RESUMO
BACKGROUND: Previous reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1ß in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. METHODS: We developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. RESULTS: The numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1ß levels in BAL fluids and the numbers of IL-1ß-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1ß was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1ß production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. CONCLUSIONS: These results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1ß. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.
Assuntos
Quitina/imunologia , Glucocorticoides/farmacologia , Inflamação/imunologia , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Hipersensibilidade Respiratória/imunologia , Administração por Inalação , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Quitina/farmacologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Resistência a Medicamentos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Pulmão/imunologia , Pulmão/fisiopatologia , Macrófagos Alveolares/imunologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ovalbumina/imunologia , Ovalbumina/farmacologia , Moléculas com Motivos Associados a Patógenos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/fisiopatologiaRESUMO
BACKGROUND: Fractional exhaled nitric oxide (FENO) is useful for the evaluation of eosinophilic airway inflammation, including that seen in asthma. Although a new electrochemical hand-held FENO analyzer, the NIOX VERO® (Aerocrine AB, Solna, Sweden), is clinically convenient to use, it has not been fully compared with the chemiluminescence stationary electrochemical analyzer NOA280i® (Sievers Instruments, Boulder, CO, USA) in terms of the level of measured FENO. The aim of this study was to determine whether there is a difference between the two analyzers. METHODS: The FENO levels measured with both NIOX VERO® and NOA280i® were evaluated in 1,369 adults at Juntendo University Hospital from May 2016 to October 2016. RESULTS: The median FENO level measured with the NIOX VERO® was significantly lower than that measured with the NOA280i® (41 ppb, range 5-368 ppb vs. 29 ppb, range 5-251 ppb; p < 0.001). There was a strong positive correlation in the measurement of FENO level between the NOA280i® and the NIOX VERO® (r = 0.942, p < 0.001). The following conversion equation was calculated: FENO (NOA280i®) = 1.362 (SE, 0.661) + 1.384 (SE, 0.021) × FENO (NIOX VERO®). CONCLUSIONS: To our best knowledge, we have provided the first report showing that the measured FENO level with the NIOX VERO® was approximately 30% lower than that with the NOA280i® and that there was a significant correlation between the measurements of these two devices. The correction equation that we provided may help assess the data obtained by these two analyzers. Abbreviations ATS American Thoracic Society BMI Body mass index ERS European Respiratory Society FENO Fractional exhaled nitric oxide GINA Global Initiative for Asthma NO Nitric oxide ppb Parts per billion ROC Receiver operating characteristic SD Standard deviation.
Assuntos
Testes Respiratórios/instrumentação , Óxido Nítrico/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Feminino , Humanos , Luminescência , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIM OF THE STUDY: In patients with asthma, chronic inflammatory processes and the subsequent remodeling of the airways contribute to the symptoms and the pathophysiological changes. Epithelial-mesenchymal transition (EMT) is thought to play an important role in tissue remodeling. Previous reports show that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily, exerts pro-inflammatory effects, and enhances transforming growth factor (TGF)-ß-induced EMT in bronchial epithelial cells. In this study, we investigated the TWEAK-induced cytokine and chemokine production in the human bronchial epithelial cell line BEAS-2B during EMT. MATERIALS AND METHODS: Quantitative real-time RT-PCR, enzyme-linked immunosorbent assays, western blotting, and immunohistochemistry were used to define the production of cytokines and chemokines. RESULTS: We found that TWEAK increases mRNA and protein levels of thymic stromal lymphopoietin (TSLP), monocyte chemoattractant protein -1 (MCP-1), regulated upon activation normal T cell express sequence (RANTES), and IL-8 in BEAS-2B bronchial epithelial cells. Moreover, co-treatment with TWEAK and TGF-ß1 induces not only features of EMT but also enhances the production of TSLP and RANTES. Thymus- and activation-regulated chemokines (TARC) production is induced by the co-treatment of TWEAK and TGF-ß1 but not by TWEAK or TGF-ß1 stimulation alone. Furthermore, the increased mRNA expression of TSLP and RANTES after co-treatment with TWEAK and TGF-ß1 is prevented by inhibitors of Smad-independent signaling pathways. CONCLUSIONS: In the present study, we have revealed a novel mechanism for the production of asthma-related cytokines and chemokines in EMT driven by the co-stimulation with TWEAK and TGF-ß1. We conclude that cellular EMT processes caused by TWEAK and TGF-ß1 may contribute to chronic airway inflammation and remodeling.
