1 type cytokines, suggesting a controlled immune response. In contrast, Pam3Cys and Poly(I:C), the agonist of TLR1/2 or TLR3, partly inhibited FI-RSV-enhanced lung inflammation. Pam3Cys inhibited Th17 type cytokine IL-17, but promoted both Th1 and Th2 type cytokines. Poly(I:C) inhibited Th2 and Th17 type cytokines, but promoted Th1 type cytokines. In addition, LPS promoted IgG and IgG2a antibody production, which might provide protection from RSV challenge. These results suggest that LPS inhibits ERD without impairment in antibody production and protection, and the mechanism appears to be related with regulation of Th responses induced by FI-RSV.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/biossíntese , Lipopolissacarídeos/farmacologia , Pneumonia/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Feminino , Formaldeído , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Lipoproteínas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/patologia , Poli I-C/farmacologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/virologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/virologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Vacinação , Vacinas de Produtos Inativados
19.
Int J Mol Med ; 44(2): 617-629, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173158

RESUMO

Classical dendritic cells (cDCs) are involved in the pathogenesis of inflammatory lung diseases; however, their contributions in acute respiratory distress syndrome (ARDS), which is pathophysiologically inflammatory, remain unknown. The present study aimed to explore the regulatory effects of pulmonary cDCs on acute lung inflammation and injury in lipopolysaccharide (LPS)­induced ARDS. Fms­like tyrosine kinase 3­ligand (FLT3L) and lestaurtinib, a specific activator and an inhibitor of FLT3 signaling respectively, were used separately for the pretreatment of C57BL/6 mice for 5 consecutive days. ARDS was induced by intratracheal injection of LPS, and mice were sacrificed 6 and 24 h later. Flow cytometry was used to measure the aggregation and maturation of pulmonary cDCs. The ratio of lung wet weight to body weight (LWW/BW) and histopathological analyses were assessed to evaluate lung edema and lung injury. Tumor necrosis factor­α and interleukin (IL)­6 levels were measured by ELISA to evaluate acute lung inflammation. The levels of interferon­Î³, IL­1ß, IL­4 and IL­10, and the expression of the transcription factors T­box­expressed­in­T­cells (T­bet) and GATA binding protein 3, were quantified by ELISA, RT­qPCR and western blotting to evaluate the balance of the Th1/Th2 response. Myeloperoxidase (MPO) activity was measured to evaluate neutrophil infiltration. The results demonstrated that the aggregation and maturation of pulmonary cDCs reached a peak at 6 h after LPS challenge, followed by a significant decrease at 24 h. FLT3L pretreatment further stimulated the aggregation and maturation of pulmonary cDCs, resulting in elevated lung MPO activity and increased T­bet expression, which in turn led to aggravated LWW/BW, acute lung inflammation and injury. However, lestaurtinib pretreatment inhibited the aggregation and maturation of pulmonary cDCs, decreased lung MPO activity and T­bet expression, and eventually improved LWW/BW, acute lung inflammation and injury. The present results suggested that pulmonary cDCs regulated acute lung inflammation and injury in LPS­induced ARDS through the modulation of neutrophil infiltration and balance of the Th1/Th2 response.


Assuntos
Lesão Pulmonar Aguda/imunologia , Células Dendríticas/imunologia , Pneumonia/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Células Dendríticas/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/patologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Tirosina Quinase 3 Semelhante a fms/imunologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-31114182

RESUMO

Purpose: COPD patients often do not report acute exacerbations to healthcare providers - unreported exacerbations. It is not known whether variances in symptoms, airway obstruction, aetiology and inflammatory responses account for differences in reporting of COPD exacerbations. The aims of the study were to compare symptoms, lung function changes, aetiology and inflammatory markers between exacerbations that were reported to healthcare providers or treated, with those that were unreported and untreated. Patients and methods: We recruited a cohort of COPD patients and collected clinical data and blood and airway samples when stable and during acute exacerbations. Virological and bacterial analyses were carried out and inflammatory markers measured. Results: We found no differences in symptoms, lung function, incidence of infection and inflammatory markers between reported and unreported exacerbations. Subjects who reported all exacerbations had higher BODE scores, lower FEV1 and more exacerbations compared with those who did not. Conclusion: The failure to report exacerbations is not related to the severity, aetiology or inflammatory profile of the exacerbation. Patients with less severe COPD and less frequent exacerbations are less likely to report exacerbations. The decision to report an exacerbation is not an objective marker of exacerbation severity and therefore studies that do not count unreported exacerbations will underestimate the frequency of clinically significant exacerbations. A better understanding of the factors that determine non-reporting of exacerbations is required to improve exacerbation reporting. Trial registration: ClinicalTrials.gov Identifier: NCT01376830. Registered June 17, 2011.


Assuntos
Pulmão/fisiopatologia , Pneumonia/diagnóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Infecções Respiratórias/diagnóstico , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Volume Expiratório Forçado , Nível de Saúde , Humanos , Mediadores da Inflamação/sangue , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/fisiopatologia , Prognóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/fisiopatologia , Infecções Respiratórias/virologia , Capacidade Vital
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA