支气管哮喘患者诱导痰中血管内皮生长因子水平的变化及意义

选择哮喘患者63例（其中哮喘急性发作期组33例，哮喘缓解期组30例）及健康对照组22例。测定三组肺功能，对诱导痰进行炎症细胞分类计数，测定诱导痰上清液中血管内皮生长因子（VEGF）水平，并分析VEGF与嗜酸粒细胞、肺功能之间的相关性。结果哮喘急性发作期组诱导痰中嗜酸粒细胞数、VEGF水平为1．8（0．7-2．9）×10^9／L、（4．8±1．1）μg／L，哮喘缓解期组为0．8（0．3—1．3）×10^9／L、（2．1±40．6）μg/L，健康对照组为0．0（0．0—0．1）×10^9／L、（0．9±0．2）μg/L。三组诱导痰中嗜酸粒细胞数、VEGF水平比较差异有统计学意义（P均〈0．05）；哮喘患者诱导痰中VEGF水平与痰中嗜酸粒细胞数呈正相关（r=0．52，P〈0．01），与FEV。占预计值百分比、FEV1／FVC呈负相关（r=-0．41、-0．56，P均〈0．01）。认为哮喘患者肺组织中VEGF表达上调可能参与了哮喘发生、发展的过程。     

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。     

硫化氢在大鼠急性支气管哮喘模型中的变化及意义

目的观察卵白蛋白（OVA）诱导的大鼠急性支气管哮喘（简称哮喘）模型，内源性硫化氢（H2S）生成的变化以及应用外源性硫氢化钠（NaHS，H2S供体）处理对哮喘大鼠的影响，探讨气体信号分子H2S在哮喘发病中的作用。方法24只健康SD大鼠按随机数字表法分为正常对照组、哮喘组和NaHS干预组，每组8只。致敏后28d测定所有大鼠肺功能并观察大鼠支气管周围炎性细胞浸润程度并进行评分；采用敏感硫电极测定血浆及肺组织H2S的生成量；采用酶促反应法测定大鼠肺组织匀浆中胱硫醚-γ-裂解酶（CSE）活性；用Western blot法测定大鼠肺组织中CSE蛋白含量（每组3只）。结果哮喘组大鼠呼气峰流量（PEF）、血浆及肺组织中H2S分别为（2．90±0．70）L／s、（10±3）、（4．9±1．3）μmoL／L，对照组分别为（6．50±0．10）L／s、（54±10）、（24．1±8．0）μmoL／L，NaHS干预组大鼠分别为（5．70±0．50）L／s、（17±4）、（15．3±4．0）μmol／L，3组间比较差异有统计学意义（F值分别为112．13、110．10、27．34，P均〈0．01）；哮喘组大鼠肺组织匀浆每毫克蛋白中CSE活性和肺组织匀浆中CSE蛋白含量[用相对吸光度（A）值表示]分别为（1．00±0．10）nmol·min^-1·mg^-1、0．20±0．10，正常对照组分别为（1．80±0．10）nmo]·min^-1·mg^-1、0．90±0．30，NaHS干预组大鼠分别为（1．60±0．20）nmo]·min^-1·mg^-1、1．10±0．20，3组间比较差异有统计学意义（F值分别为79．39、12．28，P均〈0．05）；光镜下支气管周围炎性细胞浸润程度评分[用中位数（四分位数）]表示，正常对照组为1（0～1）分，哮喘组为3（2～4）分，NaHS干预组为1（1～2）分，3组间比较差异有统计学意义（H=16．93，P〈0．01）；哮喘组肺组织H2S含量与PEF呈正相关（r=0．74，P〈0．01）；与光镜下支气管周围炎性细胞浸润程度评分呈负相关（r=-0．64，P〈0．01）。结论内源性H2S参与了大鼠急性哮喘发病过程，外源性NaHS可以减轻哮喘气道炎症，对哮喘急性发病起到保护作用。     

