呼吸道黏蛋白MUC5AC表达调控的研究进展[综述]

MUC5AC是呼吸道黏液中重要的黏蛋白，感染、炎症因子、环境污染物等多种因素可在转录、转录后和表观遗传等多水平实现对其表达调控。在多种气道黏液高分泌疾病，如哮喘、慢性阻塞性肺疾病、慢性鼻窦炎的发生、发展及预后中，MUC5AC表达异常发挥重要作用。随着研究的不断深入，对MUC5AC的表达调控是临床诊疗和新药研发的重要靶点。本文就黏蛋白生理特点、MUC5AC表达调控机制及在呼吸道疾病中的研究进展做一综述。     

跨膜蛋白16A在呼吸道黏膜上皮细胞的表达和功能研究

黏液过度分泌是变应性鼻炎、慢性鼻-鼻窦炎、哮喘、慢性阻塞性肺疾病和囊性纤维化等呼吸道炎性疾病的重要特征。杯状细胞化生、黏液纤毛清除功能障碍是导致鼻腔及呼吸道黏液积聚的重要病理改变。新近研究发现，钙激活氯离子通道（calcium-activated chloride channels，CaCCs）的分子结构跨膜蛋白16A（transmembrane protein16A，TMEM16A）与黏液分泌调控有关，不仅表现在介导电解质跨上皮转运及水合作用，还参与黏液中黏蛋白5AC的分泌调节。本文介 绍TMEM16A在呼吸道黏膜上皮的表达和功能的研究进展。     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

一氧化氮对呼吸道纤毛运动的调控机制

呼吸道上皮细胞表面的纤毛是黏液纤毛传输系统的重要组成成分,研究发现一氧化氮在纤毛运动的调控机制中发挥重要作用.本文对一氧化氮信号分子在呼吸道分布,一氧化氮对纤毛运动调控机制以及一氧化氮与鼻科相关疾病发病的相关性做一综述.     

Distribution of respiratory mucin proteins in human nasal mucosa

OBJECTIVES/HYPOTHESIS: The upper respiratory tract is involved in many acute and chronic respiratory tract diseases that present with the symptom of mucus hypersecretion. Mucin genes that encode for the backbone of glycoproteins contribute to the viscoelastic property of airway mucus. We examined the cellular expression and distribution of two major respiratory mucus-forming glycoproteins, MUC5AC and MUC5B, in normal human nasal tissues. METHODS: Immunohistochemical analysis using polyclonal antibodies against the mucins MUC5AC and MUC5B was performed in normal human nasal tissues. RESULTS: An abundant staining of submucosal mucus gland and epithelial goblet cells for MUC5B was found. Immunohistochemical analysis of MUC5AC showed staining of surface epithelium goblet cells, whereas there was no staining of glandular cells. Comparison of the expression to lower airways revealed a similar pattern of expression of both mucins. CONCLUSIONS: The data in the present study demonstrated the localization of the two major respiratory mucin proteins in human nasal mucosa with a similar distribution of expression of MUC5AC and MUC5B in normal upper and lower airways. Mucin protein expression parallels that of mucin messenger RNA expression.     

B淋巴细胞诱导成熟蛋白-1在变应性鼻炎中的作用研究进展

变应性鼻炎(AR)是特异性免疫球蛋白E介导的鼻黏膜非感染性慢性炎症性疾病,以Th2及其分泌的IL-4、IL-5参与主要炎症过程.B淋巴细胞诱导成熟蛋白-1(Blimp-1)是一种含锌指基序的转录抑制因子,调控T细胞发育、分化和功能,对活化T淋巴细胞增殖分化和免疫自稳有重要的调节作用.鉴于Blimp-1对于下呼吸道及其他...     

