第一部分 COPD稳定期患者与正常对照各因素的差异性分析 目的 分析慢性阻塞性肺疾病(COPD)稳定期患者与正常对照各因素的差异，了解本地区COPD稳定期患者氧化应激状况，寻找值得关注和进一步研究的影响因素。 方法 本研究为探索性研究，纳入2014年6月至2014年8月在本地区的西南医科大学附属医院、泸州市第三人民医院和泸州市江南医院门诊就诊的COPD稳定期患者和同期肺功能无异常的健康体检者作为研究对象，将COPD患者作为试验组(COPD组)，健康体检者作为对照组(正常对照组)，采集研究对象的一般资料、计算体质指数(BMI)、测量肺功能并采集外周血，检测血清中氧化应激指标8-羟基脱氧鸟苷(8-OHdG)、羰基化蛋白(PC)、丙二醛(MDA)和总抗氧化能力(T-AOC)的水平。比较并分析两组研究对象相关因素和氧化应激水平之间的差异。 结果 (1) 200例COPD稳定期患者和100例健康体检者被纳入研究。 (2) COPD组和正常对照组研究对象的年龄和性别构成、职业粉尘或化学接触史差异无统计学意义(P＞0.05) ； COPD组吸烟者多于正常对照组，正常对照组的文化程度高于COPD组，差异有统计学意义(P＜0.05)； COPD组BMI高于正常对照组，正常对照组肺功能优于COPD组，COPD 组最近一年内感冒次数明显多于正常对照组，差异有统计学意义(p＜ 0.05)。(3) COPD组和正常对照组血清4个氧化应激指标的水平依次分别为 8-OHdG ： 359.18[259.25，587.85](pg/ml)和 311.37[265.47， 374.08](pg/ml)， PC：3.82 [1.79，6.83](ng/ml)和 2.29[1.08，3.26](nmol/ml)， MDA： 3.89[2.77， 5.40](nmol/ml)和 3.08[2.32，4.03](nmol/ml)，T-AOC： 11.35[4.81，20.20](U/ml)和18.81[15.21，23.19](U/ml)，其中，COPD 组血清8-OHdG、PC和MDA的水平高于正常对照组，COPD组血清T-AOC水平低于正常对照组，差异有统计学意义(P＜0.05)。 结论 (1) COPD稳定期患者吸烟状况、文化程度、BMI、最近一年内感冒次数、FEV₁%预计值和氧化应激水平(血清中8-OHdG、PC、MDA和T-AOC水平)与健康体检者不同，值得关注和进一步研究。(2) COPD稳定期患者存在氧化/抗氧化失衡。 第二部分 G0PD急性加重的流行特征及危险因素分析 目的 了解本地区COPD急性加重的流行特征，探讨各个因素对COPD 急性加重及急性加重后是否住院治疗的影响，寻找COPD急性加重风险及急性加重后是否住院治疗的独立危险因素。 方法 本研究为前瞻性研究，将200例COPD稳定期患者作为研究对象，以观察到稳定期COPD患者发生急性加重或2年研究期限结束为研究终点。收集基线数据后，在COPD患者入组后第6月、第12月和第24个月三个时间点进行随访，如果观察到患者发生急性加重，则提前结束随访，否则随访至2年研究期限结束，随访时需再次采集研究对象的人口学资料和临床资料，在第一部分的基础上酌情增减，重点关注研究对象过去一年发生急性加重的情况及急性加重后是否住院治疗和最近一年内感冒次数；计算BMI、测量肺功能并采集外周血，检测血清中氧化应激指标8-OHdG、PC、MDA和T-AOC的水平。将各种原因失访的COPD患者剔除，将随访至研究终点的COPD患者分成两组，发生急性加重的COPD患者作为急性加重组，未发生急性加重的COPD患者作为未加重组。分析本地区COPD稳定期患者发生急性加重的流行特征，比较两组COPD患者氧化应激水平之间的差异并进行COPD急性加重风险的相关影响因素分析，先采用单因素Logistic回归筛选急性加重风险及急性加重后住院治疗与否的相关影响因素，再行多因素Logistic逐步回归分析，筛选出急性加重风险及急性加重后住院治疗与否的独立危险因素，探讨4个氧化应激指标作为生物标志物预测COPD急性加重及急性加重后是否住院治疗的可行性。 结果 (1)截止到2年研究期限结束，达到研究终点的一共有190例，失访10例，随访率达到95%。(2) COPD患者发生急性加重一共有131例(急性加重组)，未发生急性加重有59例(未加重组)，急性加重的发生率为68.9%。其中，半年内发生急性加重有81例，半年到一年内发生急性加重有32例，一年到两年内发生急性加重有18例。(3)将达到研究终点的190例COPD患者纳入分析。其中，性别、年龄、吸烟状况和职业粉尘或化学接触史对本地区COPD患者急性加重发生率的影响没有统计学差异(P＞0.05)；不同文化层次之间COPD患者急性加重的发生率有统计学差异(P＜0.05)，从整体上看，文化层次越高，急性加重发生率越低；不同BMI等级的COPD患者急性加重发生率有统计学差异(P＜0.05)，其中低BMI组急性加重发生率最高；最近一年内不同感冒次数等级的COPD患者急性加重的发生率有统计学差异(P＜0.05)，有感冒者急性加重的发生率明显高于未感冒者。不同严重程度等级的COPD患者之间急性加重的发生率有统计学差异(P＜0.05)，其中GOLD Ⅰ级患者急性加重发生率最低，FEV₁%预计值50%以下患者急性加重发生率明显高于50%及以上患者。(4)急性加重组和未加重组血清4个氧化应激指标的水平依次分别为8-OHdG: 545.75[277.56，959.58](pg/ml)和342.43[267.00， 597.96](pg/ml)， PC： 6.55 [3.92，11.08](ng/ml)和 1.63[0.90， 3.04](ng/ml)， MDA： 4.40[2.71， 6.16](nmol/ml)和 3.62[2.72， 4.85](nmol/ml)， T-AOC： 10.24[4.44， 18.50](U/ml)和 12.58[7.77，18.50](U/ml)，其中，急性加重组血清8-OHdG和PC的水平高于未加重组，差异有统计学意义(P ＜0.05)，急性加重组血清MDA的水平高于未加重组，急性加重组血清T-AOC水平低于未加重组，差异无统计学意义(P＞0.05) ； (5) COPD急性加重风险的单因素分析结果显示，文化程度、低BMI、最近一年内感冒次数、COPD严重程度分级、血清8-OHdG和PC水平与COPD患者发生急性加重可能存在关联(P＜0.05)，性别、年龄、吸烟状况、肥胖(BMI≥24㎏/m²)、职业粉尘或化学物质接触、血清MDA和T-AOC水平与COPD患者发生急性加重可能不存在关联(P＞0.05) ； COPD急性加重风险的多因素分析结果显示，最近一年内感冒次数、COPD严重程度分级、血清PC和MDA水平是COPD急性加重风险的独立危险因素(P＜0.05)。