Role of Macrophage and Matrix Metallproteinases in Experimental Enterpathy in Rats

背景与目的。直肠内给药吲哚美辛（indomethacin, Indo）引起大鼠小肠纵向溃疡，类似于克罗恩病。以前，我们报道了肠道菌群中的脂多糖在这种实验性肠病中起核心作用。本研究的目的是阐明巨噬细胞，巨噬细胞在大鼠中的作用。材料。方法与结果：体重190 ~ 220g的雄性wistar大鼠，结肠内给药24mg /kg Indo诱导肠病。腹腔注射含有二氯甲基二膦酸酯（Cl_2MBP）的脂质体导致小肠巨噬细胞的明显耗竭。在这只巨噬细胞缺失的大鼠中，小肠损伤显著下降到22%。抗TNF- α、IL- 1 β和IL- 6抗体以剂量依赖的方式显著改善印度肠病。三种抗体联合使用对肠病的抑制率高达87.5%，与巨噬细胞衰竭大鼠相同。另外给予重组促炎细胞因子可恢复巨噬细胞缺失大鼠的Indo肠病。在给药后3、6、12、24小时、3、7天分别观察小肠损伤情况。破坏的高峰出现在24小时内。然后，我们研究了印度肠病中MMP-2、-3和-9活性的一系列变化。广谱MMPs抑制剂GM6001以剂量依赖的方式改善印度肠病。结论。我们的研究结果表明，巨噬细胞通过产生促炎细胞因子和MMPs在大鼠的印度肠病中发挥重要作用

Backgraund & Aims. Intrarectal administration of indomethacin (Indo) induces longitudinal ulcers of the small intestine in rats which are similar to those in Crohn's desease. Previously, we reported that lipopolysaccharide from intestinal flora played a central role in this experimental enteropathy. The aims of this study are to elucidate the role of macrophage, macrophathy in rats. Materials. Methods & Results. In male wistar rats weighing 190-220g, enteropathy was inducted by intracolonic administration of 24 mg/kg of Indo. Intraperitoneal administration of liposomes containing dichloromethylene bisphosphonate (Cl_2MBP) resulted in marked depletion of macrophages in the small intestine. In this macrophage-depleted rat, small intestinal damage strikingly decreased to 22%. Administration of anti- TNF- α, IL- 1 β, and IL- 6 antibodies significantly ameliorated Indo enteropathy in a dose- dependent fashion. Inhibition of enteropathy by a combination of the three antibodies reached up to 87.5%, which was equal to that in macrophage- depleted rats. Additional administration of recombinant proinflammatory cytokines restored Indo enteropathy in macrophage- depleted rats. The small intestinal damage was serially observed 3, 6, 12, 24 hours, 3, and 7 days after Indo administration. The peak of the damage was at 24 hours. Then, we investigated serial changes in MMP-2, -3, and -9 activities in Indo enteropathy. Administration of the broad- spectrum MMPs inhibitor GM6001 ameliorated Indo enteropathy in a dose- dependent fashion. Conclusions. Our results clarified that macrophages played an important role in Indo enteropathy in rats via production of proinflammatory cytokines and MMPs