糖皮质醇激素改善慢性阻塞性肺疾病急性加重期患者肺功能的影响因素的分析

目的 对影响糖皮质醇激素改善COPD急性加重期（AECOPD）患者肺功能的可能因素进行分析,鉴定出影响FEV1改善的相关因素.方法 实验分两组,实验组AECOPD患者接受甲基泼尼松1mg· kg-1·d-1静脉滴注及其他常规治疗,对照组接受除激素以外的其他常规治疗,连续治疗1周.治疗前后对所有AECOPD患者进行诱导痰炎性细胞、炎性介质（IL-6和IL-8）、呼出气一氧化氮（FeNO）检测和肺功能的检测.利用单因素和多因素线性回归筛选FEV1改善值的影响因素.结果 AECOPD患者经激素治疗后FEV1改善值为（0.32±0.21） L[FEV1％pred改善率为（19.3±10.6）％],而对照组FEV1改善值为（0.13±0.09） L[FEV1％pred改善率为（6.8±5.1）％],两者差异有统计学意义.我们对影响激素改善FEV1值的可能因素,包括气道炎症指标（诱导痰中性粒细胞、嗜酸粒细胞、IL-6、IL-8和治疗前FeNO水平）、年龄、基础肺功能等进行分析,结果显示嗜酸粒细胞百分比、治疗前FeNO、IL-8与FEV1改善值呈正相关,相关系数分别为0.816、0.62和0.54,进一步分析提示诱导痰的嗜酸粒细胞百分比、治疗前FeNO是影响FEV1改善值的主要因素,诱导痰嗜酸粒细胞百分比比治疗前FeNO对FEV1改善值的影响意义更大.结论 嗜酸粒细胞百分比、基础FeNO可作为激素改善COPD患者FEV1的预测因素.     

变态反应性支气管肺曲菌病23例分析

目的总结分析变态反应性支气管肺曲菌病（ABPA）的临床特点,以提高对ABPA的认识,做到早诊断、早治疗。方法回顾性分析北京协和医院近20年确诊的ABPA患者的临床资料。结果ABPA患者23例,男11例,女12例,年龄（34．0±13．2）岁。确诊ABPA前曾被误诊为肺结核12例,肺炎3例,肺癌2例,Wegener肉芽肿1例。症状有咳嗽（23例）、咳痰（22例）、气喘（18例）、痰栓（16例）、发热（15例,其中高热4例）、咯血（12例）、胸背痛（8例）、消瘦（7例）。外周血嗜酸性粒细胞绝对值（0．18-15．34）×10^9／L,中位值1．43×10^9／L;嗜酸性粒细胞数为0．016～0．721,中位值0.148。外周血总IGE349～13000IU／ml,其中t〉5000IU／ml者7例,2500—5000IU／ml者6例,1000～2500IU／ml者5例。肺功能检查18例,第1秒钟用力呼气容积（FEV,）占预计值百分比为（54．7±24．1）％,（FEV1／用力呼气容积）×100％为（62．5±11．9）％,可逆试验阳性率56％。胸部CT检查22例,表现为斑片状渗出影21例,中心型支气管扩张17例,结节影9例,树权样或条状痰栓征象6例,实变5例,纵隔淋巴结增大11例;病变呈游走性17例。结论临床上ABPA极易误诊为肺结核,若患者有气喘表现,肺功能示阻塞性通气功能障碍,外周血嗜酸性粒细胞增加,胸片示肺部浸润影呈游走性,多有中心性支气管扩张,可进一步查总IgE、烟曲菌特异性IgE、烟曲菌过敏原皮试以确诊。     

根据支气管哮喘患者痰嗜酸粒细胞计数调整糖皮质激素剂量的临床意义

目的探讨根据痰嗜酸粒细胞（EOS）计数调整糖皮质激素（简称激素）剂量，改进哮喘病情控制的临床可行性。方法采用前瞻性随机对照设计，研究期为2005年2月至2006年2月。门诊持续性哮喘患者41例，随机分为2组：EOS组20例，根据痰EOS计数调整激素剂量；指南组21例，根据哮喘诊疗指南（主要包括症状和肺功能）调整激素剂量。筛选期为2周，入组后在15d、2个月、4个月、6个月时进行随访，其中后3次进行诱导痰检查，并调整激素剂量。主要观察指标是急性发作例次，其他指标包括短效β2受体激动剂用量、症状评分、呼气峰流速（PEF）变异率和第1秒用力呼气容积（FEV1）、激素用量、痰EOS变化。结果在为期6个月的观察期，急性发作总例次EOS组为11例次，指南组为26例次，两组比较差异有统计学意义（t=6．34，P=0．026）。平均每人使用短效β2受体激动剂的揿数／d、症状评分、PEF和FEV1、吸入激素用量，两组各时间点比较差异均无统计学意义。痰EOS比值[中位数（25％-75％）]EOS组基线值为0．067（0．015，0．169），随访结束时为0．048（0．015，0．150），治疗结束时与基线比较明显降低（F=3．39，P=0．02）；指南组分别为0．040（0．014，0．133）和0．045（0．012，0．236），治疗结束时与基线比较差异无统计学意义（F=1．07，P=0．37）。结论根据痰EOS计数调整激素剂量可减少哮喘急性发作次数，进一步改善病情控制状态。     