(6) COPD急性加重后住院治疗与否的单因素分析结果显示，文化程度、最近一年内感冒次数、COPD严重程度分级、血清PC水平与COPD急性加重后住院治疗可能存在关联(P＜0.05)，性别、年龄、吸烟状况、BMI分级、职业粉尘或化学物质接触、血清8-OHdG、 MDA和T-AOC水平与COPD急性加重住院治疗可能不存在关联(P＞0.05) ； COPD急性加重后住院治疗与否的多因素分析结果显示，最近一年内感冒次数、COPD严重程度分级和血清PC水平是COPD急性加重后住院治疗的独立危险因素(P＜0.05)。 结论 (1)2年时间里，本地区190例COPD患者中有131例发生急性加重，急性加重的发生率为68.9%。(2)本地区COPD患者文化程度越低、低BMI、最近一年内患过感冒、FEV₁%预计值在50%以下急性加重的发生率越高。(3) COPD患者体内氧化应激水平越高，越容易发生急性加重。(4) COPD稳定期患者过去一年内感冒次数、COPD严重程度分级、血清PC和MDA水平可能是COPD急性加重风险的独立危险因素，血清PC和MDA水平有望成为预测COPD急性加重风险的潜在生物标志物。(5)最近一年内感冒次数、COPD严重程度分级和血清PC水平可能是COPD急性加重后住院治疗的独立危险因素。 关键词 COPD；急性加重；危险因素；氧化应激

 Part Ⅰ Analysis of the differences of various factors between stable COPD patients and normal controls Objective To analysis of the differences of various factors between stable chronic obstructive pulmonary disease (COPD) and normal controls, and to evaluate the oxidative stress status of patients with stable COPD. Methods This is an exploratory study, in which patients with stable COPD and concurrent health checkups from the Affiliated Hospital of Southwest Medical University, the Third People's Hospital of Luzhou City, and the Jiangnan Hospital of Luzhou City from June to August of 2014 were recruited. Healthy subjects were set as control. Characteristics of patients were recorded. Lung function of patients was measured. The levels of oxidative stress indicators including 8-OHdG, PC, MDA and T-AOC in serum were detected. Statistical analysis was performed to assess factors that may affect the exacerbation of COPD and to compare the difference in oxidative stress levels between COPD patients and healthy subjects. Results (1) 200 patients with stable COPD and 100 healthy subjects were included in the study. (2) There was no significant difference in age and gender composition, occupational dust or chemical contact history between COPD patients and control (P>0.05). The COPD group had more smokers than the control group (P<0.05), while the control group was with higher education level than the COPD group (P<0.05). The mean body weight index (BMI) of the COPD group was higher than that of control. The lung function of the control group was better than that of the COPD group (P<0.05). The frequency of colds in the last year in COPD group was significantly higher than that in the control group (P<0.05). (3) The mean levels of four indicators of oxidative stress in serum in the COPD group and the control group were as follows: 8-OHdG, 359.18 [259.25, 587.85] (pg/ml) and 311.37 [265.47, 374.08] (pg/ml); PC, 3.82 [1.79, 6.83] (ng/ml) and 2.29 [1.08, 3.26] (ng/ml); MDA, 3.89 [2.77, 5.40] (nmol/ml) and 3.08 [2.32, 4.03] (nmol/ml); T-AOC, 11.35 [4.81, 20.20] (U/ml) and 18.81 [15.21, 23.19] (U/ml). The levels of 8-OHdG, PC and MDA in the COPD group were higher than those in the control group, and the levels of T-AOC in the COPD group was lower than that in the control group, and the difference was statistically significant (P<0.05). Conclusions (1) Factors including smoking status, education level, BMI, frequency of cold in the last year,FEV₁% predicted value and oxidative stress level (8-OHdG, PC, MDA and T-AOC