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1.
Biochem Biophys Res Commun ; 519(2): 220-226, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31493864

RESUMO

While most asthma can be treated with steroids, about 10%, called severe asthma, is refractory to steroids. It has recently been shown that in a subgroup of severe asthma cases, neutrophils that infiltrate into the airways play an important role in inflammation. However, the mechanisms underlying this increased neutrophil infiltration are not well understood. Here, using a mouse model of steroid-resistant neutrophilic inflammation, we show that mice deficient for the RNA-binding protein Mex-3B have significantly less neutrophil infiltration in the airways than wild-type mice. We further demonstrate that Mex-3B post-transcriptionally upregulates CXCL2, a chemokine that induces neutrophil chemotaxis and migration. Moreover, we show that treatment with either anti-CXCL2 antibody or anti-Mex-3B antisense oligonucleotide suppresses neutrophilic allergic airway inflammation. These results suggest that Mex-3B-mediated induction of CXCL2 is crucial for steroid-resistant neutrophilic allergic airway inflammation. Our findings suggest new strategies for therapeutic intervention in steroid-resistant severe asthma.


Assuntos
Resistência a Medicamentos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Esteroides/farmacologia , Animais , Anticorpos/imunologia , Reações Antígeno-Anticorpo , Asma/tratamento farmacológico , Asma/metabolismo , Quimiocina CXCL2/imunologia , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/metabolismo , Oligonucleotídeos/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores
2.
Mod Rheumatol ; 28(4): 621-625, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29057700

RESUMO

OBJECTIVES: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department. METHODS: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed. RESULTS: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively). CONCLUSION: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Transtornos Linfoproliferativos/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão
3.
Mod Rheumatol ; 27(1): 22-28, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27142966

RESUMO

OBJECTIVES: Acute or subacute exacerbations are recognized as a severe complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Nevertheless, the role of intensive immunosuppression in RA-ILD remains elusive. We attempted to evaluate the clinical characteristics and efficacy of immunosuppressive treatment in exacerbated RA-ILD. METHODS: Clinical data, including respiratory function, imaging, treatment, and prognosis, were retrospectively collected for 17 patients with RA-ILD who required hospitalization at the University of Tokyo Hospital due to an acute exacerbation (12 patients) or subacute exacerbation (5 patients). RESULTS: Patients with RA-ILD demonstrated a significantly higher titers of anticyclic citrullinated peptide antibodies compared with RA patients in Japanese Ninja registry, suggesting the role of adaptive immunity. Immunosuppressive treatment suppressed the deterioration of pulmonary functions with improved ground grass opacity and consolidation. In particular, in patients with less fibrosis on computed tomography (CT) images showed a better response to treatment. Although five patients treated with combination therapy, including cyclophosphamide, showed a severely decreased lung volume, these intensive therapies provided a good prognosis without fatalities for the average observation period of 474 days. CONCLUSIONS: Immunosuppressive therapy is effective for exacerbations of RA-ILD. For severe cases with low respiratory function, intensive therapy, including cyclophosphamide, has a potential to improve the prognosis.


Assuntos
Artrite Reumatoide , Ciclofosfamida/uso terapêutico , Doenças Pulmonares Intersticiais , Pulmão , Peptídeos Cíclicos/imunologia , Idoso , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Progressão da Doença , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Imunossupressores/uso terapêutico , Japão , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
4.
J Spinal Cord Med ; 40(1): 122-125, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27104610

RESUMO

CONTEXT: To our knowledge, only a few reports regarding the spinal involvement of granulomatosis with polyangiitis (GPA)-also termed as Wegener's granulomatosis-have been published. However, all these cases reportedly exhibited epidural tumor-like lesions or dural thickening. FINDINGS: We report the case of a 57-year-old woman with progressive myelopathy caused by multiple spinal lesions with GPA, which appeared to be protruding inwards, within the dura mater, on magnetic resonance imaging (MRI); these lesions were difficult to distinguish from intradural tumors. Moreover, these lesions exhibited low intensity on both T1- and T2-weighted MRI, and showed prominent enhancement on gadolinium-contrast imaging. Resection biopsy was effective for both diagnosis and the recovery of the neurological deficit. CONCLUSION: Based on these findings, we suggest that GPA lesions can exhibit variable patterns in the spine. Nevertheless, clinicians should consider the possibility of GPA in such cases, particularly when multiple, inwardly protruding tumor-like lesions are detected within the dura mater on MRI.


