辛伐他汀在慢性阻塞性肺疾病大鼠模型中的早期干預作用

楊凱　郭璐　劉躍建

[摘要] 目的 探討早期給予辛伐他汀干預對慢性阻塞性肺疾病（COPD）大鼠模型的影響及機制。 方法 將42只大鼠（Wistar，清潔級）隨機分為空白組、模型組和他汀組，每組14只。采用煙熏加氣道內滴入脂多糖法復制COPD大鼠模型，他汀組在造模2周后加用辛伐他汀（5 mg/kg）灌胃治療。觀察大鼠一般表現；監測體重變化；采用生物素雙抗體夾心酶聯免疫吸附法測定血清及支氣管肺泡灌洗液（BALF）中白細胞介素-6（IL-6）、腫瘤壞死因子-α（TNF-α）水平；血球計數儀計數BALF中白細胞計數；免疫組織化學染色法測定肺組織中基質金屬蛋白酶（MMP-9）的表達；圖像分析系統分析各組大鼠病理改變。 結果 模型組及他汀組大鼠體重較空白組減輕（P < 0.01）。血清和BALF中IL-6、TNF-α水平，模型組及他汀組較空白組增加（P < 0.05），他汀組較模型組降低（P < 0.05）。肺組織中MMP-9表達，模型組較空白組增高（P < 0.01），他汀組較模型組降低（P < 0.05）。模型組及他汀組大鼠肺組織符合COPD病理學改變，他汀組組織損傷、重塑及炎癥浸潤程度較模型組降低。 結論 香煙吸入聯合呼吸系統感染可加重肺部及全身炎性反應程度，增加蛋白酶過度表達，參與COPD的發生發展。早期給予辛伐他汀治療，可在一定程度上減輕肺組織損傷及重塑，降低炎性反應程度，緩解蛋白酶系統亢進。

[關鍵詞] 他汀；慢性阻塞性肺疾病；大鼠；基質金屬蛋白酶9

[中圖分類號] R563.9 [文獻標識碼] A [文章編號] 1673-7210（2017）12（a）-0008-05

[Abstract] Objective To explore the effects of early stage administration of Simvastatin on chronic obstructive pulmonary disease （COPD） rat model and its mechanism. Methods 42 SPF Wistar rats were randomly divided into three groups （n=14）： blank group， model group and Simvastatin group. COPD rat models were replicated with the method of inhaling cigarette smoke and intratracheal instillation of LPS. Simvastatin group rats were gave lavage treatment with Simvastatin （5 mg/kg） after 2 weeks when COPD model was established. Usual manifestations and body weights of rats from the three groups were monitored. The levels of IL-6 and TNF-α in serum and BALF were measured by double antibody sandwich enzyme-linked immuno sorbent assay （ELISA）. Leukocyte in BALF was counted by haemocytometer. The expression of MMP-9 in the lung tissues was measured by immunohistochemically. Pathological examination of lung tissues from every group was analyzed by image analysis system. Results Body weights of rats from the model group and Simvastatin group were significantly reduced compared with those of the blank group （P < 0.01）. Levels of IL-6 and TNF-α in serum and BLAF were higher in the model group and Simvastatin group than the blank group （P < 0.05）. Compared with model group， the levels in Simvastatin group were decreased （P < 0.05）. The expression of MMP-9 in lung tissues， model group was increased than the blank group （P < 0.05）， Simvastatin group was lower than the model group （P < 0.05）. The pathologic characteristics of COPD was observed in the lung tissues from Sim？鄄vastatin group and model group. Copmared with the model group， lung tissue injury， remodeling and inflammatory infiltration in Simvastation group was attenuated. Conclusion Cigarettes inhalation combined with respiratory infections can aggravate pulmonary and systemic inflammation， and up-regulate the expression of proteases， all of which are involved in the genesis and development of COPD. Simvastatin therapy as an early intervention can alleviate the lung tissue injury and remodeling to a certain degree， attenuate pulmonary and systemic inflammation and alleviate the over-activation of proteasesystem.endprint

[Key words] Statin； COPD； Rat； MMP-9

慢性阻塞性肺疾病是一種常見的以持續性呼吸道癥狀和氣流受限為特征的可以預防和治療的疾病[1]，氣流受限呈進行性發展，與肺部對有害氣體或顆粒的異常慢性炎性反應相關。因其發病率、致殘率和死亡率高而嚴重危害著人類的身體健康，給社會和家庭帶來了沉重的醫療、經濟負擔。

世界衛生組織預測，至2020年，COPD將位居世界死亡原因第三位、疾病經濟負擔第五位。COPD起病隱匿，一旦出現臨床癥狀，往往預示著患者生活質量、呼吸功能以及整體健康水平將逐漸進行性下降，其急性加重更可直接導致患者死亡，因此在疾病早期給予積極有效的治療顯得尤為重要。……