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2.
J Gastroenterol Hepatol ; 33(5): 980-989, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29319191

RESUMO

BACKGROUND AND AIM: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS: This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-µg linaclotide or placebo at centers in China, North America, and Oceania. Patients reported bowel and abdominal symptoms daily; adverse events were monitored. Co-primary and secondary endpoints were tested using a predefined three-step serial gatekeeping multiple comparisons procedure. RESULTS: The intent-to-treat population included 839 patients (mean age = 41 years; 82% female; 81% Asian). The trial met all co-primary and secondary endpoints. Co-primary responder criteria were met by 60.0% of linaclotide patients versus 48.8% of placebo patients for abdominal pain/discomfort (≥ 30% decrease for ≥ 6/12 weeks; P < 0.05), and 31.7% of linaclotide versus 15.4% of placebo patients for IBS degree of relief (score ≤ 2 for ≥ 6/12 weeks; P < 0.0001). Secondary 12-week change-from-baseline endpoints (spontaneous bowel movement/complete spontaneous bowel movement frequency, stool consistency, straining, abdominal pain, abdominal discomfort, and abdominal bloating) were significantly improved with linaclotide versus placebo (all P < 0.0001). Diarrhea was the most common adverse event (9.4% linaclotide, 1.2% placebo). Discontinuation rates due to diarrhea were low (0.7% linaclotide, 0.2% placebo). CONCLUSIONS: Once-daily 290-µg linaclotide improved bowel habits, abdominal symptoms, and global measures in a predominantly Chinese IBS-C population.


Assuntos
Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Agonistas da Guanilil Ciclase C/administração & dosagem , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Agonistas da Guanilil Ciclase C/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
3.
F1000Res ; 6: 199, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344777

RESUMO

Physical inactivity is a well-established risk factor for colorectal cancer (CRC). Recent studies have characterized physical activity (PA), sedentary behavior, and cardiorespiratory fitness as distinct, interrelated constructs that influence the risk of CRC and related outcomes. PA levels required to confer protection against CRC may be higher than previously thought. Sedentary behavior, defined as time spent sitting, increases CRC risk independent of PA and may require novel interventions distinct from those targeting PA. Finally, cardiorespiratory fitness is inversely associated with CRC risk and mortality and may provide a potential tool for risk stratification and intervention.

4.
Respirology ; 16(2): 367-77, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21199160

RESUMO

BACKGROUND AND OBJECTIVE: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition. METHODS: Primary human bronchial epithelial cells and lung parenchymal fibroblasts were infected with RV-2 or RV-16, or treated with RV-16 RNA, imiquimod (Toll-like receptor (TLR) 7/8 agonist) or polyinosinic : polycytidylic acid (poly I : C) (activator of TLR 3, retinoic-acid-inducible protein I and melanoma-differentiated-associated gene 5). Changes in ECM proteins and their transcription were measured by ELISA and quantitative real-time PCR. In addition, gene expression for ECM proteins was assessed in a mouse model of RV infection. RESULTS: RV infection increased deposition of the ECM protein, perlecan, by human bronchial epithelial cells, and collagen V and matrix-bound vascular endothelial growth factor were increased in both human bronchial epithelial cell and fibroblast cultures. Purified RV-16 RNA, poly I : C and imiquimod induced similar increases in ECM deposition to those observed with RV-infected fibroblasts. However, only poly I : C induced ECM deposition by bronchial epithelial cells, suggesting that RV-induced ECM deposition is mediated through TLR. Furthermore, gene expression for fibronectin and collagen I was increased in lung homogenates of mice infected with RV-1b. CONCLUSIONS: RV infection and TLR ligands promote ECM deposition in isolated cell systems and RV induces ECM gene expression in vivo, thus demonstrating that RV has the potential to contribute to remodelling of the airways through induction of ECM deposition.


Assuntos
Remodelação das Vias Aéreas , Asma/virologia , Brônquios/virologia , Infecções por Picornaviridae/virologia , Aminoquinolinas/farmacologia , Animais , Asma/metabolismo , Brônquios/metabolismo , Células Cultivadas , Colágeno Tipo V/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/virologia , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Imiquimode , Camundongos , Infecções por Picornaviridae/metabolismo , Poli I-C/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas
5.
Respir Res ; 7: 71, 2006 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-16670028

RESUMO

BACKGROUND: Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscle cells (HASM). We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells. METHODS: HASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity. RESULTS: RV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-kappaB + AP-1 in the non-asthmatic HASM cells. CONCLUSION: This study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.


