RESUMO
The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.
Assuntos
Neuropeptídeo Y , Receptores de Neuropeptídeo Y , Humanos , Neuropeptídeo Y/fisiologia , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/fisiologia , Animais , Doenças Respiratórias/imunologia , Asma/imunologia , Sistema Respiratório/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologiaRESUMO
A 74-year-old Japanese woman presented with a 45-year history of refractory asthma. She had been treated with inhaled corticosteroids, a long-acting ß2-agonist, and a long-acting muscarinic antagonist for 6 months. She also had a repeated viral infection. Her condition had been characterized as a refractory asthma associated with type 2 and non-type 2 traits. We began treatment with tezepelumab. The control of the patient's asthma symptoms and quality of life improved greatly within 1 month (changes in eosinophil count from 748 to 96 /µL, in FeNO from 32 to 17 ppb, in the Asthma Quality of Life Questionnaire score from 3.59 to 6.68, and in the Asthma Control Test score from 13 to 23). Tezepelumab was effective as an initial biologic agent for a patient with refractory asthma associated with type 2 and non-type 2 traits.
Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Humanos , Feminino , Idoso , Antiasmáticos/uso terapêutico , Qualidade de Vida , Asma/complicações , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêuticoRESUMO
Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1ß concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1ß concentrations in the lungs. Moreover, IL-1ß neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1ß release, and Y1 receptor antagonists inhibited IL-1ß release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1ß concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1ß release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.
Assuntos
Fibrose Pulmonar Idiopática , Humanos , Camundongos , Animais , Fibrose Pulmonar Idiopática/patologia , Neuropeptídeo Y/efeitos adversos , Neuropeptídeo Y/metabolismo , Camundongos Endogâmicos C57BL , Bleomicina/farmacologia , Pulmão/patologiaRESUMO
Neuropeptide Y (NPY) is a neuropeptide widely expressed in not only the central nervous system but also immune cells and the respiratory epithelium. Patients with chronic obstructive pulmonary disease (COPD) reportedly exhibit decreased NPY expression in the airway epithelium, but the involvement of NPY in the pathophysiology of COPD has not been defined. We investigated the role of NPY in elastase-induced emphysema. NPY-deficient (NPY-/-) mice and wild-type (NPY+/+) mice received intratracheal instillation of porcine pancreas elastase (PPE). The numbers of inflammatory cells and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates were determined along with quantitative morphometry of lung sections. Intratracheal instillation of PPE induced emphysematous changes and increased NPY levels in the lungs. Compared with NPY+/+ mice, NPY-/- mice had significantly enhanced PPE-induced emphysematous changes and alveolar enlargement. Neutrophilia seen in BAL fluid of NPY+/+ mice on day 4 after PPE instillation was also enhanced in NPY-/- mice, and the enhancement was associated with increased levels of neutrophil-related and macrophage-related chemokines and IL-17A as well as increased numbers of type 3 innate lymphoid cells in the airways. Treatment with NPY significantly reduced PPE-induced emphysematous changes. Conversely, treatment with a NPY receptor antagonist exacerbated PPE-induced emphysematous changes. These observations indicate that NPY has protective effects against elastase-induced emphysema and suggest that targeting NPY in emphysema has potential as a therapeutic strategy for delaying disease progression.
Assuntos
Enfisema , Enfisema Pulmonar , Animais , Líquido da Lavagem Broncoalveolar , Quimiocinas/metabolismo , Humanos , Imunidade Inata , Pulmão/metabolismo , Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/farmacologia , Elastase Pancreática/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/prevenção & controle , SuínosRESUMO
BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.
Assuntos
Regulação da Expressão Gênica , Fibrose Pulmonar Idiopática/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pulmão/enzimologia , Fosfotransferases/genética , RNA/genética , Idoso , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fosfotransferases/biossíntese , Estudos RetrospectivosRESUMO
RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.