Assuntos
Quimiocina CCL17/biossíntese , Quimiocina CCL5/biossíntese , Citocina TWEAK/farmacologia , Citocinas/biossíntese , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta1/farmacologia , Remodelação das Vias Aéreas , Asma/metabolismo , Brônquios/citologia , Linhagem Celular , Humanos , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: A variety of innate subsets of lymphoid cells such as natural killer (NK) cells, several populations of innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells as innate-like T lymphocytes are involved in asthma and may have important effector functions in asthmatic immune responses. In the present study, we investigated whether NK cells, ILCs, and MAIT cells in the peripheral blood of patients with asthma would be associated with clinical asthma parameters. METHODS: We recruited 75 adult patients with mild to severe asthma. The peripheral blood mononuclear cells in peripheral venous blood samples from the patients were purified and stained with different combinations of appropriate antibodies. The cells were analyzed by flow cytometry. RESULTS: The percentage of activated (i.e., CD69+) NK cells in the total NK cell population was negatively correlated with FEV1% which is calculated by the forced expiratory volume in 1 s (FEV1)/the forced vital capacity (FVC). The percentages of CD69+ ILC1s and ILC2s were negatively correlated with FEV1% and %FEV1. The percentage of CD69+ ILC3s was positively correlated with BMI, and the percentage of CD69+ MAIT cells was negatively correlated with FEV1%. Moreover, the percentage of CD69+ NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other. CONCLUSIONS: For the first time, our data showed that activated NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other and may be associated with airflow limitation in patients with asthma.
Assuntos
Asma/imunologia , Asma/fisiopatologia , Imunidade Inata , Células T Invariantes Associadas à Mucosa/imunologia , Ventilação Pulmonar , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Asma/diagnóstico , Asma/tratamento farmacológico , Biomarcadores , Moléculas de Adesão Celular/sangue , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Testes de Função Respiratória , Subpopulações de Linfócitos T/metabolismoRESUMO
OBJECTIVE: Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients. However, the precise strategy for step-down therapy has not been well defined. We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid (ICS) or a switch to a leukotriene receptor antagonist (LTRA), pranlukast hydrate. METHODS: We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy. The patients were randomly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months. RESULTS: FeNO levels in the pranlukast group were significantly increased over that in the ICS group. There were no significant differences between the two groups for lung function, FOT, at the endpoint. The percentage of patients with controlled asthma was 72.2% in the pranlukast group and 90% in the ICS group. No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed. CONCLUSIONS: Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months. However, 27.8% of the pranlukast group failed to maintain well-control, and FeNO levels increased with the switch to pranlukast at 6 months. This study was been limited by the small sample size and should therefore be considered preliminary. Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy.
Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Cromonas/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/metabolismo , Asma/fisiopatologia , Quimioterapia Combinada , Feminino , Fluxo Expiratório Forçado , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Resultado do Tratamento , Capacidade Vital , Adulto JovemRESUMO
BACKGROUND: Chronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. Chronic inflammation and damage to the airway epithelium cause airway remodeling, which is associated with improper epithelial repair, and is characterized by elevated expression of transforming growth factor-ß (TGF-ß). Epithelial-mesenchymal transition (EMT) is an important mechanism during embryonic development and tissue remodeling whereby epithelial cells gain the capacity to increase motility by down-regulation of epithelial markers and up-regulation of mesenchymal markers. TGF-ß is a central inducer of EMT, and TGF-ß-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-ß1-induced EMT in the human bronchial epithelial cell line BEAS-2B. METHODS: Quantitative RT-PCR and western blotting were used to define alterations in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were assessed for 48 h after stimulation with TGF-ß1 alone or in combination with TWEAK. RESULTS: TGF-ß1 induced spindle-like morphology and loss of cell contact, and reduced the expression of epithelial marker E-cadherin and increased the expression of mesenchymal markers N-cadherin and vimentin. Our data, for the first time, show that TWEAK reduced the expression of E-cadherin, and that co-treatment with TGF-ß1 and TWEAK enhanced the TGF-ß1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-ß1 and TWEAK, but not TNF-α. We also demonstrated that the Smad, p38 MAPK, and NF-κB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-ß1 in combination with TWEAK. CONCLUSIONS: These findings suggest that the pro-inflammatory cytokine TWEAK and TGF-ß1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.
