慢性阻塞性肺病 (chronic obstructive pulmonary disease, COPD) 是一種呼吸氣流受限疾病，主要包括慢性支氣管炎和肺氣腫 (emphysema) 兩種病況，由於長期吸菸或空氣汙染，導致肺部產生過多的氧化壓力，造成呼吸道持續發炎，活化多種蛋白酶，使肺泡細胞被破壞、失去彈性，呼進的空氣滯留於肺部，產生肺氣腫。COPD的罹患率和死亡率在全世界都逐年增加，但到目前還沒有有效的藥物來阻止COPD患者肺功能的漸進性惡化。肺泡表面蛋白質D (surfactant protein D, SP-D)，由肺泡第二型上皮細胞所分泌，屬於C型凝集素 (C-type lectin) 之一，為肺部重要的先天性免疫調節蛋白，先前的文獻顯示，COPD患者血清SP-D含量較健康者多，且在小鼠的調查中也發現，SP-D基因缺陷的小鼠具有肺氣腫的現象。由於SP-D在其中的機制尚不清楚，因此本研究目的為探討SP-D在COPD中的功能及作用機轉。臭氧 (ozone) 為環境中的污染物，當濃度過高時會造成肺部發炎，導致肺氣腫，因此我們利用臭氧來誘導小鼠產生COPD，在這個動物模式中，我們發現臭氧暴露的小鼠比起控制組，具有較差的肺功能，病理切片圖也看到了肺氣腫的現象，增加肺部免疫細胞浸潤並且產生許多發炎細胞激素。接著為了調查SP-D在慢性阻塞性肺病中的機制，我們利用SP-D基因剔除的小鼠暴露於臭氧進行調查，結果發現在未給予臭氧時SP-D基因剔除小鼠比起野生型小鼠，具有較差的肺功能及較多的免疫細胞浸潤到肺部中，而暴露於臭氧後，則產生更嚴重的發炎反應、肺部增加更多的嗜中性白血球 (neutrophil) 浸潤，說明了SP-D在COPD中可能扮演著保護的角色。為了調查SP-D的保護機制，我們利用細胞株給予過氧化氫 (hydrogen peroxide, H2O2) 來誘導產生氧化壓力，發現預給天然的SP-D可以使肺泡上皮細胞 (A549) 增加NF-E2相關因子2 （nuclear factor erythroid-2-related factor, Nrf2）的表現，可以降低活性氧化物質 (reactive oxygen species, ROS) 的產生，也可以減少肺上皮細胞的細胞凋亡現象。且在臭氧暴露小鼠模式中給予天然SP-D可以恢復老鼠的肺功能，減少氣管的發炎現象、降低免疫細胞的浸潤以及增加Nrf2的表現。綜合以上結果得知，SP-D可藉由增加Nrf2表現來抑制ROS，減少肺泡上皮細胞凋亡來改善COPD的症狀，故SP-D有可能在未來成為治療COPD的新藥物。

Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is associated with chronic bronchitis and emphysema. The common risk factors for the development of COPD are cigarettes smoking and oxidant air pollution. Surfactant protein D (SP-D) is known to play an important role in innate immunity of lung. Previous research has demonstrated that serum SP-D level is increased in COPD patients as compared with healthy people. In addition, mice with SP-D deficiency exhibit pathological characteristic of bronchitis and emphysema. However, the role and function of SP-D in COPD remain unclear. Therefore, this study is aimed to investigate the role of SP-D in COPD. We have established the ozone-induced mice model of COPD. Ozone is an environmental pollutant that stimulates airways and induces neutrophilic lung inflammation. In this mouse model, we found that SP-D deficient mice exposed to ozone for three weeks, have poorer lung function and increased number of macrophages and neutrophils infiltration in the airways as compared with those of wild type group. These results suggested that SP-D may play a protective role in the development of ozone-induced mice model of COPD. We also found that pre-treatment with native SP-D in hydrogen peroxide (H2O2)-stimulated human epithelial cell line inhibited the production of reactive oxygen species (ROS) and epithelial cell apoptosis. Further results also showed that intra-tracheal administration of exogenous SP-D in our established mice model of COPD, improved lung function, decreased number of inflammatory cells infiltration in the airways, reduced the production of inflammatory cytokines and increased the Nrf2 expression in lung. In conclusion, our results indicate that SP-D may play a protective role in ROS inhibition and decrease cell apoptosis via increased the Nrf2 protein to alleviate the symptoms of COPD, which may have clinical implication for this chronic lung diseases.

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