肺結核是由結核分枝桿菌造成的疾病，每年有上百萬的人類死於肺結核。結核分枝桿菌屬於細胞內細菌，它會藉由抑制吞噬小體與溶酶體結合而躲避毒殺並存活在巨噬細胞內，因為免疫系統無法有效清除結核分枝桿菌因此形成肉芽腫(granuloma)將細菌包覆在其中。慢性肉芽腫病(chronic granuloma disease)是一種在菸醯胺腺嘌呤二核磷酸氧化酶(NADPH oxidase)產生缺失的遺傳性疾病，被診斷具有不正常發炎的症狀並且會在組織有肉芽腫形成。慢性肉芽腫病(chronic granuloma disease)實驗小鼠模式中已經被報導因為缺乏具有功能的菸醯胺腺嘌呤二核磷酸氧化酶而無法有效地產生氧活性分子(ROS)的慢性肉芽腫疾病小鼠(NADPH oxidase基因缺陷鼠)在感染後無法有效控制分枝桿菌的生長。在感染分枝桿菌的情況下，氧活性分子對調控肺部免疫反應的影響與機制尚未被清楚，因此我們利用慢性肉芽腫疾病小鼠模式去研究在感染減毒牛分枝桿菌-BCG情況下，氧活性分子對於肺部免疫反應的調控為何。我們將野生型的C57BL/6小鼠與NADPH oxidase基因缺陷鼠經由氣管感染3x105 c.f.u的BCG，藉此觀察肺部發炎反應的情況。實驗結果顯示，在感染後NADPH oxidase基因缺陷鼠的肺部與野生型小鼠相比有嚴重的發炎反應以及免疫細胞的浸潤，並且隨著觀察時間增加有更嚴重的現象。不論是野生型或是NADPH oxidase基因缺陷鼠在肺部都有肉芽腫形成，但是與野生行相比，在NADPH oxidase基因缺陷鼠感染14天之後就能觀察到有較多的肉芽腫形成，但在野生型則要在感染後28天才容易觀察到。在肺部灌流液中也發現與野生型相比，在NADPH oxidase基因缺陷鼠中明顯有較高的細胞數並且發現是以嗜中性球為主的細胞浸潤。我們也測定了在BCG感染後肺部均質液中細胞激素表現量。結果顯示在感染後7天，NADPH oxidase基因缺陷鼠肺部有大量促發炎激素(TNF-α, IL-1β)表現，同時觀察到抗發炎激素(IL-10)的表現量在NADPH oxidase基因缺陷鼠中與野生型相比明顯下降。IFN-γ的表現量是免疫系統對抗分枝桿菌感染的指標，但在NADPH oxidase基因缺陷鼠中卻是降低表現，另外IL-17A也是測出來是降低表現的情況。Th2 細胞激素 IL-4也有類似的情況。最後我們利用抗Gr-1的單株抗體將嗜中性球移除之後感染BCG發現，缺乏嗜中性球的NADPH oxidase基因缺陷鼠在感染後的3到4天內死亡，而野生型小鼠則是可以存活到觀察時間截止的7天。因此我們得到的結論是，在分枝桿菌BCG感染之下，缺乏白血球氧活性分子會導致肺部過度發炎反應並且無法有效控制細菌生長，而其他非嗜中性球的吞噬細胞所產生的氧活性分子在對抗分枝桿菌BCG的感染的保護性免疫反應中也佔有很重要的角色。

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (M.tb), kills millions of people every year world wide. M.tb is an intracellular pathogen which can survive in macrophages by inhibiting the fusion of phagosome and lysosome and leads to granuloma formation in the tissue. It has been reported that CGD mice, which have mutation on p47phox (Ncf1-/-) and lack a functional leukocyte NADPH oxidase to generate the reactive oxygen species (ROS), cannot control the growth of mycobacterium well in experimental infection models. Chronic granulomatous disease (CGD) is an inherited disorder of children with mutation on the NADPH oxidase complex, which is also characterized by abnormal inflammation responses leading to granuloma formation. The effect of ROS on lung immune response to mycobacterium has still not been well known. Therefore, we investigated the role of ROS in lung immune response by using BCG infection model in CGD mice. The wild type (wt) C57BL/6 mice and NADPH oxidase deficiency (Ncf1-/-) mice were infected with 3x105 c.f.u BCG intratracheally. After infection, the immune cell infiltration in lung sections from CGD mice was notably more severe than that in wt mice and the difference increased with time up to 28 days after infection. Both groups of mice developed granulomas in the lung and the severity was higher in CGD mice. CGD mice less able to control bacterial growth well. Also, the bronchoaveolar fluid (BALF) from CGD mice had higher total cell count and more neutrophils than in wt mice. We also examined the cytokine production in lung homogenae after BCG infection. The results showed that the proinflammatory cytokines (TNF-α, IL-1β) were increased but that the IFN-γ, IL-4, and IL-17A were decreased in CGD mice. The antiinflammatory cytokines (IL-10) were also decreased in CGD mice. We used anti Gr-1 antibody to deplete neutrophils in mice groups to investigate the role of non-neutrophil pathology in defense against mycobacterium. We found that CGD mice became very susceptible to BCG infection but wt mice were not. In conclusion, our results showed that leukocyte ROS deficiency causes abnormal lung inflammation in lung bacterial infection.

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