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1.
Am J Respir Cell Mol Biol ; 60(3): 289-298, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30326727

RESUMO

Chemoattractant receptor homologous with T-helper cell type 2 cells (CRTH2), a receptor for prostaglandin D2, is preferentially expressed on T-helper cell type 2 lymphocytes, group 2 innate lymphoid cells, eosinophils, and basophils, and elicits the production of type 2 cytokines, including profibrotic IL-13. We hypothesized that lack of CRTH2 might protect against fibrotic lung disease, and we tested this hypothesis using a bleomycin-induced lung inflammation and fibrosis model in CRTH2-deficient (CRTH2-/-) or wild-type BALB/c mice. Compared with wild-type mice, CRTH2-/- mice treated with bleomycin exhibited significantly higher mortality, enhanced accumulation of inflammatory cells 14-21 days after bleomycin injection, reduced pulmonary compliance, and increased levels of collagen and total protein in the lungs. These phenotypes were associated with decreased levels of IFN-γ, IL-6, IL-10, and IL-17A in BAL fluid. Adoptive transfer of splenocytes from wild-type, but not CRTH2-/-, mice 2 days before injection of bleomycin resolved the sustained inflammation as well as the increased collagen and protein accumulation in the lungs of CRTH2-/- mice. We consider that the disease model is driven by γδT cells that express CRTH2; thus, the adoptive transfer of γδT cells could ameliorate bleomycin-induced alveolar inflammation and fibrosis.


Assuntos
Bleomicina/farmacologia , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Receptores Imunológicos/deficiência , Receptores de Prostaglandina/deficiência , Animais , Basófilos/imunologia , Basófilos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Imunidade Inata/imunologia , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/imunologia , Fibrose Pulmonar/imunologia , Receptores Imunológicos/imunologia , Receptores de Prostaglandina/imunologia
2.
Heart Vessels ; 29(4): 560-2, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24005764

RESUMO

A 77-year-old man was referred to our cardiovascular department for detailed examination after abnormal electrocardiography findings were obtained during a preoperative cataract surgery workup. Ultrasound echocardiography (UCG) and computed tomography (CT) revealed evidence of previous myocardial infarction with anteroseptal akinesis and a left ventricular (LV) thrombus (14 × 12 mm). Dabigatran (220 mg/day) was prescribed as an outpatient treatment, and the disappearance of the LV thrombus was confirmed by UCG and CT 27 days after dabigatran initiation. No thromboembolism occurred between treatment initiation and thrombus resolution. Our results indicate that dabigatran has thrombolytic action on an acute pre-existing intracardiac thrombus.


Assuntos
Benzimidazóis/uso terapêutico , Fibrinolíticos/uso terapêutico , Cardiopatias/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Terapia Trombolítica , Trombose/tratamento farmacológico , beta-Alanina/análogos & derivados , Idoso , Dabigatrana , Cardiopatias/diagnóstico , Ventrículos do Coração/diagnóstico por imagem , Humanos , Achados Incidentais , Masculino , Valor Preditivo dos Testes , Trombose/diagnóstico , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia , beta-Alanina/uso terapêutico
4.
Am J Physiol Lung Cell Mol Physiol ; 304(10): L701-7, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23564510

RESUMO

Neutrophilic inflammation is associated with chronic airway diseases. It has been observed that human neutrophil elastase (HNE), which is secreted by active neutrophils during inflammation, induces both mucin overproduction and goblet cell metaplasia. Several in vitro studies suggest that tumor necrosis factor-α converting enzyme (TACE) regulates the signaling axis that mediates HNE-induced mucin overproduction; however, it is unknown whether TACE performs a similar function in HNE-induced goblet cell metaplasia in vivo. We conducted this study to determine whether the inactivation of Tace gene expression attenuates HNE-induced goblet cell metaplasia in mice. Deletion of Tace is lethal shortly after birth in mice; therefore, we utilized Tace(flox/flox)R26CreER(+/-) mice and induced conditional deletion of Tace using a tamoxifen injection. Wild-type mice were given tamoxifen to control for its effect. Tace conditional deletion mice and wild-type mice were exposed to HNE via nasal instillation three times at 3-day intervals, and the lungs were harvested on day 11 after initial HNE exposure. Using periodic acid-Schiff staining and MUC5AC immunohistochemical staining to visualize goblet cells in the lungs, we found that HNE induced goblet cell metaplasia in the wild-type mice and that HNE-induced goblet cell metaplasia was significantly attenuated in the Tace conditional deletion mice. These findings suggest that TACE could be a potential target in the treatment of goblet cell metaplasia in patients with chronic airway diseases.


