結核病在台灣及全世界一直都是相當重要的傳染性疾病，在台灣目前每年仍有約14,000新增結核個案發生，全世界每年則有高達九百萬名新增個案，且估計全世界有1/3人口為潛伏性結核感染。糖尿病合併肺結核已經是目前我們所面臨更嚴峻公共衛生上的威脅之一，除了糖尿病盛行率連年激增外，目前大型跨國性公衛調查也發現糖尿病患者肺結核臨床治療整體預後都比非糖尿病患者差，但目前對於其中的免疫機轉仍了解不多。Resistin是脂肪細胞、巨噬細胞及白血球所產生的細胞激素，本身會造成insulin resistance因此命名為resistin，被認為是肥胖、糖尿病及發炎反應間的重要因子。目前的研究著重在resistin在免疫上的角色，除已證實resistin可作為包含血管硬化、關節炎甚至敗血症等發炎性疾病的生物標誌，也發現resistin可抑制顆粒白血球的ROS 產生能力，不過仍未有人去探討resistin對巨噬細胞的影響。本研究前瞻性收集結核患者血液檢體測量resistin及相關生物標誌，然後分別以THP-1細胞株及Ncf1-/- mice進行細胞及動物實驗。我們共收集297位個案並發現相對於輕度結核及健康對照組，嚴重結核及糖尿病對照組個案血中resistin有顯著上升，另外和臨床常用的C-reactive protein相比，resistin 是較好評估結核嚴重度的生物標誌。在細胞實驗中我們證實resistin的確能顯著抑制 THP-1細胞的ROS產生且其抑制效果和NADPH氧化酶抑制劑 diphenyleneiodonium chloride相當。此外我們以M. marinum感染wild type 及Ncf1-/- 小鼠進行動物實驗並證實缺乏ROS會造成廣泛且嚴重的分枝桿菌導致肉芽腫性發炎。經由上述實驗我們發現Resistin在糖尿病及嚴重結核患者都有顯著升高且有顯著抑制ROS產生的作用。ROS能有效顯著降低分枝桿菌感染後的肉芽腫性發炎，其中機制仍需進一步探討。

Mycobacterium tuberculosis (TB) infection is still an important public health problem in Taiwan and worldwide. Approximately 14,000 people in Taiwan and 9 million people in the world develop active disease each year. Population-based studies have shown that the combination of TB and diabetes mellitus (DM) is a big challenge due to not only the rising prevalence of DM, but also its detrimental impact on TB treatment outcomes. However, the immunological mechanism underlying this combination remains unclear. Resistin, an adipokine, which increases in obesity, DM, and inflammation, can inhibit essential functions of granulocytes, but its effects on macrophage-mediated immunity are not clear. In this study, we first investigated serum resistin in TB patients and control cases, then explored the in vitro anti-oxidant effect of resistin and in vivo role of ROS during mycobacterial infection. We found that serum resistin level was significantly higher in severe TB cases and diabetes-only cases. Furthermore, resistin significantly inhibits ROS production to an extent comparable to the NADPH oxidase inhibitor, diphenyleneiodonium chloride. Finally, in M. marinum infection mouse model, we demonstrated that Ncf1-/- mice had more extensive granulomatous inflammation in lung and liver than wild type mice. Thus, ROS is important in limiting mycobacterium-induced granulomatous inflammation in vivo. These findings not only showed the linkage between DM and severe TB infection, but also demonstrated the key role of ROS in immune response to mycobacterial infection.

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