褪黑素对支气管哮喘小鼠胶原沉积及基质金属蛋白酶9和基质金属蛋白酶组织抑制剂1 mRNA与蛋白表达的动态调节

目的应用小鼠慢性支气管哮喘（简称哮喘）模型，观察褪黑素对慢性哮喘小鼠肺组织中胶原沉积的影响及其机制。方法96只SPF级雄性BALB／c小鼠按随机数字表法分为5组。对照组（21只）腹腔注射生理盐水；哮喘组（22只）腹腔注射生理盐水；褪黑素组（23只）腹腔注射褪黑素；地塞米松组（23只）腹腔注射地塞米松；褪黑素拮抗组（7只）腹腔注射褪黑素拮抗剂2-苯基-N-乙酰色胺。根据实验要求每组采用卵白蛋白致敏并反复雾化吸入2、4、8周时再分为2、4、8周亚组。对照组（每组均为7只）；哮喘组（分别为7、7、8只）；褪黑素组（分别为7、8、8只）；地塞米松组（分别为7、8、8只）；而褪黑素拮抗组只做2周组（7只）。实验造成慢性哮喘模型。用Masson三原色法染胶原纤维；用免疫组化方法标记蛋白；用MetaMorph软件测量单位长度基底膜周径上的胶原面积（Wcol／Pbm）和单位面积上基质金属蛋白酶9（MMP-9）及基质金属蛋白酶组织抑制剂1（TIMP-1）免疫组化阳性面积（PA／UA）；用半定量逆转录-聚合酶链反应（RT-PCR）法测定肺组织相应蛋白mRNA水平。结果褪黑素组2、4、8周WcoL／Pbm分别为（11．8±1．3）、（12．3±1．1）、（12．7±1．4）μm^2／μm，哮喘2、4、8周组分别为（14．5±1．5）、（15．8±1．8）、（16．2±1．4）μm^2／μm，两组比较差异有统计学意义（td值分别为3．89、5．96、5．50，P均〈0．01）；褪黑素组2、4、8周MMP-9的PA／UA像素分别为（9．7±4．9）、（14．8±4．9）、（11．0±6．8）万，哮喘2、4、8周组分别为（15．7±6．1）、（26．2±6．9）、（24．6±6．0）万，两组比较差异有统计学意义（td值分别为3．00、4．83、5．50，P均〈0．01）；褪黑素组2、4、8周MMP-9mRNA水平表达分别为0．80±0．40、0．68±0．15、0．67±0．24，哮喘2、4、8周组分别为1．48±0.29、1．40±0.50、1.20±0．40，两组比较差异有统计学意义（td值分别为3．92、4．50、3．29，P均〈0．01）；地塞米松组2、4、8周Wcol／Pbm（11．6±1．3、12．3±1．0、13．0±1．7）μm^2／μm、MMP-9蛋白[（12．5±5．6）、（14．0±4．7、13．6±4．8）万]和mRNA水平（0．69±0．11、0．61±0．16、1．10±0．40）均较哮喘2、4、8周组降低。褪黑素拮抗2周组与哮喘2周组以上各指标比较差异均无统计学意义（td值=0．96，P〉0．05）。结论早期使用褪黑素可抑制胶原沉积，其作用与地塞米松相当。褪黑素可能通过MMP-9介导的途径抑制哮喘气道重塑。     

高碳酸血症对急性肺损伤保护作用及机制探讨的实验研究

目的探讨高碳酸血症对急性肺损伤模型的保护作用及可能的机制。方法24只新西兰兔按随机数字表法分为对照组、治疗组、预防组，每组8只。采用脂多糖静脉注射复制肺损伤模型，观察3组兔血流动力学、血气指标的变化；检测肺组织湿／干重（W／D）比、光镜、肺损伤组织学定量评价指标（IQA）来评估肺脏的损伤程度。通过对肺组织中髓过氧化物酶（MPO）、丙二醛（MDA）及血清和支气管肺泡灌洗液（BALF）中白细胞介素-8（IL-8）、肿瘤坏死因子-α（TNF—α）浓度及中性粒细胞凋亡率的测定，阐明高碳酸血症对肺损伤保护的可能机制。结果（1）治疗组、预防组在模型形成后平均动脉压、心率、动脉血二氧化碳分压（PaCO2）、动脉血氧分压／吸入气氧浓度（PaO2／FiO2）分别为（79±6）mm Hg（1mmHg=0．133kPa）、（180±10）次／min、（99±13）mmHg、250±26，（80±9）mmHg、（181±12）次／min、（95±11）mmHg、241±56，与对照组[（66±10）mmHg、（139±13）次／min、（31±4）mmHg、182±35]比较差异有统计学意义（t值分别为4．05、26．32、5．36、28．15、12．54、11．07、16．13、12．36。P均分别〈0．05、0．01）；（2）治疗组、预防组W／D、NPO、MDA分别为1．98±0．28、1．87±0．30、（6．1±1．6）U／g、（5．8±1．5）U／g、（20±5）mg／L、（19±4）mg／L，与对照组[2．43±0．26、（9．0±1．3）U／g、（36±8）mg／L]比较差异有统计学意义（t值分别为11．07、24．46、2．35、9．63，12．34、25．32，P分别〈0．05、0．01）；（3）治疗组、预防组血清和BALF中IL-8、TNF—α、中性粒细胞凋亡率分别为（50±8）ng／ml、（103±49）ng／ml、（94±16）ng／ml、（44±9）ng／ml、（38±9）％、（56±5）％、（49±7）ng／ml、（96±50）ng／ml、（91±14）ng／ml、（39±6）ng／ml、（39±10）％、（55±10）％，与对照组[（91±43）ng／ml、（177±60）ng／ml、（162±15）ng／ml、（67±7）ng／ml、（19±7）％、（43±7）％]比较差异有统计学意义（t值分别为7．12、5．55、7．30、3．93、13．08、8．00，P分别〈0．05、0．01）；（4）各组血清及BALF中IL-8、TNF—α与中性粒细胞凋亡率呈负相关（r值分别为-0．73、-0．72、-0．52、-0．64、-0．73、-0．56、-0．57、-0．78、-0．69、-0．75、-0．82、-0．84，P均〈0．05）。结论高碳酸血症对急性肺损伤具有保护作用，对血流动力学无明显影响。     