Assuntos
Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Fatores de Necrose Tumoral/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Antígenos CD/metabolismo , Brônquios/metabolismo , Brônquios/patologia , Caderinas/metabolismo , Linhagem Celular Transformada , Forma Celular/efeitos dos fármacos , Citocina TWEAK , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Glucuronosiltransferase/metabolismo , Humanos , Hialuronan Sintases , NF-kappa B/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fatores de Tempo , Vimentina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti-TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti-TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti-TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis.
Assuntos
Anticorpos Monoclonais/imunologia , Artrite Experimental/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Reabsorção Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Colágeno , Citocinas/biossíntese , Lipopolissacarídeos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologiaRESUMO
BACKGROUND: Macrophages include the classically activated pro-inflammatory M1 macrophages (M1s) and alternatively activated anti-inflammatory M2 macrophages (M2s). The M1s are activated by both interferon-γ and Toll-like receptor ligands, including lipopolysaccharide (LPS), and have potent pro-inflammatory activity. In contrast, Th2 cytokines activate the M2s, which are involved in the immune response to parasites, promotion of tissue remodeling, and immune regulatory functions. Although alveolar macrophages (AMs) play an essential role in the pulmonary immune system, little is known about their phenotypes. METHODS: Quantitative reverse transcription polymerase chain reaction and flow cytometry were used to define the characteristics of alveolar macrophages derived from untreated naïve mice and from murine models of both ovalbumin (OVA)-induced allergic airway inflammation and LPS-induced acute airway inflammation. AMs were co-cultured with CD4(+) T cells and were pulsed with tritiated thymidine to assess proliferative responses. RESULTS: We characterized in detail murine AMs and found that these cells were not completely consistent with the current M1 versus M2-polarization model. OVA-induced allergic and LPS-induced acute airway inflammation promoted the polarization of AMs towards the current M2-skewed and M1-skewed phenotypes, respectively. Moreover, our data also show that CD11c(+) CD11b(+) AMs from the LPS-treated mice play a regulatory role in antigen-specific T-cell proliferation in vitro. CONCLUSIONS: These characteristics of AMs depend on the incoming pathogens they encounter and on the phase of inflammation and do not correspond to the current M1 versus M2-polarization model. These findings may facilitate an understanding of their contributions to the pulmonary immune system in airway inflammation.
