RESUMO
Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular pathogen of macrophages. Intracellular pattern recognition receptors in macrophages such as nucleotide-binding oligomerization domain (NOD) proteins regulate pro-inflammatory cytokine production. NOD2-mediated signalling pathways in response to M.tb have been studied primarily in mouse models and cell lines but not in primary human macrophages. Thus we sought to determine the role of NOD2 in regulating cytokine production and growth of virulent M.tb and attenuated Mycobacterium bovis BCG (BCG) in human macrophages. We examined NOD2 expression during monocyte differentiation and observed a marked increase in NOD2 transcript and protein following 2-3 days in culture. Pre-treatment of human monocyte-derived and alveolar macrophages with the NOD2 ligand muramyl dipeptide enhanced production of TNF-α and IL-1ß in response to M.tb and BCG in a RIP2-dependent fashion. The NOD2-mediated cytokine response was significantly reduced following knock-down of NOD2 expression by using small interfering RNA (siRNA) in human macrophages. Finally, NOD2 controlled the growth of both M.tb and BCG in human macrophages, whereas controlling only BCG growth in murine macrophages. Together, our results provide evidence that NOD2 is an important intracellular receptor in regulating the host response to M.tb and BCG infection in human macrophages.
Assuntos
Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Western Blotting , Diferenciação Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoprecipitação , Inflamação/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Tirosina Quinases/genética , RNA Interferente Pequeno/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Quinase Syk , Receptor 2 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Sleep-disordered breathing (SDB) has a higher prevalence in patients with heart failure than in the general middle-aged population. Obstructive sleep apnea (OSA), one of the forms of SBD, promotes poorly controlled hypertension, coronary events, and atrial fibrillation events that can lead to acutely decompensated heart failure (ADHF), and evidence suggests that untreated OSA increases mortality in patients with heart failure. Cheyne-Stokes respiration and central sleep apnea (CSA) have long been associated with heart failure and, in many patients, can coexist with OSA. In this article, we propose a systematic approach to diagnose and treat OSA in patients with ADHF based on current evidence.
Assuntos
Respiração de Cheyne-Stokes/complicações , Insuficiência Cardíaca/etiologia , Apneia do Sono Tipo Central/complicações , Apneia Obstrutiva do Sono/complicações , Respiração de Cheyne-Stokes/epidemiologia , Respiração de Cheyne-Stokes/terapia , Pressão Positiva Contínua nas Vias Aéreas , Insuficiência Cardíaca/mortalidade , Humanos , Prevalência , Apneia do Sono Tipo Central/epidemiologia , Apneia do Sono Tipo Central/terapia , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapia , Estados Unidos/epidemiologiaRESUMO
Constrictive bronchiolitis (CB) is a rare disease with unclear etiology. We report a 37-year-old female with CB who developed progressive dyspnea and cough after completing a course of 5-fluorouracil (5-FU) for colon cancer. The patient had evidence of irreversible obstructive lung disease and lung biopsy showed typical findings of chronic inflammation, submucosal thickening and obliteration of bronchioles. To the best of our knowledge this is the first reported case of CB after treatment with 5-FU.