不同通气模式下吸痰对呼吸力学和气体交换的影响

目的比较在压力控制通气（PCV）与容量控制通气（VCV）模式下吸痰对患者气体交换和呼吸力学的影响。方法采取自身交叉对照的方法，在PCV和VCV模式下分别对23例机械通气患者进行开放式吸痰，比较不同时间点气体交换、呼吸力学及血流动力学等指标的变化。结果在PCV模式下，吸痰后30min潮气量、顺应性分别为（6．60±1．95）mL／kg、（18±7）ml／cmH2O（1cmH2O=0．098kPa），与基础水平[（9．05±0．22）mL／kg、（24±6）ml／cmH2O]比较差异有统计学意义（F值分别为8．47、8．01，P均〈0．05）；而30min时动脉血氧分压（PaO2）、动脉血二氧化碳分压（PaCO2）分别为[（87±13）mmHg（1mmHg=0．133kPa）、（53±11）mmHg]，与0min[（113±22）mmHg、（41±10）mmHg]比较差异有统计学意义（，值分别为6．18、9．13，P均〈0．05）；在VCV模式下，吸痰后30min顺应性、气道平台压、气道峰压分别为[（18±7）ml／cmH2O、（27±8）cmH2O、（33±8）cmH2O]，与基础水平[（23±7）ml／cmH2O、（22±5）cmH2O、（27±8）cmH2O]比较差异有统计学意义（，值分别为6．83、6．97、7．08，P均〈0．05）；而30min时PaO2、PaCO2分别为（105±26）mmHg、（38±11）mmHg，与0min[（109±21）mmHg、（37±14）mmHg]比较差异无统计学意义（F值分别为1．88、1．32，P均〉0．05）；在PCV模式下，吸痰后5min心率、平均动脉压（MAP）分别为（109±20）次／min、（89±10）mmHg，与基础水平[（97±17）次／min、（83±12）mmHg]比较差异有统计学意义（F值分别为5．86、9．49，P均〈0．05）。在VCV模式下，吸痰后5min心率、MAP分别为（110±17）次／min、（87±11）mmHg，与基础水平[（96±17）次／min、（79±11）mmHg]比较差异有统计学意义（F值分别为7．33、7．96，P均〈0．05）。结论吸痰在PCV和VCV模式下均引起患者气体交换受损和顺应性下降，但对气体交换的影响在PCV模式下比VCV更严重和持久。     

慢性阻塞性肺疾病患者呼出气冷凝液中检测一氧化氮、8-异前列腺素的临床意义

目的观察慢性阻塞性肺疾病（COPD）患者呼出气冷凝液（EBC）中一氧化氮（NO）、8-异前列腺素（8-isoPG）的变化及其临床意义。方法收集COPD急性发作期（AECOPD）、缓解期患者和正常对照组的EBC,用硝酸还原法检测NO的浓度,酶免疫法检测8-isoPG的浓度。结果①AECOPD组（19例）患者EBC中NO和8-isoPG的浓度显著高于正常对照组（12例）,NO测定值分别为（80．83±40．15）μmol／L和（36．95±22．47）μmol／L,8-isoPG测定值分别为（13．56±11．11）ng／L和（5．87±3．39）ng／L,P〈0．05;②10例COPD急性发作期患者EBC中NO和8-isoPG的浓度显著高于缓解期,NO测定值分别为（91．09±34．30）μmol／L和（29．65±11．76）μmol／L,8-isoPG测定值分别为（17．60±12．44）ng／L和（5．23±6．20）ng／L,P〈0．05;③AECOPD组NO测定值与FEV1呈负相关（r=0．565,P〈0．05）,与血白细胞计数呈正相关（r=0．746,P〈0．01）。结论COPD患者急性发作期气道炎症反应和氧化应激增强。     

