在工業國家中，二異氰酸甲苯這種高氧化活性的化學物是導致職業性氣喘主因之一。暴露在二異氰酸甲苯的工作環境中會導致肺發炎伴隨著免疫細胞浸潤及一氧化氮的產生。我們先前的研究指出，二異氰酸甲苯會導致細胞浸潤，其中白血球的菸醯胺腺嘌呤二核酸磷酸氧化酶是重要的。為了釐清氧化還原調控在二異氰酸甲苯導致肺發炎中所扮演的角色，我們利用正常鼠、菸醯胺腺嘌呤二核酸磷酸氧化酶基因缺失鼠、誘發型一氧化氮合成酶基因缺失鼠及菸醯胺腺嘌呤二核酸磷酸氧化酶與誘發性一氧化氮合成酶雙重基因缺失鼠進行二異氰酸甲苯刺激的實驗。從病理組織切片的結果中發現，在二異氰酸甲苯刺激後正常鼠與控制組相比支氣管及微血管周圍有嚴重免疫細胞浸潤的現象，然而在菸醯胺腺嘌呤二核酸磷酸氧化酶基因缺失鼠及誘發型一氧化氮合成酶基因缺失鼠中則較少，在雙重基因缺失老鼠中近乎沒有細胞浸潤。並且在二異氰酸甲苯刺激後正常鼠與控制組相比氧化壓力及硝化壓力指標：脂質過氧化物、誘發型一氧化氮合成酶，一氧化氮生成量及硝基酪胺酸的表現量都有顯著升高。但在菸醯胺腺嘌呤二核酸磷酸氧化酶基因缺失鼠、誘發型一氧化氮合成酶基因缺失鼠及雙重基因缺失的老鼠中則沒有差異。在二異氰酸甲苯刺激後正常鼠與控制組相比細胞激素：干擾素-，干擾素--誘發蛋白-10，白細胞介素-2，白細胞介素-4，白細胞介素-5，白細胞介素-17和腫瘤壞死因子-的表現量都有顯著升高，但在菸醯胺腺嘌呤二核酸磷酸氧化酶基因缺失鼠、誘發型一氧化氮合成酶基因缺失鼠及雙重基因缺失的老鼠中則沒有差異。我們也發現在菸醯胺腺嘌呤二核酸磷酸氧化酶基因缺失鼠的誘發型一氧化氮合成酶和細胞激素的表現量在未刺激前就比正常鼠高。總結，我們認為二異氰酸甲苯誘發的肺發炎中，菸醯胺腺嘌呤二核酸磷酸氧化酶及誘發型一氧化氮合成酶透過氧化還原調控參與其中。活性氧分子及活性氮分子在肺部發炎中都扮演著重要的角色，因為單一基因的缺陷並無法完全抑制二異氰酸甲苯誘發肺發炎；然而同時缺乏兩個基因時能有效抑制肺發炎。這些結果顯示，活性氧分子及活性氮分子能夠經由獨特作用和協同作用造成二異氰酸甲苯所誘發的職業性氣喘。

Toluene diisocyanate (TDI) is an oxidizing chemical which induces occupational asthma. Workplace exposure to TDI leads to lung inflammation with distinctive leukocyte infiltration and nitric oxide (NO) production. Our previous research showed that leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is essential for inducing pulmonary inflammation with TDI. To clarify the role of the redox regulation in TDI-induced pulmonary inflammation, we investigated the redox regulation in wild type (WT) mice, NADPH oxidase subunit p47phox/ neutrophil cytosolic factor1 deficient mice (Ncf1-/-), inducible nitric oxide synthase (iNOS) deficient mice (Nos2-/-), and Ncf1 and Nos2 double gene-deficient mice (Ncf1-/- /Nos2-/-). Histopathological evaluation demonstrated more severe inflammatory cells infiltration around the bronchiole and capillary in WT than in Ncf1-/-, Nos2-/- , and Ncf1-/- /Nos2-/- mice after TDI exposure. TDI caused both oxidative and nitrosative stress, reflected by dramatically increased levels of the lipid peroxidation end product malindialdehyde (MDA), iNOS activation, NO production, and nitrotyrosine expression in WT mice, but not in Ncf1-/-, Nos2-/-, and Ncf1-/- /Nos2-/- mice. The expression of cytokines including interferon- (IFN-), IFN--induced protein 10 (IP-10), interleukin 2 (IL-2), IL-4, IL-5, IL-17, and tumor necrosis factor- (TNF-) significantly increased after TDI exposure in WT mice. However, high baseline iNOS expression and cytokine production before TDI stimulation were noted in Ncf1-/- mice. We hence conclude that both ROS and RNS participate in the redox-regulation of TDI-induced lung inflammation. Both ROS and RNS play important roles in lung inflammation because lacking of either leukocyte NADPH oxidase or iNOS lowered but did not completely abolish TDI-induced lung inflammation, whereas lacking of both genes prevented lung inflammation. These results suggest that ROS and RNS have individual and overlapping roles in TDI-induced occupational asthma.

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