Assuntos
Proteínas ADAM/deficiência , Células Caliciformes/enzimologia , Células Caliciformes/patologia , Elastase de Leucócito/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/metabolismo , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Metaplasia , Camundongos , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Tamoxifeno/farmacologia
5.
J Cardiol Cases ; 8(2): e81-e84, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30546749

RESUMO

An 80-year-old man, who had dilated cardiomyopathy with right ventricular (RV) dilatation, underwent implantable cardioverter defibrillator (ICD) implantation for advanced atrioventricular block and primary prevention of sudden cardiac death. Tined and screw-in leads were placed on the right atrial appendage and RV apex, respectively. Ventricular pacing inhibition was detected after surgery due to oversensing by diaphragmatic myopotential occurring only during deep inspiration. We performed re-surgery and switched the screw-in lead for a tined lead. The diaphragmatic myopotential decreased, thereby improving oversensing by diaphragmatic myopotential and ventricular pacing inhibition. It might be beneficial to use a tined lead when placing the ventricular lead at the RV apex for implantation of a pacemaker or ICD if oversensing of diaphragmatic myopotential is observed using a screw-in lead. .

6.
Int Arch Allergy Immunol ; 155 Suppl 1: 6-11, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21646789

RESUMO

The prostaglandin D(2) (PGD(2))/CRTH2 pathway is important for eosinophil trafficking in vitro; however, genetic deficiency of CRTH2 does not suppress in vivo eosinophilic airway inflammation in acute models of asthma, and the role of CRTH2 in the pathogenesis of asthma is still ambiguous. Therefore, in the present study we explored whether the PGD(2)/CRTH2 pathway could affect the phenotypes of chronic asthma. Either CRTH2-deficient (CRTH2-/-) or wild-type mice were sensitized and exposed to ovalbumin (OVA) for 3 days (acute model) or 6 weeks (chronic model). While the magnitude of the acute eosinophilic inflammation was equivalent between CRTH2-/- and wild-type mice, the number of inflammatory cells and eosinophils in bronchoalveolar lavage fluid after chronic OVA exposure was significantly reduced in CRTH2-/- mice (18.0 ± 2.6 × 10(4) cells and 2.0 ± 0.5 × 10(4) cells) compared to wild-type mice (27.9 ± 2.5 × 10(4) cells and 6.8 ± 1.1 × 10(4) cells, p < 0.001). On the contrary, no difference was observed between CRTH2-/- and wild-type mice in terms of airway hyperresponsiveness or remodeling (goblet cell hyperplasia) in the chronic model of asthma. In conclusion, CRTH2 that mediates PGD(2) activity is essential for sustained eosinophilic inflammation in the airways, and its antagonists could exert an anti-inflammatory effect in chronic asthma.


Assuntos
Asma/complicações , Eosinofilia Pulmonar/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animais , Asma/imunologia , Asma/metabolismo , Asma/patologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Eosinófilos/patologia , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Cloreto de Metacolina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mucinas/metabolismo , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Eosinofilia Pulmonar/etiologia , Eosinofilia Pulmonar/patologia , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Vacinação
7.
J Immunol ; 187(2): 999-1005, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21685325

RESUMO

Allergic bronchopulmonary mycosis, characterized by excessive mucus secretion, airflow limitation, bronchiectasis, and peripheral blood eosinophilia, is predominantly caused by a fungal pathogen, Aspergillus fumigatus. Using DNA microarray analysis of NCI-H292 cells, a human bronchial epithelial cell line, stimulated with fungal extracts from A. fumigatus, Alternaria alternata, or Penicillium notatum, we identified a mucin-related MUC5AC as one of the genes, the expression of which was selectively induced by A. fumigatus. Quantitative RT-PCR, ELISA, and histochemical analyses confirmed an induction of mucin and MUC5AC expression by A. fumigatus extracts or the culture supernatant of live microorganisms in NCI-H292 cells and primary cultures of airway epithelial cells. The expression of MUC5AC induced by A. fumigatus extracts diminished in the presence of neutralizing Abs or of inhibitors of the epidermal growth factor receptor or its ligand, TGF-α. We also found that A. fumigatus extracts activated the TNF-α-converting enzyme (TACE), critical for the cleavage of membrane-bound pro-TGF-α, and its inhibition with low-molecular weight inhibitors or small interfering RNA suppressed the expression of MUC5AC. The protease activity of A. fumigatus extracts was greater than that of other fungal extracts, and treatment with a serine protease inhibitor, but not with a cysteine protease inhibitor, eliminated its ability to activate TACE or induce the expression of MUC5AC mRNA in NCI-H292. In conclusion, the prominent serine protease activity of A. fumigatus, which caused the overproduction of mucus by the bronchial epithelium via the activation of the TACE/TGF-α/epidermal growth factor receptor pathway, may be a pathogenetic mechanism of allergic bronchopulmonary mycosis.


