Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway.
Inhal Toxicol. 2010 Feb;22(2):140-50. doi: 10.3109/08958370903019885.
Airway inflammation is important in asthma pathogenesis. Recent epidemiological data have indicated an association between asthma symptoms in children and exposure to di(2-ethylhexyl) phthalate (DEHP). Thus, we have studied inflammatory responses in primary rat alveolar macrophages (AMs) after exposure to mono(2-ethylhexyl) phthalate (MEHP), the major primary metabolite of DEHP. First, we show that MEHP induces a dose-dependent release of the pro-inflammatory tumour necrosis factor-alpha (TNF-alpha) in AMs, giving a maximal (5-fold) increase at 0.7 mM. This concentration also induced some cell death. MEHP also induced phosphorylation of MAPK p38, while the p38 inhibitor SB 202190 reduced MEHP-induced TNF-alpha, suggesting a p38-dependent cytokine production. Next, we elucidated possible effects of MEHP on the 5-lipoxygenase (5-LO) pathway and found that MEHP caused increased leukotriene (LTB(4)) release. Further, we found that the 5-LO inhibitor nordihydrogualaretic acid (NDGA) significantly reduced both MEHP-induced TNF-alpha release and MEHP-induced formation of reactive oxygen species (ROS), supporting an involvement of the 5-LO pathway in MEHP induced inflammatory reactions. Last, we found that MK-886, a known inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), increased the MEHP-induced TNF-alpha response. This indicates that MEPH-PPARalpha binding mediates an anti-inflammatory signal.
气道炎症在哮喘发病机制中很重要。最近的流行病学数据表明，儿童哮喘症状与邻苯二甲酸二（2-乙基己基）酯（DEHP）暴露之间存在关联。因此，我们研究了 MEHP（DEHP 的主要初级代谢物）暴露后原代大鼠肺泡巨噬细胞（AMs）中的炎症反应。首先，我们表明 MEHP 诱导 AMs 中促炎肿瘤坏死因子-α（TNF-α）的剂量依赖性释放，在 0.7mM 时最大（5 倍）增加。该浓度也诱导了一些细胞死亡。MEHP 还诱导 MAPK p38 的磷酸化，而 p38 抑制剂 SB 202190 减少了 MEHP 诱导的 TNF-α，表明 p38 依赖性细胞因子产生。接下来，我们阐明了 MEHP 对 5-脂氧合酶（5-LO）途径的可能影响，发现 MEHP 导致白三烯（LTB4）释放增加。此外，我们发现 5-LO 抑制剂 nordihydrogualaretic acid（NDGA）显著降低了 MEHP 诱导的 TNF-α释放和 MEHP 诱导的活性氧（ROS）形成，支持 5-LO 途径参与 MEHP 诱导的炎症反应。最后，我们发现已知的过氧化物酶体增殖物激活受体α（PPARα）抑制剂 MK-886 增加了 MEHP 诱导的 TNF-α反应。这表明 MEPH-PPARα 结合介导抗炎信号。