Assuntos
Asma/virologia , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Miócitos de Músculo Liso/virologia , Rhinovirus/patogenicidade , Adolescente , Adulto , Asma/imunologia , Proteína alfa Estimuladora de Ligação a CCAAT/imunologia , Morte Celular , Células Cultivadas , Feminino , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Miócitos de Músculo Liso/imunologia , Sistema Respiratório/virologia , Rhinovirus/imunologia , Transcrição Gênica/imunologia , Transfecção
6.
Clin Pharmacokinet ; 45(3): 217-33, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16509757

RESUMO

Chronic obstructive pulmonary disease (COPD) is a multicomponent, chronic inflammatory disease of the lungs with systemic complications. The majority of the inflammation occurs in the peripheral airways and lung parenchyma. It is a progressive disease, leading to disability and eventual death, despite conventional therapy. Inflammatory activity can be reduced by increasing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) through inhibition of phosphodiesterase (PDE) IV, the principal PDE isoenzyme within pro-inflammatory cells, including eosinophils, mast cells, macrophages, lymphocytes, neutrophils and epithelial cells. PDE IV inhibition also has other effects, including relaxation of airway smooth muscle, suppression of smooth muscle mitogenesis and modulation of excitatory activity in pulmonary nerves. Cilomilast is a systemically available, second-generation, selective PDE IV inhibitor. It retains the therapeutic activity of the first-generation PDE IV inhibitors but lacks their profound emetic effect. Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits linear pharmacokinetics, with low between-subject variability. Cilomilast is highly protein bound (99.4%), but this binding is concentration-independent at clinically relevant doses, and it has a small volume of distribution at steady state (17L). Plasma clearance (approximately 2 L/h) is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours and steady state is rapidly achieved with twice-daily administration. The most abundant metabolite, formed by the action of cytochrome P450 2C8, has <10% of the activity of the parent molecule. Cilomilast pharmacokinetics in COPD patients were consistent with those in healthy subjects. Smoking, age and ethnicity had no clinically relevant effects. Total plasma cilomilast pharmacokinetic parameters did not change significantly with renal or hepatic impairment, but concentrations of unbound cilomilast increased with declining renal or hepatic function. Cilomilast had no clinically relevant interactions with a range of drugs likely to be coadministered to patients with COPD, with the exception of erythromycin where concurrent administration with cilomilast was associated with an increased incidence of gastrointestinal adverse events, a pharmacodynamic interaction predicted by their secondary pharmacology. Nausea was the principal adverse reaction seen in healthy subjects taking cilomilast, but this was reduced by administration with food or by use of simple dose-escalation regimens. Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline. Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD. It is generally well tolerated and has not generated safety concerns in any clinical study.


Assuntos
Nitrilas/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Ácidos Carboxílicos/uso terapêutico , Ácidos Cicloexanocarboxílicos , Interações Medicamentosas , Humanos , Nitrilas/efeitos adversos , Nitrilas/química , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo
7.
Eur J Heart Fail ; 7(5): 865-8, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16087139

RESUMO

BACKGROUND: Increased levels of bacterial lipopolysaccharide (LPS) have been demonstrated in chronic heart failure (CHF). LPS can induce cellular desensitization, with specific down-regulation of LPS-mediated cellular tumor necrosis factor (TNF-alpha) production which does not affect other cytokine parameters. It is not known if LPS desensitization occurs in CHF. METHODS AND RESULTS: Mononuclear cells from 24 CHF patients (mean age 70+/-2 years, age range 58 to 78 years, NYHA class 3.0+/-0.2) and 11 healthy controls (mean age 53+/-3 years, age range 39 to 75 years) were separated from venous blood and cultured for 24 h with LPS (E. coli, 0-10 ng/mL). Culture supernatants were tested for TNF-alpha and interleukin-1 receptor antagonist (IL-1RA). Patients were subgrouped into mild (n=10), moderate (n=5), and severe (n=9) CHF. Independently of age, mononuclear cells from patients with severe heart failure produced less TNF-alpha than controls (p<0.05) and patients with mild (p<0.001) or moderate CHF (p<0.05). IL-1RA release was higher for CHF patients as a group, compared with controls (p<0.05). There was no significant difference in IL-1RA release between CHF patient subgroups. CONCLUSIONS: Mononuclear cells from patients with severe heart failure produce significantly less TNF-alpha than healthy controls or patients with mild to moderate disease. Production of IL-1RA is not affected. This resembles a picture indicative of LPS desensitization occurring in patients with severe CHF.


Assuntos
Endotoxinas/sangue , Insuficiência Cardíaca/sangue , Idoso , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/metabolismo
8.
Am J Respir Cell Mol Biol ; 30(3): 342-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12871851

RESUMO

Granulocyte macrophage-colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T cell, and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-kappaB (NF-kappaB), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 microM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression, but the expression of GM-CSF was not inhibited by SB 203580 (10 microM), an inhibitor of p38-MAP kinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2, and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-kappaB:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-kappaB activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 microM), an inhibitor of NF-kappaB translocation and the specific IKK-2-Inhibitor (AS602868; 10 microM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-kappaB-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-kappaB activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/metabolismo , Adulto , Cromatina/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Inibidores Enzimáticos/farmacologia , Feminino , Flavonoides/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos dos fármacos , Histona Acetiltransferases , Humanos , Ácidos Hidroxâmicos/farmacologia , Proteínas I-kappa B/metabolismo , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase 1 , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/genética , Fosforilação/efeitos dos fármacos , Transporte Proteico , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno
9.
J Allergy Clin Immunol ; 111(2): 367-73, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12589358

