Kruidenier Laurens, van Meeteren Marieke E, Kuiper Ineke, Jaarsma Dick, Lamers Cornelis B H W, Zijlstra Freek J, Verspaget Hein W
Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Free Radic Biol Med. 2003 Mar 15;34(6):753-65. doi: 10.1016/s0891-5849(02)01426-0.
Mucosal tissue damage in chronic inflammatory bowel disease (IBD) is partly caused by an enduring exposure to excessive amounts of reactive oxygen metabolites (ROM). To protect themselves from the toxic effects of ROM, most intestinal cell types constitutively express the highly specific, key ROM-neutralizing cytosolic enzyme Cu/Zn-superoxide dismutase (SOD). Under inflammatory conditions, however, its protein and activity levels have consistently been reported as being decreased. To elucidate a direct functional relationship between intracellular Cu/Zn-SOD expression and intestinal inflammation, we investigated the effects of transgenic human Cu/Zn-SOD overexpression in acute and chronic murine dextran sodium sulfate (DSS)-induced colitis. When subjected to a mild form of acute colitis, the Cu/Zn-SOD overexpressing mice showed a significantly lower colonic activity of neutrophilic myeloperoxidase (MPO) than their nontransgenic littermates. This difference was particularly evident in the male animals. In contrast, a severe acute colitis did not lead to any differences in MPO activity between both groups. Yet, when the animals were subsequently allowed to recover, MPO levels were again significantly lower in the transgenes, suggesting an involvement of Cu/Zn-SOD in, particularly, the clearance of neutrophils. Specific, immunohistochemical identification of neutrophils confirmed the validity of the MPO activity measurements. In addition, transgenic animals showed a remarkable survival benefit from severe DSS colitis over their nontransgenic littermates, particularly during or shortly after the acute inflammatory phase. During the chronic inflammatory phase, which was not characterized by massive neutrophil infiltration, no effects of Cu/Zn-SOD overexpression were noted. Paradoxically, overexpression of Cu/Zn-SOD did not obviously improve the colitis-related (oxidative) injury or symptoms at any stage of the experiment. Surprisingly, however, we did observe a pronounced male gender preference for DSS susceptibility that was reflected by increased male colitis mortality. Our findings provide direct in vivo evidence for a protective, neutrophil-related role for Cu/Zn-SOD in intestinal inflammation. As such, they support the concept of SOD-based (adjunct) antioxidant treatment strategies for inflammatory bowel disease.
慢性炎症性肠病（IBD）中的黏膜组织损伤部分是由于长期暴露于过量的活性氧代谢产物（ROM）所致。为了保护自身免受ROM的毒性影响，大多数肠道细胞类型组成性表达高度特异性的关键ROM中和胞质酶铜/锌超氧化物歧化酶（SOD）。然而，在炎症条件下，其蛋白质和活性水平一直被报道为降低。为了阐明细胞内铜/锌SOD表达与肠道炎症之间的直接功能关系，我们研究了转基因人铜/锌SOD过表达在急性和慢性小鼠葡聚糖硫酸钠（DSS）诱导的结肠炎中的作用。当遭受轻度急性结肠炎时，铜/锌SOD过表达小鼠的结肠中性粒细胞髓过氧化物酶（MPO）活性明显低于其非转基因同窝小鼠。这种差异在雄性动物中尤为明显。相比之下，严重急性结肠炎并未导致两组间MPO活性出现任何差异。然而，当动物随后恢复时，转基因小鼠的MPO水平再次显著降低，这表明铜/锌SOD尤其参与了中性粒细胞的清除。中性粒细胞的特异性免疫组织化学鉴定证实了MPO活性测量的有效性。此外，转基因动物在严重DSS结肠炎中比其非转基因同窝小鼠具有显著的生存优势，尤其是在急性炎症期或急性炎症期后不久。在以中性粒细胞大量浸润为特征的慢性炎症期，未观察到铜/锌SOD过表达的影响。矛盾的是，在实验的任何阶段，铜/锌SOD的过表达均未明显改善结肠炎相关的（氧化）损伤或症状。然而，令人惊讶的是，我们确实观察到DSS易感性存在明显的雄性性别偏好，这表现为雄性结肠炎死亡率增加。我们的研究结果为铜/锌SOD在肠道炎症中基于中性粒细胞的保护作用提供了直接的体内证据。因此，它们支持了基于SOD的（辅助）抗氧化治疗策略用于炎症性肠病的概念。
