Validity of Measurement of Two Specific Biomarkers for the Assessment of Small Airways Inflammation in Asthma

Background: Small airways inflammation in asthma has been supposed to contribute to instability of the disease and therapy resistance. This study was designed to determine the validity of measurement of N^ε-(carboxymethyl)lysine (CML) levels in induced sputum and alveolar concentrations of nitric oxide (NO) for the assessment of small airways inflammation in asthma. Methods: The authors measured CML levels in induced sputum and the bronchial flux (Jno) and alveolar concentration (C_alv) of NO in 37 asthmatic patients and 15 normal controls. After initial analysis, all asthmatics were randomly assigned to receive inhaled fluticasone propionate (FP; 400 μg/day, n = 21) or hydrofluoroalkane–beclomethasone dipropionate (HFA-BDP; 400 μg/day, n = 16) for 12 weeks. And then the determination of exhaled NO level and sputum induction was performed after the treatment period. Results. CML levels in induced sputum were significantly higher in asthmatics than in normal controls (median [interquartile range], asthmatics: 53.0 [44.8–64.3] μg/ml, normal controls: 22.0 [14.8–28.3] μg/ml; p < .01). Similarly, Jno and C_alv were also higher in asthmatics. Moreover, CML level was closely correlated with C_alv but not with Jno in asthmatics (r = .47, p = .005). Jno was significantly correlated with forced expiratory volume in one second/forced vital capacity (FEV₁/FVC), and CML level and C_alv were correlated with forced expiratory flow between 25% and 75% of FVC (FEF_25–75), an index of small airways obstruction. After FP treatment, the decrease in CML level and Calv were very small. In contrast, these levels were markedly decreased after HFA-BDP treatment. Moreover, even after FP or HFA-BDP treatment, CML level was significantly correlated with C_alv. Conclusions: This novel, noninvasive technique of measurement of CML levels in induced sputum and C_alv may prove to be important not only in the evaluation of small airways inflammation but also in helping us move toward a better understanding of the roles of the small airways in the pathogenesis of asthma.     

一夜持续正压呼吸道通气治疗对阻塞性睡眠呼吸暂停低通气综合征患者睡眠结构的影响

目的了解一夜持续正压呼吸道通气(CPAP)治疗对阻塞性睡眠呼吸暂停低通气综合征(OSAS)患者睡眠结构的影响。方法经多导睡眠图(PSG)确诊的OSAS患者113例,经CPAP治疗一夜(≥7 h),同时行PSG监测,观察患者治疗前后睡眠结构以及病情严重程度的参数变化。结果经一夜CPAP治疗后,1、2期睡眠占睡眠总时间的比率显著降低,分别为4.5%、10.1%(P<0.05);3、4期睡眠(深睡眠)占睡眠总时间比率增加6.5%(P<0.05),快速眼动睡眠比率增加8.0%(P<0.05)。呼吸紊乱指数(AHI)下降59.6%(P<0.05);最低血氧饱和度、平均血氧饱和度分别增加18.0%、5.0%(P<0.05)。结论一夜CPAP治疗能显著改善睡眠结构,增加患者的深睡眠,降低AHI,增高血氧饱和度。     

Acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects

The German MAK value of 1-methoxypropanol-2 has been fixed at 100 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects. Twenty subjects were exposed in a crossover design to 100 ppm 1-methoxypropanol-2 and to air in an exposure chamber for 4 h. Subjective symptoms were assessed by questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1β and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1β, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric cross-over analyses. Subjects did not have any subjective irritating symptoms. The olfactory threshold was slightly elevated following exposure to 1-methoxypropanol-2. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels except for interleukin 1β were higher after exposure to 1-methoxypropanol-2. In conclusion, the acute exposure to 100 ppm 1-methoxypropanol-2 did not cause clear-cut adverse effects in test subjects     

DIFFERENTIAL SUSCEPTIBILITY TO OXIDANT EXPOSURE IN INBRED STRAINS OF MICE: NITROGEN DIOXIDE VERSUS OZONE

The contribution of genetic background to the pathogenesis of airway responses to environmental agents including air pollutants is becoming increasingly clear. Characterization of genetic mechanisms of response to these agents may assist in the identification of susceptible individuals and populations. The primary objective of this investigation was to utilize inbred strains of mice to determine (1) whether there was significant genetic contribution in susceptibility to lung injury and inflammation induced by single and repeated acute exposures to nitrogen dioxide (NO2) and (2) whether similar genetic factors control sus- ceptibility to lung injury induced by NO2 and another oxidant, ozone (O3). Nine strains of inbred mice (male, 5-6 wk) were studied: 129/ J, A/ J, AKR/ J, BALB/ cJ, C3H/ HeJ, C57BL/6J, DBA/2J, SJL/J, and SWR/J. Each was exposed for 3 h to filtered air (controls) or 15 ppm NO2, and cellular inflammation, epithelial injury, and cytotoxicity were measured 2, 6, and 24 h thereafter. NO2 exposure caused significant increases in cytotoxicity and lavageable macrophages, epithelial cells, polymorphonuclear leukocytes, and protein in all strains. Interstrain variation in each of these effects indicated that genetic background contributed a significant portion of the variance in responses to this oxidant. Two strains that were differentially susceptible to 3-h exposure to 15 ppm NO2\[C57BL/6J (B6), C3H/HeJ (C3)] were also exposed for 6 h/ day to 10 ppm NO2 on 5 consecutive days. Each of the responses to NO2 was completely adapted after 5 days in resistant C3 mice. Only the lavageable total protein response was adapted in susceptible B6 mice. To determine whether mechanisms of susceptibility to NO2 and O3 were the same, each strain was exposed for 3 h to filtered air or 2 ppm O3 and inflammation was assessed 6 and 24 h thereafter. Strain distribution patterns (SDPs) for responses to each oxidant were not significantly concordant and indicated that susceptibility mechanisms were different. Results of these studies suggest that there is a strong genetic component to NO2 susceptibility that is partially adaptable and significantly different from O3 susceptibility.     

