布地奈德联合沙丁胺醇雾化吸入对急性哮喘发作患儿诱导痰液炎性细胞和细胞因子的影响

目的 布地奈德（普米克令舒）联合沙丁胺醇雾化吸入治疗儿童哮喘急性发作前后气道炎性细胞、白介素6（IL-6）、IL-8、肿瘤坏死因子α（TNF-α）的变化，探讨其影响机制。方法 对急性哮喘发作患儿采用上述联合治疗1周，共对34例急性发作期、24例缓解期患儿和15例正常儿童的诱导痰液进行炎性细胞计数和分类，测定其中IL-6、IL-8、TNF-α水平。结果 急性组的总白细胞数，嗜酸粒细胞、中性粒细胞单核细胞比例及IL-6、IL-8、TNF-α水平均高于正常对照组。缓解组除嗜酸粒细胞及淋巴细胞比例明显高于正常对照组外，其余上述炎性细胞比例及细胞因子水平均降至正常。结论 普米克令舒联合沙丁胺醇雾化吸入可显著降低急性哮喘发作患儿气道分泌物内嗜酸粒细胞、中性粒细胞和单核细胞数量及IL-6、IL-8、TNF-α水平。     

支气管哮喘与气道反应性之间相互关系的分析

目的评价气道反应性对支气管哮喘发病的影响，探讨哮喘的病因。方法在三个县的范围内，依据哮喘患者作为指示病例确定了６４１个哮喘核心家系，对哮喘家系中的每位成员逐一询问调查，同时测定每位成员的气道反应性。用ＥＰＩ５．０１程序软件处理分析资料，计算优势比（ＯＲ）来评价气道反应性与哮喘之间的关系。结果７２％有哮喘史者气道反应测定为阳性，气道高反应性者仅有７０％的人患过哮喘；哮喘家系中气道反应阳性的亲属患哮喘的危险性显著增加，是气道反应阴性亲属的５．８倍（Ｐ＜０．０１）。结论气道高反应性是哮喘的重要危险因素之一     

Influence of sedation on the Hering-Breuer inflation reflex in healthy infants.

The airway occlusion technique for measuring passive respiratory mechanics in infants relies on an ability to evoke the Hering-Breuer inflation reflex (HBR). However, the persistence of this reflex beyond the early newborn period remains controversial. We have recently demonstrated that there is no change in the strength of this reflex during the first two months of life in healthy infants during natural sleep. Measurements beyond this immediate newborn period are difficult without sedation, but it is unclear whether sedation itself may influence this reflex. To investigate the influence of sedation, the HBR was measured in 66 healthy, full-term infants aged 4-8 weeks. Thirty-three infants were measured during natural sleep, and 33 after triclofos sodium sedation (75 mg.kg-1). The strength of the HBR was assessed from the change in expiratory time (TE) following brief end-inspiratory airway occlusion, as compared to TE during spontaneous breathing. The mean increase in TE following occlusion was 89.45% (SD, 29.8; range, 44-175) in infants sleeping naturally, and 92.42% (SD, 31.2; range, 34-179) in sedated infants. Using unpaired t tests, no statistically significant difference was found between groups (P = 0.7516). We conclude that the strength of the HBR in healthy infants is not influenced by sedation with triclofos sodium, in doses normally used for lung function testing.     