Assuntos
Aspergillus fumigatus/enzimologia , Aspergillus fumigatus/imunologia , Regulação Fúngica da Expressão Gênica/imunologia , Mucina-5AC/biossíntese , Mucinas/biossíntese , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Serina Proteases/metabolismo , Proteínas ADAM/fisiologia , Proteína ADAM17 , Animais , Aspergillus fumigatus/genética , Linhagem Celular Tumoral , Células Cultivadas , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Receptores ErbB/fisiologia , Regulação Enzimológica da Expressão Gênica/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mucina-5AC/genética , Mucinas/genética , Mucosa Respiratória/enzimologia , Fator de Crescimento Transformador alfa/fisiologia
8.
Wound Repair Regen ; 19(2): 229-40, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21362091

RESUMO

Lysophospatidic acid (LPA) is a bioactive lipid mediator implicated in tissue repair and wound healing. It mediates diverse functional effects in fibroblasts, including proliferation, migration and contraction, but less is known about its ability to evoke paracrine signaling to other cell types involved in wound healing. We hypothesized that human pulmonary fibroblasts stimulated by LPA would exhibit ectodomain shedding of epidermal growth factor receptor (EGFR) ligands that signal to lung epithelial cells. To test this hypothesis, we used alkaline phosphatase-tagged EGFR ligand plasmids transfected into lung fibroblasts, and enzyme-linked immunosorbent assays to detect shedding of native ligands. LPA induced shedding of alkaline phosphatase-tagged heparin-binding epidermal growth factor (HB-EGF), amphiregulin, and transforming growth factor-a; non-transfected fibroblasts shed amphiregulin and HBEGF under baseline conditions, and increased shedding of HB-EGF in response to LPA. Treatment of fibroblasts with LPA resulted in elevated phosphorylation of extracellular signal-regulated kinase 1/2, enhanced expression of mRNA for c-fos, HB-EGF and amphiregulin, and enhanced proliferation at 96 hours. However, none of these fibroblast responses to LPA required ectodomain shedding or EGFR activity. To test the ability of LPA to stimulate paracrine signaling from fibroblasts, we transferred conditioned medium from LPA-stimulated cells, and found enhanced EGFR and extracellular signal-regulated kinase 1/2 phosphorylation in reporter A549 cells in excess of what could be accounted for by transferred LPA alone. These data show that LPA mediates EGF-family ectodomain shedding, resulting in enhanced paracrine signaling from lung fibroblasts to epithelial cells.


Assuntos
Receptores ErbB/metabolismo , Fibroblastos/metabolismo , Pulmão/citologia , Lisofosfolipídeos/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Anfirregulina , Células Cultivadas , Família de Proteínas EGF , Fibroblastos/efeitos dos fármacos , Glicoproteínas/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Am J Respir Cell Mol Biol ; 45(2): 376-85, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21097655

RESUMO

Bronchoconstriction applies compressive stress to airway epithelial cells. We show that the application of compressive stress to cultured murine tracheal epithelial cells elicits the increased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt through an epidermal growth factor receptor (EGFR)-dependent process, consistent with previous observations of the bronchoconstriction-induced activation of EGFR in both human and murine airways. Mechanotransduction requires metalloprotease activity, indicating a pivotal role for proteolytic EGF-family ligand shedding. However, cells derived from mice with targeted deletions of the EGFR ligands Tgfα and Hb-egf showed only modest decreases in responses, even when combined with neutralizing antibodies to the EGFR ligands epiregulin and amphiregulin, suggesting redundant or compensatory roles for individual EGF family members in mechanotransduction. In contrast, cells harvested from mice with a conditional deletion of the gene encoding the TNF-α-converting enzyme (TACE/ADAM17), a sheddase for multiple EGF-family proligands, displayed a near-complete attenuation of ERK and Akt phosphorylation responses and compressive stress-induced gene regulation. Our data provide strong evidence that TACE plays a critical central role in the transduction of compressive stress.