Effects of bacterial toxins on air-exposed cultured human respiratory sinus epithelium

The present study was designed to investigate the effects of the bacterial toxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on air-exposed cultured human respiratory sinus epithelium. The morphological changes, proliferation, and differentiation of sphenoid sinus mucosa were examined after incubation with different LPS or LTA concentrations. Air-exposed cultured sinus mucosa differentiated from pseudostratified respiratory epithelium to squamous ciliated epithelium with few goblet cells. High concentrations of bacterial toxins induced a significant increase in mucus production and a decrease in ciliated cells. Ki67 immunostaining showed an increased cell proliferation after incubation with moderate levels of LPS or LTA. High concentrations of bacterial toxins, on the other hand, induced a decreased proliferation. Involucrin expression was clearly altered by incubation with high levels of bacterial toxins, indicating an increased degree of terminal differentiation. These results indicate that the bacterial toxins LPS and LTA both induce comparable dose-dependent morphological changes in sinus epithelium.     

Upregulation of MUC8 and Downregulation of MUC5AC by Inflammatory Mediators in Human Nasal Polyps and Cultured Nasal Epithelium

Polyps are believed to be the source of mucus hypersecretion in chronic inflammation of the sinus. However, it is not clear which mucins are responsible for the hypersecretion of mucus by nasal polyps. We describe the over-expression of MUC8 mRNA in nasal polyps and the upregulation of MUC8 mRNA expression and downregulation of MUC5AC mRNA expression by inflammatory mediators. We found that the level of MUC8 mRNA, but not the level of MUC5AC mRNA, increased in nasal polyps. We also found that there was an increase in intracellular mucin in nasal polyps, compared to the normal nasal inferior turbinate. A mixture of inflammatory mediators increased MUC8 mRNA expression and decreased MUC5AC mRNA expression in cultured normal human nasal epithelial cells. Among inflammatory mediators, IL-4 is responsible for the decrease in MUC5AC mRNA and MUC5AC mucin secretion. These results indicate that MUC8 may be one of the major mucins secreted from the polyp epithelium and that it may play an important role in the pathogenesis of mucus hypersecretion in chronic sinusitis with polyps.     

Upregulation of MUC8 and downregulation of MUC5AC by inflammatory mediators in human nasal polyps and cultured nasal epithelium

Polyps are believed to be the source of mucus hypersecretion in chronic inflammation of the sinus. However, it is not clear which mucins are responsible for the hypersecretion of mucus by nasal polyps. We describe the over-expression of MUC8 mRNA in nasal polyps and the upregulation of MUC8 mRNA expression and downregulation of MUC5AC mRNA expression by inflammatory mediators. We found that the level of MUC8 mRNA, but not the level of MUC5AC mRNA, increased in nasal polyps. We also found that there was an increase in intracellular mucin in nasal polyps, compared to the normal nasal inferior turbinate. A mixture of inflammatory mediators increased MUC8 mRNA expression and decreased MUC5AC mRNA expression in cultured normal human nasal epithelial cells. Among inflammatory mediators, IL-4 is responsible for the decrease in MUC5AC mRNA and MUC5AC mucin secretion. These results indicate that MUC8 may be one of the major mucins secreted from the polyp epithelium and that it may play an important role in the pathogenesis of mucus hypersecretion in chronic sinusitis with polyps.     

EP4 agonist inhibits lipopolysaccharide-induced mucus secretion in airway epithelial cells

OBJECTIVES: We examined the in vivo effects of agonists for prostaglandin E2 receptors (EP1, EP2, EP3, and EP4) on mucus hypersecretion. We also examined the in vitro effects of EP agonists on airway epithelial cells. METHODS: For the in vivo study, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. For the in vitro study, we used NCI-H292 cells and cultured human nasal epithelial cells. RESULTS: Subcutaneous injection of the EP4 agonist (1 to 100 microg/kg) dose-dependently inhibited LPS-induced mucus production and neutrophil infiltration. The EP3 agonist (100 microg/kg) also had some inhibitory effects on mucus production, whereas the EP1 and EP2 agonists showed no effect. The LPS-induced mucus secretion was significantly inhibited by the EP3 and EP4 agonists at 10(-6) mol/L in cultured epithelial cells. The LPS-induced interleukin-8 secretion was also inhibited by the EP3 and EP4 agonists. CONCLUSIONS: These results indicate that the EP4 agonist inhibited LPS-induced airway mucus hypersecretion directly or indirectly through the suppression of interleukin-8 secretion and neutrophil infiltration.     