Assuntos
Hipersensibilidade/imunologia , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Ovalbumina/imunologia , Alérgenos/imunologia , Animais , Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/fisiologia , Citocinas/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The interaction between the TNF receptor family member CD27 and its ligand CD70 provides a costimulatory signal for T-cell activation. In this study, we investigated the effects of neutralizing anti-CD70 monoclonal antibody (mAb) in a murine model of allergic lung inflammation to determine whether CD27 contributes to the development of pathogenic Th2 cells and pulmonary inflammation. BALB/c mice were immunized by an injection of ovalbumin (OVA) with alum adjuvant and challenged with aerosolized OVA in PBS. Some groups of mice were treated with anti-CD70 mAb or control rat IgG during the induction or effector phase. The administration of anti-CD70 mAb during the induction phase, but not the effector phase, reduced eosinophil infiltration in lung tissue compared with control IgG-treated mice. Treatment with anti-CD70 mAb also resulted in the decreased production of Th2 cytokines (IL-4, IL-5, and IL-13) in the bronchoalveolar lavage fluid and draining lymph node cell cultures. We further revealed that antigen-specific CD4 T cells were separated into CD27(+) and CD27(-) populations in the lymph nodes of OVA-immunized DO11.10/Rag-2(-/-) mice. The CD27(+) CD4 T cells produced a high concentration of IFN-γ, representing Th1 cells. In contrast, CD27(-) CD4 T cells produced high concentrations of IL-4, IL-5, and IL-13, representing Th2 cells. Moreover, the population of CD27(-) Th2 cells was significantly reduced by the anti-CD70 mAb treatment. These results indicate an important role for CD27 in the development of pathogenic Th2 cells in a murine model of allergic lung inflammation.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Ligante CD27/imunologia , Hipersensibilidade/terapia , Pneumonia/terapia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Hipersensibilidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/imunologiaRESUMO
Allergen immunotherapy is a promising treatment for allergic diseases that induce immune tolerance through the administration of specific allergens. In this study, we investigate the efficacy of sublingual immunotherapy (SLIT) in asthmatic patients with SAR-JCP and the dynamics of the parameters before and after treatment in a real-world setting. This was a prospective single-center observational study. Patients with asthma and SAR-JCP (n = 24) were recruited for this study and assessed using symptom questionnaires before SLIT and a year after the SLIT. In addition, a respiratory function test, forced oscillation technique, and blood sampling test were performed during the off-season before and after SLIT. The one-year SLIT for asthma patients with SAR-JCP significantly improved not only allergic rhinitis symptoms, but also asthma symptoms during the JCP dispersal season, and significantly improved airway resistance during the off-season. The change in the asthma control test and the visual analog scale score during the season before and after SLIT was negatively and positively correlated with the change in peripheral blood γδ T cells off-season before and after SLIT, respectively. It was suggested that improvement in asthma symptoms during the JCP dispersal season after SLIT was associated with reduced peripheral blood γδ T cells.
Assuntos
Asma , Cryptomeria , Rinite Alérgica Sazonal , Imunoterapia Sublingual , Asma/terapia , Humanos , Pólen , Estudos Prospectivos , Rinite Alérgica Sazonal/terapiaRESUMO
Objective Based on the increasing incidence of smell and taste dysfunction among coronavirus disease 2019 (COVID-19) patients, such issues have been considered an early symptom of infection. However, few studies have investigated the type of taste components that are most frequently affected in COVID-19 patients. This study investigated the difference in frequencies of the types of taste component disorders among hospitalized COVID-19 patients. Methods In this retrospective, single-center, observational study, patients' background characteristics, clinical course, laboratory and radiological findings, and details on taste and/or smell disorders were collected and analyzed from medical records. Patients A total of 227 COVID-19 patients were enrolled, among whom 92 (40.5%) complained of taste disorders. Results Multiple types of taste disorders (hypogeusia/ageusia and hypersensitivity, or hypersensitivity and changing tastes) were reported in 10 patients. In particular, 23 patients reported hypersensitivity to at least 1 type of taste, and 2 patients complained of a bitter taste on consuming sweet foods. Impairment of all taste components was found in 48 patients (52.2%). The most frequent taste disorder was salty taste disorder (81 patients, 89.0%). Hypersensitivity to salty taste was most frequently observed (19 patients, 20.9%). Conclusion Patients with COVID-19 develop multiple types of taste disorders, among which salty taste disorder was the most frequent, with many patients developing hypersensitivity to salty taste. As smell and taste are subjective senses, further studies with the combined use of objective examinations will be required to confirm the findings.
