RESUMEN
It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2â weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3â days or 1â month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2â weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1â month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6â months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
Asunto(s)
Elastina , Enfermedad Pulmonar Obstructiva Crónica , Animales , Autoinmunidad , Modelos Animales de Enfermedad , Humanos , Pulmón , Ratones , Ratones Endogámicos C57BL , Humo/efectos adversos , Fumar/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVE: Nuclear erythroid 2 p45-related factor-2 (Nrf2) is known to play important roles in airway disorders, whereas little has been investigated about its direct role in airway mucus hypersecretion. The aim of this study is to determine whether this factor could protect pulmonary epithelium and mouse airway from cigarette-induced mucus overproduction. METHODS: Using genetic approaches, the role of Nrf2 on cigarette smoking extracts (CSE) induced MUC5AC expression was investigated in lung A549 cells. Nrf2 deficiency mice were smoked for various periods, and the airway inflammation and mucus production was characterized. RESULTS: Acute smoking exposure induced expression of MUC5AC and Nrf2 in both A549 cells and mouse lungs. Genetic ablation of Nrf2 augmented, whereas overexpression of this molecule ameliorated CSE-induced expression of MUC5AC. Nrf2 knockout mice, after exposure to cigarette smoking, displayed enhanced airway inflammation and mucus production. CONCLUSION: Nrf2 negatively regulated smoking-induced mucus production in vitro and in vivo, suggesting therapeutic potentials of this factor in airway diseases with hypersecreted mucus.
Asunto(s)
Pulmón/fisiopatología , Moco/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Mucosa Respiratoria/fisiopatología , Fumar/efectos adversos , Animales , Línea Celular Tumoral , Regulación de la Expresión Génica , Humanos , Inflamación/etiología , Inflamación/metabolismo , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Mucina 5AC/genética , Mucina 5AC/metabolismo , Moco/metabolismo , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Primary tracheal tumors are relatively rare. Here we report one case of primary adenoid cystic carcinoma of the trachea which was ever misdiagnosed as asthma and hysteria. In this case, the pulmonary function test was normal, and firstly no obvious abnormalities were found in laryngoscopy, bronchoscopy and CT scan of chest. Later a sagittal and coronal reconstruction CT scan of trachea showed a mass situated in the subglottic trachea. Lastly a laryngoscopy was again done after a tracheal incision and showed a small mass in the posterior wall of the subglottic trachea, and tumor ablation was performed. In addition, we reviewed the literature of primary tracheal tumors and summarized the epidemiology, presenting features, available therapeutic options of the disease.
Asunto(s)
Carcinoma Adenoide Quístico/diagnóstico , Neoplasias de la Tráquea/diagnóstico , Femenino , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: To explore the effect of serum from partial hepatectomy (PH) rat and hepatocyte growth factor (HGF) on expression of albumin and AFP of bone marrow cells. METHODS: The bone marrow mono-nucleated cells were separated from SD rats and cultured in three groups: (1) The medium only group as control was added normal fetal bovine serum; (2) Rat hepatic injury serum group (was added 15% rat serum from 2-AAF+PH model); (3) HGF group (HGF 20 ng/ml). The role of these factors was determined by RT-PCR, immunohistochemistry (IHC) and Western blot, using AFP and albumin as special hepatocytic markers. RESULTS: By immunohistochemical staining and Western blot, the fresh bone marrow cells were AFP-negative, same as the cells cultured with medium only group. While bone marrow cells, co-cultured with rat hepatic injury serum or HGF at day 10 and 20, expressed AFP protein. AFP mRNA expression could be found in bone marrow cells after 10 and 20 days cultured with rat hepatic injury serum or HGF, but not in fresh bone marrow cells and bone marrow cells cultured with medium only. Albumin mRNA expression was weak in fresh bone marrow cell and increased in groups 2 and 3. CONCLUSION: The rat hepatic injury serum or HGF could stimulate the expression of AFP protein and it's mRNA of bone marrow cells. Also they can stimulate albumin mRNA expression. It seems that, in bone marrow, there is a kind of cells so called bone marrow derived liver stem cell which can express albumin mRNA in a weak style.