嗜酸粒细胞性支气管炎患者气道炎症细胞及介质特征的探讨

目的观察嗜酸粒细胞性支气管炎(EB)诱导痰和支气管肺泡灌洗液(BALF)中细胞分类和炎症介质浓度,探讨EB的气道炎症特征。方法对43例EB(EB组)患者行诱导痰检查,将20例咳嗽变异型哮喘(CVA)患者(CVA组)、16例典型支气管哮喘(哮喘组)患者和21名健康人(健康对照组)行对照诱导痰检查,并对部分EB(11例)和CVA患者(10例)行支气管肺泡灌洗(BAL)。观察检测诱导痰、BALF中的细胞分类、嗜酸粒细胞阳离子蛋白(ECP)、白三烯C4(LTC4)和组胺的浓度。结果EB组患者诱导痰中嗜酸粒细胞(EOS)百分比为0.1130±0.1470,CVA组为0.1900±0.1800,哮喘组为0.3860±0.2670,与健康对照组(0.0020±0.0050)比较差异有统计学意义(P均<0.01);哮喘组与CVA组、CVA组与EB组比较差异均有统计学意义(P均<0.05);EB组BALF中EOS为0.011±0.016,CVA组为0.053±0.040,两组比较差异有统计学意义(P<0.05);EB组诱导痰中的ECP浓度为(0.62±0.66)mg/L、CVA组为(1.27±1.74)mg/L,对照组为(0.07±0.10)mg/L,3组间比较差异有统计学意义(P<0.01);CVA组诱导痰中的LTC4浓度为(0.65±0.62)μg/L,EB组为(0.39±0.61)μg/L,对照组为(0.15±0.11)μg/L,3组间比较差异有统计学意义(P分别<0.05、0.01);CVA组BALF中组胺浓度为(3.4±1.4)μg/L,EB组为(1.6±1.5)μg/L,两组比较差异有统计学意义(P<0.05)。结论EB组EOS炎症主要局限于中心气道,部分气道炎性介质水平低于CVA组。上述气道炎性特征可能是EB患者无非特异性气道高反应性的重要机制。     

Mild exacerbations and eosinophilic inflammation in patients with stable, well-controlled asthma after 1 year of follow-up

OBJECTIVES: To determine the time to exacerbation and probability of a mild exacerbation of asthma, and the impact of eosinophilic inflammation on these parameters in patients with stable, well-controlled asthma. PATIENTS AND METHODS: A cohort of 31 patients with stable, well-controlled asthma receiving inhaled steroid treatment regularly were followed up for 1 year or until a mild exacerbation occurred. Mild exacerbation was defined as symptoms of asthma lasting > 48 h with a fall in peak expiratory flow > 20%. FEV(1), provocative concentration of methacholine causing a 20% fall in FEV(1), eosinophil count, and eosinophilic cationic protein (ECP) levels in blood and in sputum were measured at the first visit and every 2 months. RESULTS: At baseline, the mean (SD) eosinophil count was 0.39 x 10(9)/L (0.21 x 10(9)/L) in blood and 13% (14%) in sputum; ECP was 30 microg/L (28 microg/L) in blood and 75 microg/L (85 microg/L) in sputum. Thirteen subjects experienced a mild exacerbation during the 1-year follow-up period. The mean time to mild exacerbation was 293 days (95% confidence interval [CI], 248 to 337 days), and the cumulative probability of not experiencing a mild exacerbation in 1 year was 49% (95% CI, 39 to 59%). An increased risk of mild exacerbation was associated with blood eosinophil count > 0.4 x 10(9)/L (relative risk 4.5; 95% CI of relative risk, 1.8 to 38.0), blood ECP > 20 microg/L (relative risk, 2.1; 95% CI of relative risk, 1.0 to 9.2), and sputum ECP > 40 microg/L (relative risk, 2.5; 95% CI of relative risk, 1.2 to 11.2), but was unassociated with other variables. CONCLUSIONS: Patient with stable, well-controlled asthma are at risk of mild exacerbation during 1 year of follow-up despite regular inhaled steroid treatment. Eosinophilic inflammation expressed as eosinophil count and ECP is associated with higher risk of mild exacerbation.     