Assuntos
Proteínas ADAM/fisiologia , Células Epiteliais/metabolismo , Mecanotransdução Celular/fisiologia , Estresse Mecânico , Traqueia/metabolismo , Proteína ADAM17 , Animais , Células Cultivadas , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Immunoblotting , Integrases/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Traqueia/citologia , Fator de Necrose Tumoral alfa/fisiologia
10.
Respirology ; 14(6): 822-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19703064

RESUMO

BACKGROUND AND OBJECTIVE: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC(4) synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC(4) synthase gene polymorphisms, were also investigated. METHODS: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV(1) after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. RESULTS: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC(4) synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). CONCLUSIONS: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug.


Assuntos
Antiasmáticos/farmacocinética , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Cromonas/farmacocinética , Cromonas/uso terapêutico , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Asma/etnologia , Feminino , Volume Expiratório Forçado/fisiologia , Glutationa Transferase/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Farmacogenética , Polimorfismo Genético/genética , Estudos Retrospectivos , Resultado do Tratamento
11.
Eur J Pharmacol ; 600(1-3): 133-9, 2008 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-18950617

RESUMO

There are reports indicating that thromboxane A(2) receptors (TP receptors) may stimulate the eosinophil accumulation in the lower airways of asthmatics, however, the mechanisms behind such an effect remain unknown. We quantified the synthesis of eosinophil chemotactic activity and eosinophilic CC chemokines, including CCL5, CCL7, CCL8, CCL11, CCL13, CCL24, and CCL26 in primary cultures of human bronchial smooth muscle cells (BSMC) stimulated with a prostanoid TP receptor agonist, IBOP (10(-9)-10(-7) M). The activation of prostanoid TP receptors in BSMC induced the release of potent eosinophil chemoattractant(s) in the presence of interleukin (IL)-4. CCL11/eotaxin-1 was the only synthesis significantly increased by IBOP co-stimulated with IL-4, and pretreatment with an anti-CCL11 antibody abrogated the eosinophil chemotactic activity released from IBOP/IL-4-stimulated BSMC. The effect of IBOP was also completely blocked by pretreatment with a prostanoid TP receptor-specific antagonist, AA-2414. IBOP had no effect on the expression of IL-4 receptor-alpha, or on the IL-4-induced phosphorylation of STAT6 in BSMC. In conclusion, activation of prostanoid TP receptors in a Th2-dominant microenvironment might exacerbate the eosinophilic inflammation of the airways by synthesis and release of CCL11 from BSMC.


Assuntos
Quimiocinas CC/metabolismo , Eosinófilos/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Asma/fisiopatologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Quimiocina CCL11/metabolismo , Quimiotaxia de Leucócito/fisiologia , Ácidos Graxos Insaturados/farmacologia , Humanos , Interleucina-4/farmacologia , Receptores de Tromboxano A2 e Prostaglandina H2/agonistas
12.
Nihon Kokyuki Gakkai Zasshi ; 46(9): 748-52, 2008 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-18939420

RESUMO

Prader-Willi syndrome (PWS) is a genetic disorder, characterized by shorter height, severe obesity and muscular hypotonicity. In particular, sleep disordered breathing (SDB) is a well-known complication in PWS. We encountered one case of PWS, complicated by typical obesity hypoventilation syndrome. A 23-year-old woman had been given a diagnosis of PWS as age 1, therefore she was treated with growth hormone replacement therapy, and with uvulopalatopharyngoplasty (UPPP) for her narrow throat. Her weight increased greatly to 96kg, body mass index (BMI) 51 kg/m2, resulting in hypersomnolence, cyanosis, heavy snoring, and nocturnal awakening. Eventually, she was admitted because of urinary incontinuence and loss of consciousness. On admission, she had severe hypoxia plus substantial hypercapnia, and her chest X-ray film showed severe cardiomegaly with massive pleural and pericardial effusion. On polysomnography (PSG) one week later, her apnea hypopnea index (AHI) was 16 with a mean nocturnal arterial saturation of 74%, mean percutaneous PCO2 59 Torr, which rose to 73 Torr during REM sleep. Non-invasive positive pressure ventilation (NPPV) was initiated, and improved her condition greatly. She was discharged, but continued to recieve NPPV, and her condition has stayed improved.


