Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
J Lipid Res. 2018 Oct;59(10):1841-1850. doi: 10.1194/jlr.M084285. Epub 2018 Aug 7.
Intestinal alkaline SMase (Alk-SMase) cleaves phosphocholine from SM, platelet-activating factor (PAF), and lysophosphatidylcholine. We recently found that colitis-associated colon cancer was 4- to 5-fold enhanced in Alk-SMase KO mice. Here, we further studied the pathogenesis of colitis induced by dextran sulfate sodium (DSS) in WT and KO mice. Compared with WT mice, KO mice demonstrated greater body weight loss, more severe bloody diarrhea, broader inflammatory cell infiltration, and more serious epithelial injury. Higher levels of PAF and lower levels of interleukin (IL)10 were identified in KO mice 2 days after DSS treatment. A greater and progressive increase of lysophosphatidic acid (LPA) was identified. The change was associated with increased autotaxin expression in both small intestine and colon, which was identified by immunohistochemistry study, Western blot, and sandwich ELISA. The upregulation of autotaxin coincided with an early increase of PAF. IL6 and TNFα were increased in both WT and KO mice. At the later stage (day 8), significant decreases in IL6, IL10, and PAF were identified, and the decreases were greater in KO mice. In conclusion, deficiency of Alk-SMase enhances DSS-induced colitis by mechanisms related to increased autotaxin expression and LPA formation. The early increase of PAF might be a trigger for such reactions.
肠碱性鞘磷脂酶 (Alk-SMase) 可从 SM、血小板激活因子 (PAF) 和溶血磷脂酰胆碱中切割磷酸胆碱。我们最近发现，Alk-SMase KO 小鼠结肠炎相关结肠癌的发生率增加了 4-5 倍。在此，我们进一步研究了 WT 和 KO 小鼠中葡聚糖硫酸钠 (DSS) 诱导的结肠炎的发病机制。与 WT 小鼠相比，KO 小鼠的体重下降更明显，血性腹泻更严重，炎症细胞浸润更广泛，上皮损伤更严重。在 DSS 处理后 2 天，KO 小鼠中 PAF 水平升高，而白细胞介素 (IL)10 水平降低。发现溶血磷脂酸 (LPA) 水平升高且呈进行性增加。这种变化与免疫组织化学研究、Western blot 和夹心 ELISA 鉴定的小肠和结肠中转氨酶表达增加有关。自动蛋白水解酶的上调与 PAF 的早期增加相吻合。WT 和 KO 小鼠中的 IL6 和 TNFα 均增加。在后期（第 8 天），发现 IL6、IL10 和 PAF 显著降低，KO 小鼠的降低更为明显。总之，Alk-SMase 缺乏通过与增加的自动蛋白水解酶表达和 LPA 形成相关的机制增强 DSS 诱导的结肠炎。PAF 的早期增加可能是这种反应的触发因素。