Effects of different anti-asthmatic agents on induced sputum and eosinophil cationic protein in mild asthmatics

OBJECTIVES: Inhaled corticosteroids, leukotriene receptor antagonists, and theophylline are recommended for the treatment of mild persistent asthma. The aim of this study was to compare the changes in sputum total cell and eosinophil counts, and eosinophil cationic protein (ECP) levels in serum and sputum following treatment with leukotriene receptor antagonists, inhaled corticosteroids, and theophylline in patients with mild persistent asthma. METHODOLOGY: Total cell counts, eosinophil percentage, and ECP levels in induced sputum and serum were determined both before and after treatment. Prior to sputum induction, FEV1 and PEF values and symptom scores were recorded at baseline and after 8 weeks of treatment. After baseline measurements, the asthmatic patients (n = 30) were randomized into three groups. A total of 10 patients were treated with zafirlukast, 20 mg bd, 10 with budesonide inhaler 200 microg bd, and 10 with theophylline 200 mg bd. RESULTS: There were significant decreases in sputum total cell counts and eosinophil percentage in all treatment groups. However, the decrease in sputum eosinophil counts was more significant in the corticosteroid-treated group. Although sputum ECP levels decreased significantly in the groups treated with zafirlukast and budesonide (zafirlukast group, 580-135 microg/L, P < 0.01; budesonide group, 683-268 microg/L, P < 0.01), the decrease was not statistically significant in the theophylline-treated group (498-361 microg/L, P > 0.05). In contrast, there were no significant changes in serum ECP levels in any of the treatment groups. CONCLUSIONS: All three treatments resulted in significant decreases in sputum total cell counts and eosinophil percentage, but the decrease in sputum ECP level was only seen in the groups treated with budesonide and zafirlukast. These results suggest that although all three treatments are considered as first-line treatments in most consensuses, theophylline seems to have less of an inhibitory effect on eosinophil activation.     

Inhaled Fluticasone and Salmeterol Suppress Eosinophilic Airway Inflammation in Chronic Obstructive Pulmonary Disease: Relations with Lung Function and Bronchodilator Reversibility

The aim of this study was to determine whether combined inhaled corticosteroids and long-acting β₂ agonists can suppress eosinophilic inflammation in chronic dostructive plumonary disease (COPD) and to investigate the association between the level of eosinophilia and the degree of bronchodilator reversibility. Sixty-two patients with stable COPD (forced expiratory volume in 1 [FEV₁] of 30%–70% predicted before bronchodilation) were enrolled from our outpatient clinic. Patients received inhaled fluticasone (100 μg)/salmeterol (50 μg) twice daily for two months. Lung function measurements, bronchodilator tests, and sputum induction were performed. The number of inflammatory cells and mediators, including interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and eosinophilic cationic protein (ECP), were measured. Treatment with inhaled fluticasone and salmeterol significantly suppressed eosinophilic inflammation in COPD patients with sputum eosinophilia (mean 8.9% ± 2.0% vs. 1.6% ± 0.5%, p = 0.003), but insignificant differences in FEV₁ and FVC between patients with and without eosinophilia suggested that suppression of eosinophilic inflammation had no effect on FEV₁ or FVC. Reduction in the percentage of eosinophils was significantly correlated with decreased levels of ECP (r = 0.48, p < 0.001). Levels of neutrophils, IL-8, and TNF-α were not affected. Sputum eosinophilia was not related to the degree of bronchodilator reversibility. The degree of bronchodilator reversibility did not predict the increase in FEV₁ and FVC after treatment with inhaled corticosteroids/long-acting β₂ agonists. Suppression of eosinophilic inflammation and bronchodilator responsiveness indices were not correlated with clinical outcomes in COPD patients treated with inhaled corticosteroids/long-acting β₂ agonists. Diahn-Warng Perng and Cheng-Che Wu contributed equally to this work.     

吸入性糖皮质激素对支气管哮喘患儿气道重塑的影响

目的探讨吸入性糖皮质激素对支气管哮喘（简称哮喘）患儿气道重塑的影响。方法对年龄在5～15岁的30例中重度持续哮喘的住院患儿（哮喘组）、30例健康儿童（对照组）、15例经规范化糖皮质激素吸入治疗6个月以上的哮喘缓解期（缓解组）患儿用5％高渗盐水进行超声雾化诱导痰液,以酶联免疫吸附试验（ELISA）测定诱导痰中IL-5水平,免疫细胞化学方法测定诱导痰中转化生长因子β1（TGF-β1）表达,同时进行诱导痰中嗜酸粒细胞（EOS）计数,测定第1秒用力呼气容积占预计值百分比（FEV1％pred）,进行肺部高分辨CT（HRCT）检查,测定肺CT的段及亚段支气管壁厚度／气道外径（T／D）和气道壁面积占气道总面积百分比（WA％）。结果①哮喘组EOS计数为（17．24±12．11）％、IL-5为（25．45±18．05）pg／L;缓解组EOS计数为（3．66±2．13）％、IL-5为（7．33±4．39）pg／L;对照组EOS计数为（1．40±1．27）％、IL-5为（6．49±5．31）pg／L,哮喘组与对照组、哮喘组与缓解组比较差异有统计学意义,P值均〈0．01。②30例哮喘患儿有27例痰液中出现TGF-β1阳性表达,缓解组有2例TGF-β1阳性表达,而对照组中未见有TGF-β1阳性表达。③哮喘组T／D（18．16±2．42）％、WA％（59．25±6．54）％、FEV1％pred（71．82±23．08）％;缓解组T／D（17．17±1．9）％、WA％（56．01±3．91）％、FEV1％pred（96．18±12．8）％;对照组T／D（16．45±2．30）％、WA％（53．91±7．72）％、FEV1％pred（107.46±17．11）％,哮喘组与对照组、哮喘组与缓解组比较差异有统计学意义,P值均〈0．05。结论气道重塑在儿童哮喘中已经形成;吸入糖皮质激素可有效地调控气道炎症的发生、发展,经较长疗程的吸入糖皮质激素治疗后气道重塑部分可以逆转。     