Assuntos
Síndrome de Hipoventilação por Obesidade/etiologia , Síndrome de Prader-Willi/complicações , Adulto , Feminino , Humanos , Síndrome de Hipoventilação por Obesidade/terapia , Respiração com Pressão Positiva , Síndrome de Prader-Willi/terapia , Resultado do Tratamento
13.
Nihon Kokyuki Gakkai Zasshi ; 46(8): 673-8, 2008 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-18788439

RESUMO

We reported a case of overlap syndrome involving severe obstructive sleep apnea syndrome (OSAS) associated with chronic obstructive lung disease (COPD). This patient was a 52-year-old heavy smoking man, who had suffered from snoring and apnea for five years, and was admitted to our hospital because of worsening dyspnea. His BMI was 25 Kg/M2, His jaw was very small and he had a narrow upper airway. Chest X-ray showed hyperlucency throughout both lung fields with a markedly dilatation pulmonary arteries. His PaO2 was 62Torr, PaCO2 was 47Torr, FEV(1.0%) was 59%, mean pulmonary artery pressure was 27 mmHg, PSG showed that AHI was 70, were most pronounced during rapid eye movement sleep. He was given a diagnosis of overlap syndrome of OSAS associated with COPD. Generally, Overlap syndrome was believed that chronic bronchitis type (blue bloater) was more frequent than emphysema type. This case was a very rare case, with no obesity, moderate COPD, associated with pulmonary hypertension and hypercapnea, and then to be severe OSAS. However we should be more careful about the OSAS associated with overlap syndrome of the Japanese patients, because to be one factor of exacerbation of respiratory failure.


Assuntos
Doença Pulmonar Obstrutiva Crônica/complicações , Apneia Obstrutiva do Sono/complicações , Humanos , Masculino , Pessoa de Meia-Idade
14.
J Immunol ; 180(1): 541-9, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18097056

RESUMO

Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Prostaglandina D2/metabolismo , RNA de Cadeia Dupla/imunologia , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Hipersensibilidade Respiratória/imunologia , Animais , Eosinófilos/imunologia , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Mutantes , Poli I-C/imunologia , Ratos , Ratos Endogâmicos , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Hipersensibilidade Respiratória/patologia
15.
J Immunol ; 178(1): 489-95, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17182588

RESUMO

Respiratory infections with RNA viruses, such as rhinovirus or respiratory syncytial virus, are a major cause of asthma exacerbation, accompanied by enhanced neutrophilic and/or eosinophilic inflammation of the airways. We studied the effects of dsRNA synthesized during RNA virus replication, and of its receptor, TLR3, on the synthesis of eosinophilic chemokines in bronchial smooth muscle cells (BSMC). Synthetic dsRNA, polyinosinic-cystidic acid (poly(I:C)), induced the synthesis of eosinophilic chemokines, eotaxin-1/CCL11 and RANTES/CCL5, from primary cultures of human BSMC, and IL-4 increased synergistically the synthesis of poly(I:C)-induced CCL11. A robust eosinophil chemotactic activity was released from BSMC stimulated with poly(I:C) and IL-4, which was mostly inhibited by preincubation with an anti-CCL11, but not with an anti-CCL5 Ab. Although the immunoreactivity of TLR3 was detectable on the cellular surface of BSMC by flow cytometric analysis, pretreatment with an anti-TLR3-neutralizing Ab failed to block the poly(I:C)-induced synthesis of CCL11. We have determined by confocal laser-scanning microscopy that the immunoreactivity of TLR3 was aggregated intracellularly in poly(I:C)-stimulated BSMC, colocalizing with fluorescein-labeled poly(I:C). The synthesis of CCL11 was prominently inhibited by the transfection of TLR3-specific small interfering RNA or by bafilomycin A1, an endosomal acidification inhibitor, further supporting the essential role played by intracellular TLR3 in the synthesis of poly(I:C)-induced CCL11 in BSMC. In conclusion, these observations suggest that, by activating intracellular TLR3 in BSMC, respiratory RNA virus infections stimulate the production of CCL11 and enhance eosinophilic inflammation of the airways in the Th2-dominant microenvironment.