支气管哮喘和慢性阻塞性肺疾病患者诱导痰中基质金属蛋白酶及其抑制剂与气道炎症及气流受限

目的探讨支气管哮喘（简称哮喘）和慢性阻塞性肺疾病（COPD）患者诱导痰中基质金属蛋白酶9（MMP-9）和基质金属蛋白酶抑制剂1（TIMP-1）的水平及其与炎性细胞数、肺功能的关系。方法分别选择14例缓解期哮喘患者（哮喘组）、12例稳定期COPD患者（COPD组）和10名健康对照者（健康对照组）进行肺功能测定和用诱导痰检查方法对痰炎性细胞进行分类计数，并用酶联免疫吸附试验（ELISA）法测定诱导痰上清液中自细胞介素4（IL-4）、MMP-9和TIMP-1浓度。结果哮喘组患者诱导痰中嗜酸粒细胞、中性粒细胞分别为0．181±0．067、0．30±0．07，健康对照组为0．007±0．005、0．26±0．06，COPD组为0．042±0．017、0．50±0．10，3组细胞间比较差异有统计学意义（F值分别为4．32、4．13，P均〈0．05）。哮喘组、COPD组、健康对照组间诱导痰中IL-4浓度分别为（19±7）×10^-3／L、（14±6）×10^-3g／L、（11±4）×10^-3g／L，3组诱导痰中IL-4浓度比较差异无统计学意义（F=1．56，P均〉0．05），且分别与嗜酸粒细胞、中性粒细胞和第一秒用力呼气容积占预计值百分比（FEV1占预计值％）无相关（r分别为0．33、0．11、0．19、0．25、0．39、0．40、0．21、0．35、0．17，P均〉0．05）。哮喘组和COPD组诱导痰中MMP-9、TIMP-1浓度分别为（15．9±6．0）g／L、（13．4±5．1）g／L、（19．8±8．5）g／L、（16．7±7．6）g／L，健康对照组分别为（1．8±1．1）g／L、（1．3±0．9）g／L，两组MMP-9、TIMP-1浓度比较差异有统计学意义（F值分别为2．99、4．22，P均〈0．05）。哮喘组MMP-9浓度与嗜酸粒细胞呈正相关（r=0．71，P〈0．05）；COPD组MMP-9浓度与中性粒细胞呈正相关（r=0．59，P〈0．05），但与FEV。占预计值％和第一秒用力呼气容秽用力肺活量（FEV1／FVC）无相关（r分别为0．22、0．16、0．25、0．30，P均〉0．05）。哮喘组和COPD组TIMP．1浓度均与嗜酸粒细胞和中性粒细胞无相关（r分别为0．27、0．31、0．20、0．35，P均〉0．05），但与FEV。占预计值％呈负相关（r分别为-0．58、-0．62，P均〈0．05）。哮喘组和COPD组诱导痰中MMP-9／TIMP-1比值分别为0．8±0．7、0．8±0．6，两组比较差异无统计学意义（F=1．78，P〉0．05），但与健康对照组（1．5±0．6）比较差异有统计学意义（F=3．70，P〈0．05），且与FEV1占预计值％呈正相关（r分别为0．56、0．61，P均〈0．05）。结论哮喘组和COPD组患者诱导痰中MMP-9／TIMP-1比值的失衡与气道炎症和气流受限有关，这种失衡在哮喘和COPD细胞外基质的重塑和气流受限的发病机制中发挥重要作用。     

Irritant induced cough as a model of intrapulmonary airway reactivity

Theophylline, papaverine and isoprenaline produced dose-related inhibition of citric acid induced cough. In addition, cough susceptibility correlated well with the susceptibility of intrapulmonary airways to constrict whether aerosolised citric acid or intravenous histamine were used as the agonists. The anti tussive activity of isoprenaline could be inhibited with propranolol whereas that of theophylline was unaffected. Atropine and propranolol alone failed to modify citric acid induced cough. We suggest that the reactivity of intrapulmonary airway smooth muscle dictates the cough response following inhalation of a citric acid mist.     

Variability of Inflammatory Cell Counts on Bronchial Biopsies of Normal Subjects

Bronchial biopsies are currently used to study the pathophysiology of airway diseases, and comparisons are often made with biopsies from healthy volunteers. It is therefore important to evaluate the variability in each parameter analyzed in bronchial biopsies of healthy volunteers in order to be able to discriminate significant changes. We analyzed bronchial biopsies of 31 nonsmoking, nonatopic healthy subjects who volunteered as normal controls for studies on pathophysiology of asthma. Mean % epithelial desquamation was 23.7% of observed total epithelial length. No subepithelial fibrosis was observed. Inflammatory cell counts (/mm² connective tissue surface) were variable among subjects but not different between small (0.25 mm²) and large biopsies. Medians (range) of positive cells were for CD3: 20.5 (0–530.0), CD4: 6.2 (0–124.4), CD8: 1.8 (0–81.5), CD25: 0 (0–62.3), HLA-DR: 80.0 (3.5–524.2), EG1: 5.3 (0–180.6), EG2: 6.4 (0–48.8), AA1: 51.3 (0–286.4), CD45: 39.7 (0–448.5) and CD45ro: 28.6 (0–425.2). Subjects living in an urban area had significantly higher CD8-positive cell counts than those from suburban areas (p = 0.0001). The presence of an animal at home was associated with lower positive cell counts for CD4 (p = 0.02), CD45 (p = 0.02) and HLA-DR (p = 0.01). In conclusion, the variability in the number and expression of markers of activity of bronchial immune cells in normal subjects likely reflects variable host responses to environmental exposures and must be taken into account when compared to specimens obtained in subjects with airway diseases.     