Assuntos
Granulomatose com Poliangiite/diagnóstico , Doenças da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/diagnóstico , Diagnóstico Diferencial , Dura-Máter/diagnóstico por imagem , Dura-Máter/patologia , Feminino , Humanos , Pessoa de Meia-Idade
5.
Cell Rep ; 16(9): 2456-71, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27545879

RESUMO

Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.


Assuntos
Hiper-Reatividade Brônquica/terapia , Células Epiteliais/efeitos dos fármacos , Interleucina-33/imunologia , MicroRNAs/imunologia , Oligonucleotídeos Antissenso/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Sequência de Bases , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , MicroRNAs/genética , Conformação de Ácido Nucleico , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Ovalbumina , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologia
6.
Biochem Biophys Res Commun ; 443(1): 266-71, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24309112

RESUMO

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.


Assuntos
Hipersensibilidade/tratamento farmacológico , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Monoterpenos/uso terapêutico , Eosinofilia Pulmonar/tratamento farmacológico , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Hipersensibilidade/prevenção & controle , Imunossupressores/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/prevenção & controle , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monoterpenos/efeitos adversos , Ovalbumina/imunologia , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/prevenção & controle
7.
J Immunol ; 191(6): 2879-89, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23935198

RESUMO

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.


Assuntos
Alendronato/farmacologia , Conservadores da Densidade Óssea/farmacologia , Eosinófilos/imunologia , Macrófagos/efeitos dos fármacos , Pneumonia/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Quimiocina CCL24/biossíntese , Quimiocina CCL24/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Eosinófilos/metabolismo , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
8.
Case Rep Med ; 2013: 750275, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23983712

RESUMO

We report a case of rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis who responded to single course of polymyxin b-immobilized fiber column treatment. Initial treatment with pulsed corticosteroids and cyclophosphamide, intravenous immunoglobulin, and cyclosporine seemed to suppress the activity of interstitial lung disease temporarily, but signs of relapse were detected such as elevation of serum KL-6 level and progressing pulmonary shadows in chest computed tomography scan. After polymyxin b-immobilized fiber column treatment, the areas of pulmonary shadows drastically decreased. Gradually, arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio recovered, and serum ferritin level and KL-6 level decreased. These findings indicate that polymyxin b-immobilized fiber column treatment could be promising in combination with conventional therapy for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis, especially at the early phase of relapse.

9.
J Immunol ; 187(10): 5077-89, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21998459

RESUMO

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22-producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4(+) T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22-binding protein abolished IL-22-induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22.


Assuntos
Regulação para Baixo/imunologia , Eosinofilia/imunologia , Eosinofilia/patologia , Imunossupressores/metabolismo , Interleucina-10/fisiologia , Interleucinas/biossíntese , Regulação para Cima/imunologia , Animais , Regulação para Baixo/genética , Eosinofilia/genética , Técnicas de Transferência de Genes , Humanos , Imunossupressores/administração & dosagem , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucinas/administração & dosagem , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regulação para Cima/genética , Interleucina 22
11.
Int Arch Allergy Immunol ; 149 Suppl 1: 14-20, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19494499

