Nishise Shoichi, Takeda Yuji, Fujishima Shoichiro, Orii Tomohiko, Sato Takeshi, Sasaki Yu, Nishise Yuko, Takeda Hiroaki, Kawata Sumio
Department of Gastroenterology, Yamagata University School of Medicine, Yamagata, Japan.
Ther Apher Dial. 2010 Aug 1;14(4):386-91. doi: 10.1111/j.1744-9987.2010.00820.x.
Both granulocyte/monocyte adsorptive apheresis (GMA) and ulinastatin, a serine protease inhibitor, are reported to be effective in patients with ulcerative colitis; however, combination therapy with GMA and ulinastatin has not been attempted. Investigating the effect of ulinastatin on GMA is required for combination therapy since the inhibition of serine protease suppresses the reaction of GMA. To clarify the effects of ulinastatin on GMA, we investigated whether granulocyte adsorption to cellulose acetate beads (carriers for GMA) and interleukin-1 receptor antagonist (IL-1ra) release were inhibited by ulinastatin. Peripheral blood containing ulinastatin, a different serine protease inhibitor (gabexate mesilate), or signal-transduction inhibitors was incubated with cellulose acetate beads in vitro, and the ratios of adsorbed granulocytes and IL-1ra release were measured. Granulocyte adsorption and IL-1ra release were significantly suppressed with increasing gabexate mesilate concentrations; however, the adsorption was not significantly inhibited by ulinastatin. Furthermore, IL-1ra release was augmented by the addition of a high dose of ulinastatin or PD98059 as compared to a low dose. The activation levels of extracellular signal-regulated protein kinase may regulate IL-1ra release induced by the carrier, because both ulinastatin and PD98059 inhibit extracellular signal-regulated protein kinase. High concentrations of ulinastatin increased IL-1ra release without inhibiting granulocyte adsorption to cellulose acetate beads. This result warrants clinical trials of a combination of ulinastatin and GMA for the treatment of ulcerative colitis.
据报道，粒细胞/单核细胞吸附性单采术（GMA）和丝氨酸蛋白酶抑制剂乌司他丁对溃疡性结肠炎患者均有效；然而，尚未尝试过GMA与乌司他丁的联合治疗。由于丝氨酸蛋白酶的抑制会抑制GMA的反应，因此联合治疗需要研究乌司他丁对GMA的影响。为了阐明乌司他丁对GMA的影响，我们研究了乌司他丁是否会抑制粒细胞对醋酸纤维素珠（GMA的载体）的吸附以及白细胞介素-1受体拮抗剂（IL-1ra）的释放。将含有乌司他丁、另一种丝氨酸蛋白酶抑制剂（甲磺酸加贝酯）或信号转导抑制剂的外周血在体外与醋酸纤维素珠一起孵育，并测量吸附的粒细胞比例和IL-1ra的释放量。随着甲磺酸加贝酯浓度的增加，粒细胞吸附和IL-1ra释放均受到显著抑制；然而，乌司他丁并未显著抑制吸附。此外，与低剂量相比，添加高剂量的乌司他丁或PD98059可增加IL-1ra的释放。细胞外信号调节蛋白激酶的激活水平可能调节载体诱导的IL-1ra释放，因为乌司他丁和PD98059均抑制细胞外信号调节蛋白激酶。高浓度的乌司他丁可增加IL-1ra的释放，而不会抑制粒细胞对醋酸纤维素珠的吸附。这一结果为乌司他丁与GMA联合治疗溃疡性结肠炎的临床试验提供了依据。