Elevated Tissue Kallikrein Activity in Airway Secretions from Patients with Tracheobronchitis Associated with Prolonged Mechanical Ventilation

The clinical course of patients undergoing prolonged mechanical ventilation is often complicated by the development of purulent tracheobronchitis. The purpose of this study was to assess whether ventilator-associated hypersecretion is associated with elevated levels of tissue kallikrein (TK) activity. TK can induce marked bronchial inflammation in animal models and TK activity is increased in the airway secretions of symptomatic asthmatics. It has not been studied in conditions with predominantly neutrophilic bronchial secretions, although animal data indicate that neutrophil elastase may stimulate TK activity. We measured TK activity in airway secretions of patients undergoing mechanical ventilation for more than 4 weeks (PMV group) and in two comparator groups: patients with cystic fibrosis, who were colonized with Pseudomonas aeruginosa (CF group) and patients undergoing mechanical ventilation for less than one week who did not have clinical evidence of purulent airway secretions (acute mechanical ventilation, AMV group). We also compared the level of neutrophil elastase (NE) activity, an index of neutrophil activation, in the three patient groups. TK and NE activity in the sol phase were measured by the degradation of chromogenic substrates (DL Val-Leu-Arg pNA and N-Methoxy Succinyl Ala-Ala-Pro-Val pNA, respectively). Intergroup differences in cell counts were not significant. However, TK activity was significantly less in the AMV group than in the PMV and cystic fibrosis patients (Kruskal-Wallis ANOVA, p < 0.05). Elastase activity was significantly greater in the CF group (p < 0.05) than in the other two groups. Compared to patients undergoing short-term mechanical ventilation (AMV group), TK activity was elevated in patients with purulent tracheobronchitis associated with prolonged mechanical ventilation (PMV group). The elevation in TK activity in these patients is comparable to levels in sputum from patients with cystic fibrosis (CF group), although the latter had a significantly higher level of NE activity. The observation of increased TK activity in patients with neutrophilic airway inflammation suggests that TK may play a role in modulating inflammation in ventilator-associated tracheobronchitis and may be worthy of further study to determine its source and significance.     

Emodin ameliorates ovalbumin-induced airway remodeling in mice by suppressing airway smooth muscle cells proliferation

Increased number of airway smooth muscle cells (ASMCs) is a characteristic of airway remodeling in asthma. In this study we investigated whether emodin alleviated airway remodeling in a murine asthma model and reduced the proliferation of ASMCs in vitro. We provided in vivo evidence suggesting that intraperitoneal injection of emodin (20 mg/kg) 1 h prior to OVA challenge apparently alleviated the thickness of airway smooth muscle, the mass of alpha-smooth muscle actin (α-SMA), collagen deposition, epithelial damage, goblet cell hyperplasia, airway inflammation and airway hyperresponsiveness (AHR) in lung tissue. Meanwhile, we found that emodin suppressed the activation of the Akt pathway in lung tissue of allergic mouse models. Additionally, we found that emodin inhibited cellular proliferation and Akt activation in a dose-dependent manner in vitro. Furthermore, LY294002, an inhibitor for PI3K, abrogated serum-induced phosphorylation of Akt, and decreased the proliferation of ASMCs. These findings indicated that emodin alleviated ASMCs proliferation by inhibiting PI3K/Akt pathway in vivo and in vitro, which may provide a potential therapeutic option for airway smooth muscle remodeling in asthma.