Induced sputum in adolescents with severe stable asthma. Safety and the relationship of cell counts and eosinophil cationic protein to clinical severity.

This study examined the safety of sputum induction and the relation between sputum cell counts and clinical parameters in adolescents with severe persistent asthma. Within 5 days, induced sputum and reversibility in forced expiratory volume in one second (FEV1), quality of life, provocative concentration causing a 20% fall in FEV1 (PC20) of adenosine monophosphate and histamine, exercise-induced bronchoconstriction, overall asthma severity index, and blood eosinophils were collected in 20 atopic adolescents with moderate-to-severe persistent asthma (12-18 yrs of age, FEV1 65-110% of predicted, on 500-2,000 microg inhaled steroids daily). FEV1 was reversible by 13.3-2.3% pred. After sputum induction, FEV1 was still increased by 9.0+/-2.6% pred as compared to the pre-salbutamol baseline. Sputum contained, median (range): 12.4 (0.4-59.5)% squamous cells, 47.3 (6.8-84.0)% macrophages, 39.0 (4.6-84.8)% neutrophils, 4.8 (1.0-12.4)% lymphocytes, 0.4 (0-10.8)% eosinophils and 3.6 (0-23.4)% bronchial epithelial cells. Sputum eosinophils showed a trend towards a significant association with the overall asthma severity index (r=0.46, p=0.06) and correlated inversely with baseline FEV1 (r=-0.51, p=0.03). In conclusion, sputum can be induced safely in adolescents with moderate-to-severe persistent asthma, if pretreated with beta2-agonists. Despite relatively low sputum eosinophil counts in these patients on inhaled steroids, the association of eosinophil numbers with baseline forced expiratory volume in one second and asthma severity index favours a role of induced sputum in monitoring adolescents with severe asthma.     

支气管哮喘患者呼出气冷凝液和诱导痰中炎性指标检测的临床意义

目的 通过测定支气管哮喘(以下简称哮喘)患者呼出气冷凝液(EBC)和诱导痰中炎性指标的浓度,分析其与临床指标的关系,探讨炎性指标用于病情和疗效评估的价值.方法 选四川大学华西医院呼吸内科门诊接受吸入糖皮质激素联合长效β2受体激动剂治疗的中重度慢性持续期哮喘患者,记录治疗前和治疗1个月后哮喘症状积分,测定第1秒钟用力呼气容积(FEV1)占预计值百分比,采集诱导痰和EBC标本,测定标本中过氧化氧(H2O2)、硝酸盐/哑硝酸盐(NO3-/N2-)和半胱氨酰白三烯E4(LTE4)浓度.结果 共有25例中重度哮喘患者按研究方案完成治疗和随访.哮喘患者经联合治疗1个月后临床症状积分和FEV1占预计值百分比明显改善(P<0.01);EBC和诱导痰中H2O2、NO3-/NO2-和LTE4浓度均降低,但仍高于健康对照者;H2O2和NO3-/NO2-的下降比LTE4明显;哮喘患者EBC中的H2O2和NO3-/NO2-;浓度与FEV1呈负相关(P<0.01),与症状积分呈正相关(P<0.01),LTE4与症状积分和FEV1均无相关性.诱导痰中H2O2浓度与FEV1占预计值百分比呈负相关(P<0.01),与症状积分呈正相关(P<0.01);NO3-/NO2-浓度与FEV1占预计值百分比呈负相关(P<0.01),与症状积分无相关性;LTE4浓度与症状积分和FEV1占预计值百分比均无相关性.治疗后FEV1占预计值百分比增高程度与EBC和诱导痰中H2O3、NO3-/NO2-浓度降低水平呈正相关(P<0.01).诱导痰和EBC对应的炎性指标之间有相关性(P值均小于0.01).EBC和诱导痰中H2O2浓度与NO3-/NO2-浓度呈正相关(P<0.01),与LIE4之间无相关性.结论 中重度哮喘患者联合治疗后在临床症状和肺功能改善的同时,气道炎症显著减轻.EBC的安全性和可重复性优于诱导痰,H2O2和NO3-/NO2-的敏感性优于LTE4.     