Quantitative Study of Nasal Secretory Cells in Normal Subjects and Patients With Chronic Sinusitis

The contribution of nasal secretory cells to mucus hypersecretion in chronic sinusitis was investigated. The mucosae of the inferior turbinate were obtained from 18 normal control subjects and 65 patients with chronic sinusitis. Histochemical quantitation showed that there was no significant difference in the number of goblet cells between normal controls and chronic sinusitis. On the other hand, the number of submucosal acinar cells in chronic sinusitis was significantly higher than that in normal controls ( P < 0.01). The area occupied by the acini in lamina propria was also increased in chronic sinusitis ( P < 0.01). There was no significant difference in the distribution of the intra-acinar glycoproteins between normal control subjects and patients with chronic sinusitis. Results suggest that hyperplasia and hypertrophy of nasal acinar cells may have an important role in mucus hypersecretion in chronic sinusitis.     

Laryngeal cancer and passive smoking: the neglected factor?

In the present paper we investigate the relationship of environmental tobacco smoke (ETS) exposure to laryngeal cancer. 209 patients who were diagnosed with laryngeal cancer from 2000 to 2009 at the University Hospital of Patras, Western Greece, were reviewed with regard to patient age, disease stage at presentation, tumor differentiation, tobacco product use, alcohol consumption, occupation, and ETS exposure in the working environment. Pearson Chi-square method was used to determine the effect of ETS exposure on cancer stage, TNM classification and tumor differentiation in the dichotomized population (exposed vs. not exposed) and in groups of low, medium and high ETS exposure. ETS exposure in the working environment was found to significantly affect overall disease stage and T stage (p < 0.01) both in the dichotomic analysis and the group analysis. Minor significance was also noted for N stage (p = 0.047) in the exposure group analysis. Our data suggest that occupational ETS exposure presents a contributing risk factor for laryngeal cancer that requires further research to determine its significance.     

Respiratory diseases and genotoxicity in tobacco smoke exposed children

BACKGROUND: Tobacco smoke, containing more than 4800 chemical substances with a large number of mutagenic and carcinogenic compounds, is the most important indoor pollution. Aim of the study was to analyse the relationship between exposure of children (2-15 years) to environmental tobacco smoke (ETS) with the amount of respiratory diseases, the occurrence of atopic diseases and the risk for genotoxic damage. PATIENTS AND METHODS: Within the last 1.5 years 216 children were included in the study. Smoking habits of the family, environmental settings, housing, nutrition, social and economic factors were assessed by a detailed questionnaire. Two different effect markers were used to assess molecular and genetic damage. Biochemical effect of ETS was quantified by 4-aminobiphenyl-hemoglobin (4-ABP-Hb) adducts and the genotoxic damage was determined by chromosomal damage as seen in the micro nucleus test in lymphocytes. RESULTS: Chronic rhinosinusitis and allergic rhinitis are accumulated in the ETS-exposed children. In the ETS-group atopic diseases (allergic rhinitis, extrinsic asthma or neurodermatitis) were significantly more frequent (39.5 %, p = 0.01) than in the non-exposed group (23 %). In addition the genetic predisposition was significantly decreased in the ETS-group (20.8 %, p = 0.048) compared to the non-exposed group (45 %).Until now, blood samples of 63 individuals were analysed for Hb adducts and 92 for micro nuclei. Hemoglobin adducts of 4-ABP, a human carcinogenic aromatic amine, were significantly elevated in children with smoking parents (mean: 82.2pg/g Hb, p = 0.003) compared to children with non-smoking parents (mean: 60.6 pg/g Hb). ETS-exposed children showed significantly higher micro nucleus frequencies (mean ETS: 8.0/1000 binucleate (BN) cells, p = 0.001) than non-ETS exposed children (mean: 6.2/1000 BN cells). CONCLUSION: Our data underline the thesis, that ETS plays an important role for the development of atopic diseases. The significantly increased effect markers of tobacco smoke in exposed children give evidence, that ETS causes elevated molecular and genotoxic damage in children.