Assuntos
Asma , Bronquiectasia , Humanos , Óxido Nítrico/análise , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/epidemiologia , Eosinófilos , Bronquiectasia/diagnóstico , Bronquiectasia/tratamento farmacológico , Bronquiectasia/epidemiologia , Corticosteroides/uso terapêutico , ExpiraçãoRESUMO
Acute exacerbation of idiopathic pulmonary fibrosis has a poor prognosis associated with neutrophilic inflammation. Interleukin-23 is a proinflammatory cytokine involved in neutrophilic inflammation. However, little is known about its role in acute exacerbation of pulmonary fibrosis. This study was performed to determine the role of interleukin-23 in acute exacerbation of pulmonary fibrosis. For assessment of acute exacerbation of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Cytokine levels were measured in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients with or without acute exacerbation. Interleukin-23, -17A, and -22 levels were increased in the airway of mice with acute exacerbation of pulmonary fibrosis. Interleukin-23p19-deficient mice with acute exacerbation of pulmonary fibrosis had markedly reduced airway inflammation and fibrosis associated with decreased levels of interleukin-17A and -22 compared with wild-type mice. Treatment with an anti-interleukin-23 antibody attenuated airway inflammation and fibrosis and reduced interleukin-17A and -22 levels in mice with acute exacerbation of pulmonary fibrosis. T-helper type 17 cells were the predominant source of interleukin-17A in mice with acute exacerbation of pulmonary fibrosis. Interleukin-23 levels in bronchoalveolar lavage fluid tended to be higher in idiopathic pulmonary fibrosis patients with than without acute exacerbation. The data presented here suggest that interleukin-23 is essential for the development of acute exacerbation of pulmonary fibrosis and that blockade of interleukin-23 may be a new therapeutic strategy for acute exacerbation of pulmonary fibrosis.
Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/imunologia , Inflamação/metabolismo , Interleucina-23/metabolismo , Doença Aguda , Animais , Fibrose Pulmonar Idiopática/metabolismo , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos , Células Th17/imunologia , Células Th17/metabolismoRESUMO
BACKGROUND: IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. METHODS: We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33-/- mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. RESULTS: Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33-/- mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33-/- and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33-/- mice than WT mice. IL-33-/- mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. CONCLUSION: These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.
Assuntos
Interleucina-33/deficiência , Pulmão/metabolismo , Elastase Pancreática , Pneumonia/metabolismo , Enfisema Pulmonar/metabolismo , Fumaça , Produtos do Tabaco , Animais , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-33/genética , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/etiologia , Pneumonia/genética , Pneumonia/patologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologiaRESUMO
Cryptococcosis is an invasive mycosis that has become increasingly prevalent in immunocompromised patients. Pregnant women are also one of the risk populations for cryptococcosis. Reversal of Th2 to Th1 response following resolution of immunosuppression during the postpartum period can lead to overt clinical manifestations of a previously silent infection, resembling an immune reconstitution inflammatory syndrome. Here, we report a case of a 30-year-old woman who had an exacerbation of pulmonary cryptococcosis in the postpartum period mimicking an immune reconstitution inflammatory syndrome. In the present case, chest computed tomography showed multiple small nodules on the day of the delivery; however, pulmonary cryptococcosis, which was subclinical during pregnancy, rapidly worsened to mass-like consolidation at one month after the delivery. Pathohistological examination of the lung specimen showed lung parenchyma infiltration with histiocytes and numerous lymphocytes without granulomatous formations, and a small number of yeast-like organisms consistent with Cryptococcus without capillary involvement. Immunohistochemical staining showed predominance of CD3+ cells and CD4+ cells over CD8+ cells. In addition, GATA3+ cells dominated over T-bet + cells. These data suggested exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period.
Assuntos
Criptococose , Pneumopatias Fúngicas , Adulto , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/tratamento farmacológico , Período Pós-Parto , Gravidez , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response. Persistent inflammation results in irreversible alveolar fibrosis. Because hydrogen gas possesses anti-inflammatory properties, we hypothesized that daily repeated inhalation of hydrogen gas could suppress persistent lung inflammation by inducing functional changes in macrophages, and consequently inhibit lung fibrosis during late-phase lung injury. METHODS: To test this hypothesis, lung injury was induced in mice by intratracheal administration of bleomycin (1.0 mg/kg). Mice were exposed to control gas (air) or hydrogen (3.2% in air) for 6 h every day for 7 or 21 days. Respiratory physiology, tissue pathology, markers of inflammation, and macrophage phenotypes were examined. RESULTS: Mice with bleomycin-induced lung injury that received daily hydrogen therapy for 21 days (BH group) exhibited higher static compliance (0.056 mL/cmH2O, 95% CI 0.047-0.064) than mice with bleomycin-induced lung injury exposed only to air (BA group; 0.042 mL/cmH2O, 95% CI 0.031-0.053, p = 0.02) and lower static elastance (BH 18.8 cmH2O/mL, [95% CI 15.4-22.2] vs. BA 26.7 cmH2O/mL [95% CI 19.6-33.8], p = 0.02). When the mRNA levels of pro-inflammatory cytokines were examined 7 days after bleomycin administration, interleukin (IL)-6, IL-4 and IL-13 were significantly lower in the BH group than in the BA group. There were significantly fewer M2-biased macrophages in the alveolar interstitium of the BH group than in the BA group (3.1% [95% CI 1.6-4.5%] vs. 1.1% [95% CI 0.3-1.8%], p = 0.008). CONCLUSIONS: The results suggest that hydrogen inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of lung injury.