Leukotriene modifier vs inhaled corticosteroid in mild-to-moderate asthma: clinical and anti-inflammatory effects

STUDY OBJECTIVE: Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited. There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids. This study was designed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma. METHODS: Forty-nine patients with newly diagnosed asthma were recruited. They were randomly assigned to groups that received, for a 6-week period, either (1) budesonide, 600 microg bid (1,200 microg/d) or (2) budesonide, 200 microg (400 microg/d), and zafirlukast, 20 mg bid. The variables of asthma control were recorded daily. Sputum induction and methacholine provocation tests were performed. RESULTS: The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects (ie, eosinophil percentage, and eosinophilic cationic protein [ECP] and cysteinyl leukotriene C4 levels in induced sputum). Nineteen (group 1, 8 patients; group 2, 11 patients) of 49 patients (38.8%) had returned to normal airway responsiveness after treatment. Among these patients, 16 patients (84.2%) had normal ECP levels and 10 patients (52.6%) had normal percentages of eosinophils. ECP level, but not the eosinophil percentage, was significantly associated with symptom scores. The peak expiratory flow rate (PEFR) showed a significant correlation with the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) instead of with symptom scores. CONCLUSIONS: The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma. In addition to symptoms and PEFR, the monitoring of ECP and PC20 may be of great value in achieving optimal control of asthma.     

Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline

Bronchodilator agents are central to the symptomatic management of Chronic Obstructive Pulmonary Disease (COPD), and long-acting inhaled bronchodilators are regarded as more convenient. The role of inhaled corticosteroids still remains controversial, but there is increasing evidence that they may improve FEV(1) and symptoms in the long-term. AIM: of the present small pilot study was to compare Salmeterol & Fluticasone (SM&FP) 50/250 microg bid via a single Diskus inhaler with SM 50 microg bid alone, and with placebo (P) in the treatment of moderate COPD. METHODS: Eighteen moderate COPD patients (53-77 yr, mean basal FEV(1)=49.1% pred.+/-5.0 s.d.; mean FEV(1) reversibility=3.6% bsln+/-3.8 s.d.) treated with theophylline 400 mg/day and beta(2) short acting prn, were divided into three matched groups of six subjects according to a double-blind design, and treated with SM&FP 50/250 microcg, or SM 50 microcg alone, or P via Diskus inhaler bid for 52 weeks. In bsln, after 4, 12, 24, 36 and 52 weeks, FEV(1) (% pred), morning PEF (l/s), the daily symptom score, and the number of exacerbations (compared with the previous year) were considered. Statistics. t-test, anova in each treatment group, and anova among basal values and among the 52 week values were used, being p<0.05 accepted. Also changes (DeltaFEV(1)) from baseline were compared at different control times. RESULTS: The mean number of exacerbations/yr decreased from 3.5+/-0.8 to 1.16+/-0.75 s.d. exacerbation/yr in the SM&FP group (t-test p<0.001); from 3.0+/-0.89 to 2.3+/-0.81 s.d. in the SM group (t-test p=ns); and from 3.16+/-1.16 to 4.16+/-0.75 s.d. in the P group (t-test p=ns).Patients receiving SM&FP showed the highest mean improvement in FEV(1) (+7.3%+/-3.3 s.d.) over the baseline pre-treatment value after 36 weeks of treatment (anova p<0.001), being FEV(1) unchanged after 52 weeks of treatment in SM group (+0.33%+/-2.4 s.d.) and with a substantial decrease following P (-2.6%+/-1.2 s.d.) (anova p<0.001).Morning PEF (l/min) increased in subjects treated with SM&FP (anova p<0.001), while it remained unchanged in SM and P group (in both, anova p=ns).After 52 weeks of treatment, only subjects treated with SM&FP showed a reduction of the daily symptoms score from 3.6+/-0.7 to 2.0+/-0.2 s.d. (anova p=0.008). Daily beta(2) short acting prn consumption was reduced only in SM&FP group from 4.2+/-0.81 to 2.2+/-1.2 s.d. after 52 weeks (anova p<0.001). CONCLUSIONS: SM&FP 50/250 microcg regularly assumed in combination via a single Diskus inhaler for a 52 week period improves respiratory function (such as FEV(1), morning PEF), and and symptom score significantly in moderate COPD previously treated with theophylline, and at an higher extent than SM alone or P. The use of beta(2) short acting prn is also reduced, together with the number of exacerbations.     

哮喘和慢性阻塞性肺疾病患者糖皮质激素治疗前后痰液炎性标志物 …

探讨哮喘和慢性阻塞性疾病患者吸入糖皮质激素治疗后痰液中细菌因子和嗜酸细胞阳离子蛋白浓度及糖皮质激素对其影响。方法采用荧光酶联免疫法检测糖皮质激素治疗前后痰液中白细胞介素（ＩＬ）－５、ＩＬ－８、ＥＣＰ浓度及嗜酸细胞和嗜中性粒细胞计数。