Assuntos
Ageusia , COVID-19 , Ageusia/epidemiologia , Ageusia/etiologia , COVID-19/complicações , Disgeusia/complicações , Disgeusia/etiologia , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Paladar , Distúrbios do Paladar/diagnóstico , Distúrbios do Paladar/epidemiologia , Distúrbios do Paladar/etiologiaRESUMO
The abundance of transforming growth factor-beta (TGF-ß) in normal airway epithelium suggests its participation in physiological processes to maintain airway homeostasis. The current study was designed to address the hypothesis that TGF-ß1 and TGF-ß2 might contribute to normal reparative response of airway epithelial cells (AECs). Treatments with exogenous TGF-ß1 or TGF-ß2 significantly enhanced wound repair of confluent AEC monolayers. Mechanical injury of AEC monolayers induced production of both TGF-ß1 and TGF-ß2. Wound repair of AECs was significantly reduced by a specific inhibitor of TGF-ß type I receptor kinase activity. We investigated whether the TGF-ß-enhanced repair required epidermal growth factor receptor (EGFR) transactivation and secretion of EGFR ligands. Both TGF-ß1 and TGF-ß2 enhanced EGFR phosphorylation and induced production of heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-α) in AECs. Moreover, treatment with a broad-spectrum metalloproteinase inhibitor or anti-HB-EGF and anti-TGF-α antibodies inhibited the wound repair and the EGFR phosphorylation by TGF-ß1 and TGF-ß2, indicating that the TGF-ß1 and TGF-ß2 effects on wound repair required the release of HB-EGF and TGF-α. Our data, for the first time, have shown that both TGF-ß1 and TGF-ß2 play a stimulatory role in airway epithelial repair through EGFR phosphorylation following autocrine production of HB-EGF and TGF-α. These findings highlight an important collaborative mechanism between TGF-ß and EGFR in maintaining airway epithelial homeostasis.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Regeneração , Mucosa Respiratória/lesões , Mucosa Respiratória/fisiologia , Fator de Crescimento Transformador alfa/biossíntese , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Linhagem Celular , Receptores ErbB/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Fosforilação , Mucosa Respiratória/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta2/farmacologiaRESUMO
BACKGROUND AND OBJECTIVE: Little is known about the aetiology and clinical characteristics of COPD among people who have never smoked. METHODS: A case-control study was conducted to describe the potential risk factors for clinically significant COPD among smokers and people who had never smoked. Medical record reviews and scoring of high-resolution computed tomography (HRCT) findings were performed in patients with clinically significant COPD (defined as having post-bronchodilator FEV(1)/FVC < 0.7 and FEV(1) < 60% of the predicted values). Pathological analyses were performed in some patients following autopsy. RESULTS: Among the 9493 subjects screened, 424 (4.5%) were diagnosed with clinically significant COPD. Forty-nine (11.6% of clinically significant COPD) were never smokers (NSCOPD), and a comparative group of 98 smoking patients with COPD was randomly selected (SMCOPD). NSCOPD was characterized by predominantly female sex (87.8%) and a high prevalence of physician-diagnosed asthma (61.2%). Similar levels of reduction in %FEV(1) and %FEF(25-75%) were found in NSCOPD and SMCOPD, but there were higher %DL(CO) values and fewer low attenuation areas on HRCT in NSCOPD. More than half of the NSCOPD patients without a history of asthma had features of asthma. More than one-third of NSCOPD patients with an asthma history had never had a severe attack. At autopsy, both NSCOPD and SMCOPD showed wall thickening and inflammatory cell infiltration in small airways, and the number of CD4(+)-T cells was increased in NSCOPD. CONCLUSION: In elderly Japanese, COPD among never smokers is largely attributable to asthma. Airflow limitation in NSCOPD results from small airway disease (airway predominant phenotype) rather than parenchymal destruction (emphysematous phenotype).
Assuntos
Asma/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico por imagem , Asma/patologia , Autopsia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Humanos , Japão , Masculino , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membrane of asthmatic patients. Although serum periostin has been accepted as a type 2 biomarker, serum TNC has not been evaluated as a systemic biomarker in asthma. Therefore, the objective of this study was to evaluate whether serum TNC can serve as a novel biomarker for asthma. METHODS: We evaluated 126 adult patients with mild to severe asthma. Serum TNC, periostin, and total IgE concentrations were quantified using enzyme-linked immunosorbent assays. RESULTS: Serum TNC levels were significantly higher in patients with severe asthma and high serum total IgE levels. Patients with both high serum TNC (> 37.16 ng/mL) and high serum periostin (> 95 ng/mL) levels (n = 20) or patients with both high serum TNC and high serum total IgE (> 100 IU/mL) levels (n = 36) presented higher disease severity and more severe airflow limitation than patients in other subpopulations. CONCLUSIONS: To our knowledge, this is the first study to show that serum TNC levels in asthmatic patients are associated with clinical features of asthma and that the combination of serum TNC and periostin levels or combination of serum TNC and total IgE levels were more useful for asthma than each single marker, suggesting that serum TNC can serve as a novel biomarker for asthma.