Assuntos
Hidrogênio/farmacologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/fisiopatologia , Administração por Inalação , Animais , Antibióticos Antineoplásicos , Bleomicina , Interleucinas/metabolismo , Lesão Pulmonar/induzido quimicamente , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório/complicaçõesRESUMO
Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the NPY Y1 receptor. NPY modulates these cells via its Y1 receptor; however, involvement of NPY in the pathophysiology of bronchial asthma, particularly airway hyperresponsiveness (AHR), has not been defined. NPY-deficient and wild-type mice were intranasally sensitized and challenged to house dust mite (HDM) extract, and airway responses were monitored. After sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice. Flow cytometry analysis showed that the number of CD4 T cells and CD11c+ antigen-presenting cells (APCs) was significantly lower in the lungs of NPY-deficient mice than in wild-type mice following sensitization and challenge. Significantly fewer CD11c+ APCs phagocytosed HDM in the mediastinal lymph nodes of NPY-deficient mice than in those of wild-type mice. Treatment with BIBO-3304, a NPY receptor antagonist, significantly suppressed development of HDM-induced AHR and inflammation in wild-type mice. These data identify an important contribution of NPY to allergen-induced AHR and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response. Thus, manipulating NPY represents a novel therapeutic target to control allergic airway responses.
Assuntos
Células Dendríticas/metabolismo , Inflamação/patologia , Pulmão/patologia , Neuropeptídeo Y/metabolismo , Hipersensibilidade Respiratória/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Eosinófilos/imunologia , Hipersensibilidade/patologia , Inflamação/genética , Camundongos Transgênicos , Neuropeptídeo Y/genética , Hipersensibilidade Respiratória/patologiaRESUMO
BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. METHODS: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. RESULTS: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. CONCLUSION: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.
Assuntos
Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/metabolismo , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/metabolismo , Animais , Bexaroteno/farmacologia , Bexaroteno/uso terapêutico , Fumar Cigarros/efeitos adversos , Feminino , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Enfisema Pulmonar/induzido quimicamenteRESUMO
BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. METHODS: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. RESULTS: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression. CONCLUSION: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.
Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Receptores X de Retinoides/imunologia , Animais , Antiasmáticos/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Receptores X de Retinoides/agonistas , Resultado do TratamentoRESUMO
Lavender essential oil (Lvn) has anti-inflammatory effects in an ovalbumin-sensitized murine model of asthma, and inhibits inflammatory cell infiltration into the lungs. The anti-inflammatory effects of Lvn on cell adhesion molecules are not clear. Here we evaluated the effects of Lvn and its main constituents, linalyl acetate (LA) and linalool (LO), on the expression of tumor necrosis factor-alpha (TNF-α)-induced cell adhesion molecules in murine brain endothelial bEnd.3 cells and human umbilical vein endothelial cells (HUVECs). The bEnd.3 cells were treated with Lvn, LA, or LO and subsequently stimulated with TNF-α. The mRNA expression levels of cell adhesion molecules were detected using RT-PCR. E-selectin and P-selectin protein and phosphorylated-NF-κB p65 were detected by western blotting. The effects of Lvn on HUVECs were measured by RT-PCR. In bEnd.3 cells, Lvn and LA suppressed TNF-α-induced E-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and phosphorylated-NF-κB p65 in the nucleus; LO did not suppress P-selectin or phosphorylated-NF-κB p65. Lvn inhibited TNF-α-induced E-selectin mRNA in HUVECs. These results indicate that Lvn and LA inhibit TNF-α-induced cell adhesion molecules in endothelial cells through the suppression of NF-κB activation. Consequently, Lvn or other essential oils including LA may be useful as alternative anti-inflammatory medicines.
