血清生長因子的濃度與慢性阻塞性肺病之關連性

Association study of serum growth factors in patient with COPD

田鴻毅(Hong-Yih Tien)

指導教授 ： 余忠仁

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201901815

摘要

慢性阻塞性肺病（COPD）其特徵為持續的呼氣氣流受阻，常為漸進性且伴有肺臟及呼吸道對有害微粒或氣體的慢性發炎反應。急性發作惡化與共病症（包括心血管疾病、骨骼肌失能、代謝症候群、骨質疏鬆、憂鬱症以及肺癌）與疾病的整體嚴重度有關。COPD 早期症狀並不明顯，同時也缺乏特異性，因此很容易被誤診為其他疾病，如氣喘感冒。和氣喘不同，COPD 的呼吸道阻塞及肺部傷害皆屬於不可逆反應，再加上病程進展緩慢，等到臨床上發現時往往已發展至中後期，延誤了早期治療的先機。

將COPD病患依據肺量計檢查（spirometric classification）分為四級；需FEV1 / FVC <70% 的病人，分成輕度GOLD 1: FEV1 ≥ 80% 預測值，中度GOLD 2: 50% ≤ FEV1 < 80% 預測值，重度GOLD 3: 30% ≤ FEV1 < 50% 預測值，極重度GOLD 4: FEV1 < 30% 預測值。根據GOLD (Global Initiative for Chronic Obstructive Lung Disease) 分級系統所累積的大量證據顯示，呼氣氣流受阻加重時，急性惡化、住院及死亡的風險也會增加。

慢性阻塞性肺病的病人因慢性發炎，會造成肺部上皮細胞的破壞，而生長因子也和COPD慢性發炎有關，有研究顯示這些生長因子可能與病患肺部破壞的嚴重度、急性惡化、肺功能變化、臨床結果和預後有關，可視為生物標記物。其中以血清生物標記是最常被廣泛用來預測疾病嚴重度、結果與預後的指標。雖然生物標記的來源很多，不僅限於血清生物標記，包括痰液誘導和支氣管沖洗液等，但因缺乏標準化及檢體取得困難的缺點，所以限制了這些非血清生物標記在大型臨床試驗的運用。血清生物標記已被許多研究建立出標準的取得和加工萃取檢體的方法。

藉由檢測血清中參與慢性阻塞性肺病發炎反應的許多生長因子，例如：Brain-derived neurotrophic factor(BDNF)、Leukemia inhibitory factor (LIF)和纖維母細胞生長因子(Fibroblast growth factor, FGF-2)、血管內皮生長因子(Circulating vascular endothelial growth factor, VEGF-D)...等，來觀察其濃度與病患臨床症狀的變化和疾病急性惡化的關聯性。

目前針對其治療的新藥發展也遇到瓶頸。除了避免接觸致病的危險因子如吸菸，並儘可能早期診斷以獲得正確的治療，若能發展出具有預測性質的生物標記物，預測疾病進展與臨床結果(outcome)，早期介入治療和控制疾病進展，將可減少病患的醫療費用支出，以及相關的社會成本。藉由偵測病患血清中生長因子的濃度，來比較在不同嚴重程度COPD病患的相關性，例如肺功能(FEV1)變化和急性惡化等，並視為監測COPD的生物標記。

本研究認為，生長因子VEGF-D和FGF-2對於區分收案前一年頻繁惡化者是達統計顯著意義。FGF-2可用於預測收案一年後病患急性發作，其數值越高則急性發作風險越低。所以對於預測COPD急性發作和頻繁惡化，若能結合其它生長因子(例如: FGF-2、VEGF-D、NGF等)，應能提高預測靈敏度。因此，測量COPD病患血清VEGF-D、FGF-2和NGF濃度，應可作為運用/預測病患急性發作的敏感指標。

關鍵字

慢性阻塞肺疾病 ； 生長因子 ； 生物標記 ； 血管內皮生長因子 ； 纖維母細胞生長因子 ； 神經生長因子 ； C-反應蛋白

並列摘要

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by complex inflammatory, neuronal and fibrotic changes. Growth factor plays a key regulator of neuronal plasticity, and a crucial role in tissue repair and emphysema pathogenesis. The aims of this study was to determine which blood-based molecules (growth factors) have been evaluated as possible biomarkers to diagnose outcome of chronic obstructive pulmonary disease (COPD), to be correlated with lung function of forced expiratory volume in one second (FEV1% of predicted), and to predict risk of acute exacerbations.