levels) in patients with stable COPD are significantly different from those of healthy subjects. (2) Oxidation/antioxidant imbalance exists in patients with stable COPD. Part Ⅱ Epidemiological characteristics and risk factors of acute exacerbation of COPD Objective To investigate the epidemiological characteristics of acute exacerbation of COPD in Luzhou, and to assess the impact of various risk factors on acute exacerbation of COPD and hospitalization or not after acute exacerbation. Methods This is a prospective study,a total of 200 patients with stable COPD were enrolled in the study. After collecting baseline data, a 2-year follow-up was performed at the 3rd, 12th, and 24th month after enrollment of COPD patients. Once exacerbation was observed, follow-up was terminated. At each time point of follow-up, the demographic and clinical data of the study subjects, as well as their exacerbations and hospitalization or not after exacerbations, and frequency of colds in the last year, were collected. In particular, BMI, pulmonary function, serum levels of oxidative stress indicators (8-OHdG, PC, MDA and T-AOC) of subjects were recorded. After excluding those who are lost to follow-up, COPD patients were divided into exacerbation group and non-exacerbation groups. Based on the collected data, single factor logistic regression was applied to screen the influencing factors of exacerbation and hospitalization or not after exacerbation, and then multivariate logistic stepwise regression analysis was used to screen out independent factors for exacerbation risk and hospitalization or not after exacerbation. Results (1) A total of 190 cases completed the follow-up, and 10 cases were lost to follow-up. The follow-up rate was 95%. (2) There were 131 patients with acute exacerbations of COPD, and 59 patients without acute exacerbations. The exacerbation rate was 68.9%. 81 cases of exacerbation were observed within half a year, 32 cases within half a year to one year, and 18 cases within one to two years.(3) There were no significant differences in the incidence of acute exacerbation of COPD patients with different gender, age, smoking status, and occupational dust or chemical exposure (P>0.05). The incidence of acute exacerbations of COPD among patients with different education levels was statistically different (P<0.05). In general, higher the education level is associated with lower the incidence of acute exacerbation. The incidence of acute exacerbations in COPD patients with different BMI grades was statistically different (P﹤0.05), while the incidence of acute exacerbation was highest in patients with low BMI grade. The incidence of acute exacerbations in COPD patients with different frequency of colds in the past one year was statistically different (P<0.05), and significantly lower incidence was observed in those without colds. The incidence of acute exacerbations among patients with different severity of COPD was statistically different (P<0.05). Among them, the