評估基質金屬蛋白酵素9 (MMP-9)做為呼吸器相關肺炎的診斷及預測預後的可能性

Elevated Plasma Matrix Metalloproteinase-9 and Its Correlations with Severity of Disease in Patients with Ventilator-Associated Pneumonia

李雅婷(Yia-Ting Li)

指導教授 ： 楊順發 ； 盧敏吉

中山醫學大學/醫學院/醫學研究所/博士(2017年)

摘要

呼吸器相關肺炎 (Ventilator-associated pneumonia ; VAP)是常見
的院內感染，其會增加病患的死亡率及浪費許多醫療成本，正確且及時的診斷VAP，可以幫助臨床人員及早給予適當治療，降低病情嚴重度及死亡率。目前在VAP的診斷上，仍舊存有疑慮，客觀的診斷方式 (生物標誌－Biomarker)可以減少個人判讀的誤差。過去的研究指出，在免疫調節機制上，基質金屬蛋白酵素 (Matrix metalloproteinases ;MMPs)佔有一個重要的位置，而在MMPs家族中，基質金屬蛋白酵素9 (Matrix metallo-proteinase 9；MMP-9)被證實和嗜中性白血球的遷移、吞噬細菌能力及活性氧 (Reactive Oxygen Species；ROS)的產生有關聯性，而且，在呼吸道發炎及肺部感染疾病上，均可見MMP-9濃度與活性的增加。多篇研究佐證MMP-9在肺部的發炎機制上，佔有一席之地，但並未有研究探討呼吸器相關肺炎與MMP-9的關聯性，因此，本研究試圖使用MMP-9做為呼吸器相關肺炎病患診斷的依據。本研究為回溯性觀察型研究，共收錄30個VAP及12個未發展成VAP的呼吸器使用病患，另外收集了30個健康的個案做為對照組，VAP的診斷方式依據American Thoracic Society (ATS)標準。收集的個案血液檢體使用免疫酵素連結反應 (ELISA)和明膠酶譜分析法 (zymography)進行MMP-9濃度及活性的偵測。在結果上面，我們發現VAP病患血漿中的MMP-9活性量及濃度明顯高於非VAP病患和健康的族群，而經過治療後的VAP病患，MMP-9活性量及濃度均呈現明顯的下降；另外，血漿中的MMP-9表現量和臨床肺部感染指數clinical pulmonary infection (CPIS) score (r=0.409, p=0.007)，白血球White blood cell (WBC) (r=0.620, p<0.01)及嗜中性白血球neutrophils counts (r =0.335, p=0.035)有著明顯的正相關性；使用MMP-9做為VAP病患的診斷工具，設定cut-off為92.62 ng/ml ，在ROC curve上，表現出良好的辨識力 (AUC=0.863, 95% CI=0.761 to 0.932)。總結以上的結果，MMP-9似乎可以被運用於呼吸器相關肺炎的診斷，未來或許可以更進一步的應用在相關的治療上。

關鍵字

呼吸器相關肺炎 ； 基質金屬蛋白酵素9 ； 臨床肺部感染指數

並列摘要

Ventilator associated pneumonia (VAP) increase both patients’ mortality and medical expenditure. A real time and reliable method for rapid diagnosis of VAP may help to reduce subsequent fatal complication. Certain biomarkers have been proposed to facilitate the diagnosis of VAP. Previous studies have pointed out that Matrix metalloproteinases (MMPs) play an importance role in the immuneregulatory mechanism. In the family of MMPs, MMP-9 was identified to be associated with the migration and phagocytic ability of neutrophils. As well as the production of reactive oxygen species (ROS). An increased in the amount and activity of MMP-9 could be observed in many of the inflammatory and infective lung diseases. Several studies have proved that MMP-9 plays an importance role in the mechanism of lung inflammation. There were however, no related studies that discussed on the relationship between VAP and MMP-9. Therefore, we examined the usefulness of plasma level of MMP-9 for the recognition of VAP. The retrospective observational study recruited 30 healthy volunteers, 12 mechanically ventilated patients without the development of VAP (non-VAP subjects) and 30 patients with the clinical diagnosis of VAP. The diagnostic criteria for VAP were based on the guidelines of the American Thoracic Society (ATS), and the activity and the level of plasma MMP-9 was determined by the method of gelatine zymography and enzyme-linked immunosorbent assay (ELISA). Plasma MMP-9 activity and level was significantly elevated in the acute stage of patients with VAP when compare with the healthy controls and non-VAP subjects. Subsequently, plasma MMP-9 of VAP patients decreased significantly after treatment. Furthermore, the plasma MMP-9 concentration were positively correlated with clinical pulmonary infection (CPIS) score (r= 0.409, p=0.007), quantity of WBCs (r=0.620, p<0.001) and neutrophils counts (r=0.335, p=0.035). In addition, plasma MMP-9 was an excellence tool for the recognition of VAP when the cut-off level was set to be 92.62 ng/ml (AUC=0.863, 95% CI=0.761 to 0.932). MMP-9 could be a biological marker for the diagnosis of VAP, which could potentially employed to direct the development of VAP therapies.

並列關鍵字

Ventilator associated pneumonia (VAP) ； matrix metalloproteinases-9 (MMP-9) ； Clinical Pulmonary Infection Score(CPIS)

參考文獻

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