Methods: In the present study, patients over 40 and under 100 years of age with COPD (spirometry GOLD stages 1–4) were studied. Lung function, smoking history, medication, eosinophil of peripheral blood and serum concentrations of growth factors were assessed in all participants. There were 11 kinds of growth factors in this study, including NGF(Nerve growth factor-beta), BDNF(Brain-derived neurotrophic factor), EGF(Epidermal growth factor), FGF-2 (fibroblast growth factor-2), HGF( Hepatocyte growth factor), LIF(Leukemia inhibitory factor), PDGF (Platelet-derived growth factor), PLGF Placental growth factor), SCF(Stem cell Factor), VEGF-A and VEGF-D(Vascular endothelial growth factor-D). Spearman rank correlation was used to assess the relationship between growth factors and FEV1 predicted levels. The trend of levels of growth factors across COPD severity (GOLD grading or ABCD group classification) was assessed by the Jonckheere-Terpstra test. We also compared levels of growth factors between subgroups of FEV1% of predicted (< 50% vs. ≥ 50%), eosinophil (≥ 2% vs. < 2%), and frequent acute exacerbation (AE) in the previous year (0-1 vs. 2-3) by the Mann-Whitney U-test. The associations between growth factors and binary outcomes (e.g., GOLD grading 3-4, FEV1% of predicted <50%) were determined using multivariable logistic regression analysis with adjustment with sex, age, smoking status and body mass index. The performance of growth factors to discriminate frequent AE was evaluated by Receiver Operating Characteristic (ROC) curve analysis. The validation using outcome in the next year was also performed.

Results: A total of 138 participants were enrolled who male is predominant (98.6%) and with a mean age of 68.3 years (standard deviation [SD], 9 years). The mean FEV1 predicted levels were 55.7% (SD, 18.4%). Number of GOLD stages 1–4 was 16 (11.6%), 67 (48.6%), 45 (32.6%) and 10 (7.2%) respectively. Number of COPD group classification A, B, C and D was 58 (42.0%), 28 (20.3%), 30 (21.7%), and 22 (15.9%) respectively. No significant correlation between the 11 growth factors and FEV1 predicted levels was found. There were no significant trend of levels of the 11 growth factors across GOLD grading or COPD group classification. There were no significant difference in levels of the 11 growth factors between subgroup of FEV1 predicted (< 50% vs. ≥ 50%) and eosinophil (≥ 2% vs. < 2%). Notably, serum levels of both FGF-2 and VEGF-D were significantly decreased in patients with frequency of acute exacerbations of COPD (AECOPD) compared with patients with infrequency of AECOPD (both P < 0.05) in previous year. The ROC curves showed the area under the curve (AUC) of FGF-2 was 0.704 (95% confidence interval [CI], 0.620 to 0.778, P = 0.010), the optimum cut point for Youden index was ≤4.76 with a sensitivity of 81.8% and a specificity of 62.2%. Another AUC of VEGF-D was 0.700 (95% CI, 0.616 to 0.775, P = 0.004), its Youden index is optimally ≤10.02 with a sensitivity of 100% and a specificity of 43.3%. After combining FGF-2 and VEGF-D in the logistic regression, the result showed that the AUC was 0.777 (95% CI, 0.697 to 0.844, P < 0.001).

A total of 112 participants were enrolled for validation study in the next year. Higher FGF-2 level was associated with a lower risk of acute exacerbations of COPD one year later (odds ratio, 0.972; 95% CI, 0.949-0.997). The ROC curves showed the area under the curve (AUC) of FGF-2 was 0.614 (95% CI, 0.518 to 0.705, P = 0.032), the optimum cut point for Youden index was ≤9.12. Higher NGF was associated with a lower risk of frequent AE of COPD one year later(odds ratio, 0.93; 95% CI, 0.87-0.99).Similarly, using the ROC curve, the AUC of the NGF was 0.797 (P < 0.001), which reached an acceptable discriminating power for predict of frequency of acute exacerbations of COPD, the optimum cut point for the Younden index is ≤ 25.23.

Conclusion:
FGF-2 and VEGF-D concentrations are associated with increased frequency of acute exacerbations of COPD in previous year. FGF-2 was used to predict acute exacerbation of COPD after one year later. For predicting acute exacerbation, if combined with other growth factors (eg, FGF-2, VEGF-D, NGF, etc.), the prediction sensitivity should be improved. Therefore, measuring serum VEGF-D, FGF-2 and NGF concentrations in patients with COPD should be a sensitive indicator for predictive acute exacerbation of patients. Therefore, this may be used as a biomarker for COPD.

並列關鍵字

Chronic Obstructive Pulmonary Disease (COPD) ； Growth Factors ； Biomarker ； Vascular Endothelial Growth Factor ； Fibroblast Growth Factor ； Nerve Growth Factor ； C-reactive protein (CRP)

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