Mechanics of airflow in the human nasal airways

The mechanics of airflow in the human nasal airways is reviewed, drawing on the findings of experimental and computational model studies. Modelling inevitably requires simplifications and assumptions, particularly given the complexity of the nasal airways. The processes entailed in modelling the nasal airways (from defining the model, to its production and, finally, validating the results) is critically examined, both for physical models and for computational simulations. Uncertainty still surrounds the appropriateness of the various assumptions made in modelling, particularly with regard to the nature of flow. New results are presented in which high-speed particle image velocimetry (PIV) and direct numerical simulation are applied to investigate the development of flow instability in the nasal cavity. These illustrate some of the improved capabilities afforded by technological developments for future model studies. The need for further improvements in characterising airway geometry and flow together with promising new methods are briefly discussed.     

MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation

Although β(2)-adrenergic receptors (β(2)AR) are expressed on most cell types, mechanisms that establish expression levels and regulate expression by chronic agonist remain unclear. The 3' UTR of ADRB2 has a conserved 8-nucleotide seed region that we hypothesized is targeted by the let-7 family of miRNAs leading to translational repression. In luciferase assays with transfected cells, luc-β(2)WT3'UTR had decreased expression when cotransfected with let-7f, but a mutated luc-β(2)3'UTR lacking the seed was unaffected by let-7f; a mutated let-7f also had no effect on luc-β(2)WT3'UTR expression. ADRB2 mRNA was in greater abundance in immunoprecipitates of Ago2, a core component of the miRNA-induced silencing complex, when cells were transfected with let-7f, but not with a mutated let-7f, indicating a direct interaction with the silencing mechanism. H292 cells transfected with let-7f caused ～60% decrease in native β(2)AR expression, but transfection with let-7f-specific locked nucleic acid anti-miRNA increased β(2)AR expression by ～twofold. We considered that an increase in let-7f leading to greater repression of translation contributes to agonist-promoted down-regulation. Paradoxically, in cells and in lungs from mice treated in vivo, an ～50% decrease in let-7f occurs during long-term agonist exposure, indicating a counterregulatory event. Consistent with this notion, let-7f locked nucleic acid transfection caused depressed agonist-promoted down-regulation. Thus, let-7f miRNA regulates baseline β(2)AR expression and decreases in let-7f evoked by agonist attenuate down-regulation. This positive feedback loop has not previously been described for a G protein-coupled receptor and its miRNA. Methods to decrease let-7f expression in targeted cells may increase therapeutic responses to β-agonist by increasing β(2)AR expression or minimizing tachyphylaxis.     

以上气道受累为首发表现的结节病四例并文献复习

目的 了解以上气道(鼻/鼻窦、咽、喉、中耳)受累为发表现的结节病的临床特点,以减少特殊表现结节病的误诊和漏诊.方法 回顾性分析北京同仁医院经组织病理学确诊的以上气道受累为首发表现的结节病4例,复习以“上气道结节病”为首发或主要表现的文献报道,分析上气道结节病的临床特征及诊断方法.结果 4例患者中女性3例,男性1例,年龄分别为52、53、34和15岁,分别以“鼻腔肿物”、“慢性中耳炎”、“声音嘶哑”和“慢性扁桃体炎”就诊;体格检查及影像学检查发现3例伴有肺、淋巴结等器官受累;经支气管黏膜活检、外周肿大淋巴结活检并行耳鼻咽喉病变部位的组织活检最终明确结节病诊断.以“结节病”为关键词,应用CNKI数据库检索中文文献(1915-2011),发现7篇结节病累及上气道的文献报道,均为结节病累及鼻.以相同关键词应用Pubmed数据库检索英文文献,发现结节病累及上气道的发生率为2.3％～6.0％,常伴有肺、淋巴结等其他器官病变,而以中耳、鼻、咽喉症状为首发表现者仅见个案报告.结论 以上气道受累为首发表现的结节病临床少见,是“常规治疗无效”的慢性耳鼻咽喉疾病的病因之一.详细的病史询问、体格检查和必要的辅助检查,特别是对该病特殊表现的充分认识,有助于减少误诊和漏诊.     

氧化亚氮全麻对食管引流型喉罩充气或充水套囊内压力值的影响

目的观察小儿全麻下持续吸入50%氧化亚氮（N2O）时,食管引流型喉罩（充空气、50%氧化亚氮或充水）套囊内压力的变化。方法选择60例小儿,随机分为3组（n=20）,A组选用空气充填通气罩;B组选用50%N2O充填通气罩;C组选用水充填通气罩。喉罩插入后持续吸入50%氧化亚氮,观察喉罩套囊内压力的变化。结果持续吸入50%氧化亚氮30min后,A组喉罩套囊内压力为（88.7±9.2）mmHg;B组喉罩套囊内压力为（30.1±1.0）mmHg;C组喉罩套囊内压力为（29.8±0.9）mmHg。结论持续吸入50%氧化亚氮30min后,食管引流型喉罩充空气套囊内压力明显升高,充50%N2O和充水套囊内压力没有变化。