Assuntos
Moléculas de Adesão Celular/análise , Células Endoteliais/efeitos dos fármacos , Monoterpenos/farmacologia , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Monoterpenos Acíclicos , Animais , Moléculas de Adesão Celular/genética , Células Endoteliais/química , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lavandula , Camundongos , NF-kappa B/fisiologia , Óleos Voláteis/análise , Óleos de Plantas/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Although recent retrospective studies suggested that the use of ß-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of ß-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective ß-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.
Assuntos
Bisoprolol/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Simpatolíticos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Estudos Clínicos como Assunto , Humanos , Hipertensão/tratamento farmacológico , Japão/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologiaRESUMO
We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)-induced emphysema. The proliferation of T-helper type 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema, a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23-/-) and wild-type (WT) mice were compared. Intratracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared with WT mice, IL-23-/- mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses after PPE instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage fluid of WT mice was attenuated in IL-23-/- mice, and the reduction was associated with decreased levels of keratinocyte-derived cytokine and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice. These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema, mediated through an IL-23/IL-17 pathway. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.
Assuntos
Interleucina-23/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Quimiocinas/metabolismo , Progressão da Doença , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-23/deficiência , Cinética , Pulmão/patologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Elastase Pancreática , Pneumonia/complicações , Pneumonia/patologia , Enfisema Pulmonar/complicações , Enfisema Pulmonar/patologia , Sus scrofaRESUMO
KL-6 is a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, and often shows increased serum levels in patients with interstitial pneumonia. We report a case of mycobacterium avium complex (MAC) infection whose disease activity was correlated with KL-6 levels in serum. During treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with prednisolone, chest image findings improved in association with decreased KL-6 levels. Following tapering of prednisolone, chest image findings deteriorated again as levels of KL-6 increased, suggesting recurrence of RA-ILD. Bronchoscopic examination revealed active MAC infection. Treatment of MAC infection not only improved chest image findings but also decreased KL-6 levels in serum, suggesting that KL-6 was increased by active MAC infection by itself, not by recurrence of RA-ILD. To the best of our knowledge, this is the first documentation of KL-6 elevation in serum in association with active MAC infection.
RESUMO
Heerfordt's syndrome is a rare manifestation of sarcoidosis and is defined as a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. We report a case of Heerfordt's syndrome presenting with a high fever and increased serum tumor necrosis factor alpha (TNF-α) levels. The patient had facial palsy, parotid swelling, uveitis, and swelling of the right supraclavicular and hilar lymph nodes. Corticosteroid therapy was initiated, and her symptoms soon resolved completely, in tandem with a decrease in TNF-α serum levels.
Assuntos
Febre/complicações , Fator de Necrose Tumoral alfa/sangue , Febre Uveoparotídea/sangue , Febre Uveoparotídea/patologia , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Prednisolona/uso terapêutico , Febre Uveoparotídea/tratamento farmacológicoRESUMO
Acquired hemophilia A is a rare disease in which autoantibodies to factor VIII are present. It is often manifested as a sudden onset of a critical bleeding episode, and its incidence is reported to be 1.48 cases per million persons per year. We report herein on a case of acquired hemophilia A associated with a submucosal hematoma of the oral floor, pharynx, and larynx. A 78-year-old male presented with fresh bleeding from his mouth, associated with hematoma of the oral floor, pharynx, and larynx. Laboratory test showed that the activated partial thromboplastin time was prolonged, and the platelet count and prothrombin time were normal. Coagulation tests revealed decreased factor VIII levels, and the presence of factor VIII inhibitor. A diagnosis of acquired hemophilia A was made, and immunotherapy with corticosteroids was initiated. After treatment, the bleeding tendency was controlled. On hospital day 29, the symptoms disappeared. Although acquired hemophilia A is a rare coagulopathic condition, it should be considered as one of the differential diagnoses in a case of sudden onset of severe hemorrhagic tendency of unknown origin.