RESUMO

BACKGROUND: Protease-activated receptors 1 and 2 (PAR-1 and PAR-2) are 7-transmembrane G protein-coupled receptors activated by serine proteases in many cell types, including monocytes-macrophages, leading to the production of pro-inflammatory mediators, cytokines, and growth factors. OBJECTIVE: We determined the influence of chronic smoking and asthma on the expression of PAR-1 and PAR-2 receptors on alveolar macrophages (AMs). METHODS: We used RT-PCR and immunocytochemistry with confocal microscopy to determine mRNA and protein expression of PAR-1 and PAR-2 in AMs obtained from healthy smokers, asthmatic patients, and healthy subjects. In addition, we examined the effect of IL-1beta and LPS. RESULTS: PAR1 mRNA was decreased, whereas PAR2 mRNA was increased in 24-hour cultured AMs from smokers when compared with values in AMs from healthy subjects. Paradoxically, there was a higher degree of PAR-1 protein staining in AMs from smokers, whereas PAR-2 staining was similar in smokers and healthy subjects. PAR-1 and PAR-2 mRNA and protein expression were similar in asthmatic patients and control subjects. IL-1beta and LPS had no effect on PAR1 and PAR2 gene expression by AMs. CONCLUSIONS: There is a dissociation between gene and protein expression of PAR-1 and PAR-2. PAR-1 protein overexpression in AMs from smokers might be important in the pathophysiology of chronic airways disease.


Assuntos
Inflamação/metabolismo , Macrófagos Alveolares/metabolismo , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Adulto , Asma/genética , Asma/metabolismo , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Inflamação/genética , Interleucina-1/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor PAR-1 , Receptor PAR-2 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fumar/genética , Fumar/metabolismo
10.
Am J Respir Crit Care Med ; 166(5): 724-31, 2002 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12204872

RESUMO

Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21(CIP1/WAF1) is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21(CIP1/WAF1) protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x(L), an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21(CIP1/WAF1) and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.


Assuntos
Apoptose , Asma/patologia , Ciclinas/análise , Macrófagos Alveolares/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Fumar/patologia , Adulto , Western Blotting , Líquido da Lavagem Broncoalveolar/citologia , Broncoscopia , Estudos de Casos e Controles , Divisão Celular , Células Cultivadas , Doença Crônica , Inibidor de Quinase Dependente de Ciclina p21 , Feminino , Humanos , Imuno-Histoquímica , Ativação de Macrófagos/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Proteína bcl-X
11.
Am J Respir Crit Care Med ; 166(3): 392-6, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12153977

RESUMO

Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein-associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.


Assuntos
Asma/genética , Asma/fisiopatologia , Expressão Gênica/genética , Histona Desacetilases/genética , Histona Desacetilases/fisiologia , Sistema Respiratório/fisiopatologia , Administração por Inalação , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Broncoscopia , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/fisiopatologia , Masculino , Testes de Função Respiratória , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética
12.
Proc Natl Acad Sci U S A ; 99(13): 8921-6, 2002 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-12070353

RESUMO

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/biossíntese , Mediadores da Inflamação/metabolismo , Teofilina/farmacologia , Adulto , Asma/enzimologia , Asma/genética , Sequência de Bases , Líquido da Lavagem Broncoalveolar/citologia , Broncodilatadores/uso terapêutico , Estudos de Casos e Controles , Estudos Cross-Over , Primers do DNA , Dexametasona/farmacologia , Método Duplo-Cego , Indução Enzimática , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Regiões Promotoras Genéticas , Teofilina/uso terapêutico
13.
Eur J Pharmacol ; 441(3): 193-202, 2002 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-12063092

RESUMO

The two kinin receptors, B(1) and B(2), are upregulated in inflammation and may play a role in diseases such as asthma. In pulmonary A549 cells, TNF-alpha or interleukin-1 beta dramatically increased bradykinin B(1) and B(2) receptor mRNA expression and this response was prevented by dexamethasone. In primary human bronchial epithelial cells, bradykinin B(1) receptor mRNA expression showed a similar trend, whereas bradykinin B(2) receptor showed almost constitutive expression. Radioligand-binding studies revealed significant increases in bradykinin B(2) receptor protein expression following both interleukin-1 beta and TNF-alpha treatment of A549 cells; however, no evidence was found for bradykinin B(1) receptor. Functionally, the bradykinin B(2) receptor ligand, bradykinin, but not the B(1) ligand, des-Arg(10)-kallidin, produced a marked increase in prostaglandin E(2) release when administered following interleukin-1 beta treatment. Arachidonic acid release in response to bradykinin was markedly enhanced by prior incubation with interleukin-1 beta and this was prevented by the prior addition of dexamethasone.


Assuntos
Citocinas/farmacologia , Dexametasona/farmacologia , Células Epiteliais/efeitos dos fármacos , Inflamação/metabolismo , Receptores da Bradicinina/biossíntese , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Cultivadas , Citocinas/fisiologia , Dinoprostona/biossíntese , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , RNA Mensageiro/biossíntese , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina
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