RESUMO
A 64-year-old man who ingested liquid paraffin as a laxative for over two years, was admitted to our hospital with a persistent interstitial lung shadow and marked elevation of serum KL-6. He had no overt symptoms although his chest radiograph revealed ground glass opacities in the left lower lung field and right middle and lower lung fields. We performed fiberoptic bronchoscopy. Exogenous lipoid pneumonia was diagnosed based on microscopic analysis of the bronchoalveolar lavage fluid that revealed the presence of lipid-laden alveolar macrophages. We instructed the patient to discontinue liquid paraffin ingestion and observed his clinical course. The chest radiograph and thoracic computed tomography revealed a tendency to improve and serum KL-6 decreased with time. Serum KL-6 may be an important index of the severity of exogenous lipoid pneumonia.
Assuntos
Laxantes/efeitos adversos , Óleo Mineral/efeitos adversos , Mucina-1/sangue , Pneumonia Lipoide/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Lipoide/sangue , Pneumonia Lipoide/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL-1ß and tumor necrosis factor (TNF)-α. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1ß/TNF-α. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3' untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1ß/TNF-α, TGF-ß1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1ß/TNF-α and TGF-ß1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD.
Assuntos
Fibroblastos/metabolismo , Regulação da Expressão Gênica , Pulmão/patologia , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Regiões 3' não Traduzidas/genética , Adulto , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Doença Crônica , Dinoprostona/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
INTRODUCTION: T cell immunoglobulin and mucin domain-2 (TIM-2) has been shown to regulate CD4 T cell activation. However, the role of TIM-2 in the autoimmune disease models has not been clarified yet. In this study, we investigated the effects of anti-TIM-2 monoclonal antibodies (mAbs) in collagen-induced arthritis (CIA) to determine whether TIM-2 contributes to the development of T helper (Th) 1 or Th17 cells and joint inflammation. METHODS: DBA/1 mice were treated with anti-TIM-2 mAbs during the early or late phase of CIA. Type II collagen (CII)-specific CD4 T-cell proliferative response and cytokine production were assessed from lymph node cell culture. The serum levels of CII-specific antibody were measured by ELISA. The expression of TIM-2 on CD4 T cells or B cells was determined by flow cytometric analysis. RESULTS: Administration of anti-TIM-2 mAbs in early phase, but not late phase, significantly exacerbated the development of CIA. Although anti-TIM-2 mAbs treatment did not affect the development of Th1 or Th17 cells in the draining lymph node, the serum levels of anti-CII antibodies were significantly increased in the anti-TIM-2-treated mice. TIM-2 expression was found on splenic B cells and further up-regulated by anti-immunoglobulin (Ig)M, anti-CD40, and interleukin(IL)-4 stimulation. In contrast, CD4 T cells did not express TIM-2 even when stimulated with both anti-CD3 and anti-CD28 mAbs. Interestingly, anti-TIM-2 mAbs enhanced proliferation and antibody production of activated B cells in vitro. CONCLUSIONS: TIM-2 signaling influences both proliferation and antibody production of B cells during the early phase of CIA, but not induction of Th1 or Th17 cells.
Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Artrite Experimental/metabolismo , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Separação Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoprecipitação , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Ratos , Ratos Sprague-DawleyRESUMO
We report a case of bucillamine-induced interstitial pneumonia accompanied by severe hypoxemia in an 83-year-old woman who had rheumatoid arthritis. Respiratory failure worsened even after withdrawal of bucillamine and administration of high-dose corticosteroids, and mechanical ventilation was required. A review of 15 cases with bucillamine-induced pulmonary injury suggests that advanced age may be associated with the development of severe interstitial pneumonia. Bucillamine can cause corticosteroid-resistant and life-threatening lung injury, especially in the elderly.