incidence was the lowest in patients with GOLD grade Ⅰ, and the incidence was significantly higher in patients with FEV₁% predicted value < 50% than that with FEV₁% value >50%. (4) The mean levels of four indicators of oxidative stress in serum in exacerbation group and non- exacerbation group were as follows: 8-OHdG, 545.75 [277.56, 959.58] (pg/ml) and 342.43 [267.00, 597.96] (pg/ml); PC, 6.55 [3.92, 11.08] (ng/ml) and 1.63 [0.90, 3.04] (ng/ml); MDA, 4.40 [2.71, 6.16] (nmol/ml) and 3.62 [2.72, 4.85] (nmol/ml)); T-AOC, 10.24 [4.44, 18.50] (U/ml) and 12.58 [7.77, 18.50] (U/ml). The serum levels of 8-OHdG, MDA and PC in exacerbation group were higher than that in the non-exacerbation group (P<0.05), while the serum level of T-AOC was lower than that in non-exacerbation group (P﹥0.05). (5) The univariate analysis of the risk of exacerbation of COPD showed that the degree of education, low BMI, frequency of cold in the last year, classification of severity of COPD, serum concentration of 8-OHdG and PC may be associated with exacerbations of COPD (P<0.05), whereas gender, age, smoking status, obesity (BMI ≥ 24 ㎏/㎡), occupational dust or chemical exposure, serum level of MDA and T-AOC may not be associated with exacerbations of COPD ( P>0.05). The multivariate analysis of the risk of acute exacerbation of COPD showed that frequency of cold, classification of severity of COPD, serum level of PC and MDA were independent risk factors (P <0.05). (6) The univariate analysis of hospitalization or not after exacerbation of COPD showed that the degree of education, frequency of cold in the last year, classification of severity of COPD, serum concentration of PC may be associated with hospitalization after exacerbations of COPD (P<0.05), whereas gender, age, smoking status, BMI grades, occupational dust or chemical exposure, serum level of 8-OHdG,MDA and T-AOC may not be associated with hospitalization after exacerbations of COPD( P>0.05). The multivariate analysis of hospitalization after exacerbations of COPD showed that frequency of cold, classification of severity of COPD, serum level of PC were independent risk factors (P <0.05). Conclusions (1) In 2 years, 131 out of 190 COPD patients in Luzhou experienced acute exacerbation, and the exacerbation rate is 68.9%. (2) Higher incidence of acute exacerbations was observed in COPD patients with lower the educational level, lower BMI scores, FEV₁% predicted value below 50%, or having a cold in the last one year.(3) Higher incidence of acute exacerbations was observed in COPD patients with higher the levels of oxidative stress. (4) Frequency of cold in the past year, classification of severity of COPD, serum level of PC and MDA may be independent risk factors for acute exacerbation of COPD.(6) Frequency of cold in the past year, classification of severity of COPD, serum level of PC may be independent risk factors for hospitalization after exacerbations of COPD. Key Words COPD; acute exacerbation; risk factors; oxidative stress