RESUMO

Hepatocyte growth factor (HGF) has an important role in many biological events such as angiogenesis and cell proliferation, as well as anti-fibrotic and anti-apoptotic effects. In addition, we found that HGF suppresses antigen-induced immune responses in the airway by suppressing dendritic cell functions, using a HGF-producing plasmid vector. In the present study, we examined whether delivery of the HGF protein in the lung attenuates allergic airway inflammation in a mouse model. Generally, HGF is rapidly cleared from organs. So, to achieve the efficient delivery of HGF, we prepared a slow-releasing form by mounting recombinant human (rh) HGF protein in biodegradable gelatin hydrogels. BALB/c mice were immunized and then challenged with ovalbumin (OVA) to induce eosinophilic airway inflammation. Intratracheal delivery of a very small amount of gelatin-coupled rhHGF (0.3 microg) just once before the inhalation of OVA significantly suppressed eosinophilic airway inflammation. In addition, cytokine production in thoracic lymph nodes and the antigen-presenting capacity of lung CD11c+ cells were reduced. In contrast, delivery of 1.0 microg of rhHGF did not exhibit any significantly suppressive effect. These results suggest that the controlled release of rhHGF protein can suppress antigen-induced allergic immune responses in the lung. Therefore, HGF could be a novel therapeutic option for asthma.


Assuntos
Asma/tratamento farmacológico , Fator de Crescimento de Hepatócito/administração & dosagem , Animais , Preparações de Ação Retardada , Gelatina/administração & dosagem , Géis/administração & dosagem , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/administração & dosagem
12.
Int Arch Allergy Immunol ; 149 Suppl 1: 25-30, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19494501

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is now considered a chronic inflammatory disease. Although dendritic cells (DCs) are thought to play a key role in immune responses, studies investigating the role of DCs in COPD are quite limited. METHODS: Porcine pancreas elastase was intratracheally administered to C57BL/6J mice on day 0. On days 2, 7 and 14, emphysema formation was evaluated by pressure-volume relationships and microscopic findings, including measurement of the mean linear intercept. Lung DCs were isolated on day 2, and their ability to stimulate allogeneic T cells and to produce cytokines was examined. RESULTS: Pathologic emphysematous change was observed on day 2 and a significant increase in lung volume was observed on day 14. Lung DC function, such as the induction of T-cell proliferation and IL-10 production, was upregulated. CONCLUSIONS: Upregulation of DC function was observed in elastase-induced emphysema. Further investigation on the contribution to emphysema formation may provide a useful target for future therapy.


Assuntos
Células Dendríticas/imunologia , Enfisema/imunologia , Regulação para Cima , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Proliferação de Células , Modelos Animais de Doenças , Interleucina-10/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática/imunologia , Linfócitos T/citologia
13.
Nihon Kokyuki Gakkai Zasshi ; 45(10): 766-71, 2007 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-18018624

RESUMO

We treated a case of chronic pigeon breeder's disease with pulmonary cysts. The patient was a 49-year-old woman whose husband had started to breed pigeons 23 years earlier. She was given a diagnosis of hypersensitivity pneumonitis due to pigeons 1 year previously, but since her husband refused to stop keeping the birds, she could not stay out of contact with them. A chest CT scan showed bilateral multiple pulmonary cysts and a diffuse groundglass appearance. The transbronchial lung biopsy (TBLB) specimens showed bronchioloalveolitis characterized by infiltration of lymphocytes and plasma cells into the walls of the bronchioles and the surrounding alveolar walls. Tests for antibodies to extracts of both pigeon droppings and budgerigar droppings were positive. After admission to our hospital and avoidance of contact with birds, the groundglass changes, dyspnea, and hypoxemia ameliorated. Multiple pulmonary cysts in a non-smoker is a rare manifestation of chronic pigeon breeder's disease.


Assuntos
Pulmão do Criador de Aves/complicações , Pulmão do Criador de Aves/patologia , Cistos/etiologia , Cistos/patologia , Pneumopatias/etiologia , Pneumopatias/patologia , Pulmão do Criador de Aves/diagnóstico , Pulmão do Criador de Aves/terapia , Doença Crônica , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade
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