RESUMO
Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression.
Assuntos
Hipertensão Pulmonar Primária Familiar/genética , MicroRNAs/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Células Cultivadas , Citocromos c/genética , Citocromos c/metabolismo , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-n-(3,5-dichloropyrid-4-yl)benzamide) was the first agent of a novel pharmacological class, selective phosphodiesterase 4 (PDE(4)) inhibitors, approved for the use of chronic obstructive pulmonary disease (COPD). The molecular mechanism of action of roflumilast is inhibition of the PDE(4) isoenzyme with a consequent increase of cyclic adenosine monophosphate. Roflumilast evidently has several pharmacological effects: antiinflammatory, anti-emphysema, and antibiotic actions. This drug also inhibits pulmonary hypertension and reduces mucus hypersecretion. The pharmacological actions leading to these effects are: a) inhibition of reactive oxygen species formation in epithelial cells, neutrophils and smooth muscle cells; b) inhibition of smooth muscle cell proliferation in the pulmonary artery, endothelial cells and probably some inflammatory cells causing pulmonary vascular remodeling; c) inhibition of fibroblasts, with a consequent reduction in pulmonary remodeling and, finally, d) inhibition of mucus production and improved ciliary beat frequency. In summary, roflumilast is the first non-steroidal anti-inflammatory drug that can be used in the treatment of COPD.
Assuntos
Aminopiridinas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Divisão Celular/efeitos dos fármacos , Cílios/efeitos dos fármacos , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Muco/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Ratos , Fumaça/efeitos adversos , NicotianaAssuntos
Anti-Inflamatórios/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Cílios/efeitos dos fármacos , Cílios/fisiologia , AMP Cíclico/fisiologia , GMP Cíclico/fisiologia , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapêutico , Humanos , Inflamação , Isoenzimas/fisiologia , Mucinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Diester Fosfórico Hidrolases/fisiologia , Circulação Pulmonar/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/enzimologia , Enfisema Pulmonar/enzimologia , Sistemas do Segundo MensageiroRESUMO
Primary ciliary dyskinesia is a genetically inherited syndrome characterized by cilia immotility or dysmotility. Deficiency in mucociliary clearance produces chronic respiratory infections since birth, male sterility by spermatozoid immotility and situs inversus in 40-50% of patients (Kartagener's syndrome). Diagnosis is made by analyzing cilia motility with high-speed digital video and ciliar ultrastructure. The wide distribution and functions of the cilia in the body mean that this dysfunction can generate other ciliopathies apart from primary ciliary dyskinesia.