Assuntos
Brônquios/metabolismo , Quimiocinas CC/metabolismo , Miócitos de Músculo Liso/metabolismo , Vírus de RNA/imunologia , RNA de Cadeia Dupla/farmacologia , Receptor 3 Toll-Like/metabolismo , Brônquios/citologia , Brônquios/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL11 , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Quimiocinas CC/genética , Quimiotaxia de Leucócito , Eosinófilos/imunologia , Humanos , Interleucina-4/farmacologia , Miócitos de Músculo Liso/química , Miócitos de Músculo Liso/efeitos dos fármacos , Poli I-C/farmacologia , RNA Interferente Pequeno/farmacologia , Receptor 3 Toll-Like/análise , Receptor 3 Toll-Like/antagonistas & inibidores
16.
J Cardiovasc Pharmacol ; 48(3): 95-102, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17031262

RESUMO

Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/metabolismo , Ecocardiografia , Masculino , Metaloproteases/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Estreptozocina/farmacologia , Taxa de Sobrevida , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Crescimento Transformador beta/metabolismo
18.
J Pharmacol Exp Ther ; 312(3): 954-60, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15528449

RESUMO

Mast cell-derived prostaglandin D(2) (PGD(2)) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD(2), prostaglandin D(2) receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th(2) cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD(2)-induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD(2) and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD(2) in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD(2), 11-deoxy-11-methylene-15-keto-PGD(2), and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD(2), but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A(2) receptor (TP) agonist ([1S-1alpha,2beta(5Z), 3alpha(1E,3R*),4alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD(2) or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,548 (5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-[1S-[1alpha,2alpha(Z),3alpha,4alpha]]), or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD(2). These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD(2)-related airway inflammation.


Assuntos
Prostaglandina D2/farmacologia , Eosinofilia Pulmonar/induzido quimicamente , Receptores Imunológicos/fisiologia , Receptores de Prostaglandina/fisiologia , Animais , Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Interleucina-5/farmacologia , Masculino , Eosinofilia Pulmonar/patologia , Ratos , Ratos Endogâmicos BN
19.
Artigo em Inglês | MEDLINE | ID: mdl-15519496

RESUMO

Thromboxane A2 receptor (TP) mediates bronchial smooth muscle cell (BSMC) contraction, airway hyperresponsiveness, and airway inflammation in patients with asthma. In the present study, a pathogenic role of TP activation in airway remodeling was examined using primary cultures of human BSMC. A TP agonist, I-BOP, concentration-dependently enhanced not only bromodeoxyuridine (BrdU) uptake but also cell proliferation of BSMC. A TP-selective antagonist, AA-2414, blocked the effects of I-BOP on both BrdU uptake and cell proliferation. I-BOP-induced BrdU uptake was significantly blocked by two non-selective tyrosine kinase inhibitors, genistein and herbimycin A, or a Src family tyrosine kinase inhibitor, PP2, but not by an inhibitor of epidermal growth factor (EGF) receptor-associated tyrosine kinase, AG1478. In conclusion, TP receptor activation causes DNA synthesis and cell proliferation of human BSMC by activating tyrosine kinases including Src, but not by EGF receptor transactivation.


Assuntos
Brônquios/citologia , Músculo Liso/citologia , Músculo Liso/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/agonistas , Bromodesoxiuridina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Ácidos Graxos Insaturados/agonistas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Músculo Liso/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo
20.
Cardiovasc Res ; 64(3): 526-35, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15537506

RESUMO

OBJECTIVE: Transforming growth factor (TGF)-beta promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. METHODS: Anterior MI was produced in mice by ligating the left coronary artery. TGF-beta mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-beta signaling during the early phase of MI, an extracellular domain of TGF-beta type II receptor (TbetaIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. RESULTS: TbetaIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-beta signaling during the later phase, TbetaIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TbetaIIR. CONCLUSIONS: The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.


Assuntos
Infarto do Miocárdio/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Remodelação Ventricular , Animais , Quimiocina CCL2/genética , Ecocardiografia , Expressão Gênica , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia , Infiltração de Neutrófilos , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo II , Fatores de Tempo , Transfecção/métodos
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