Children's Hospital, University of Helsinki, FIN-00029 HUS, Helsinki, Finland.
World J Gastroenterol. 2013 Jun 7;19(21):3272-80. doi: 10.3748/wjg.v19.i21.3272.
To investigate whether matrix metalloproteinases-9 (MMP-9) or trypsinogens could serve as histological markers for an aggressive disease course in pediatric ulcerative colitis (UC).
We identified 24 patients with pediatric onset (≤ 16 years) UC who had undergone surgery during childhood/adolescence a median of 2.1 years (range 0.1-7.4 years) after the diagnosis (between 1990 and 2008) in Children's Hospital, Helsinki, Finland. We also identified 27 conservatively treated UC patients and matched them based on their age at the time of diagnosis and follow-up at a median of 6 years (range 3-11 years) to serve as disease controls. Twenty children for whom inflammatory bowel disease (IBD) had been excluded as a result of endoscopy served as non-IBD controls. Colon biopsies taken by diagnostic endoscopy before the onset of therapy were stained using immunohistochemistry to study the expression of MMP-9, trypsinogen-1 (Tryp-1), Tryp-2, and a trypsin inhibitor (TATI). The profiles of these proteases and inhibitor at diagnosis were compared between the surgery group, the conservatively treated UC patients and the non-IBD controls.
The proportions of Tryp-1 and Tryp-2 positive samples in the colon epithelium and in the inflammatory cells of the colon stroma were comparable between the studied groups at diagnosis. Interestingly, the immunopositivity of Tryp-1 (median 1; range 0-3) was significantly lower in the epithelium of the colon in the pediatric UC patients undergoing surgery when compared to that of the conservatively treated UC patients (median 2; range 0-3; P = 0.03) and non-IBD controls (median 2; range 0-3; P = 0.04). For Tryp-2, there was no such difference. In the inflammatory cells of the colon stroma, the immunopositivities of Tryp-1 and Tryp-2 were comparable between the studied groups at diagnosis. Also, the proportion of samples positive for TATI, as well as the immunopositivity, was comparable between the studied groups in the colon epithelium. In the stromal inflammatory cells of the colon, TATI was not detected. In UC patients, there were significantly more MMP-9 positive samples and a higher immunopositivity in the stromal inflammatory cells of the colon when compared to the samples from the non-IBD patients (P = 0.006 and P = 0.002, respectively); the immunopositivity correlated with the histological grade of inflammation (95%CI: 0.22-0.62; P = 0.0002), but not with the other markers of active disease. There were no differences in the immunopositivity or in the proportions of MMP-9 positive samples when examined by epithelial staining. The staining profiles in the ileal biopsies were comparable between the studied groups for all of the studied markers.
For pediatric UC patients who require surgery, the immunopositivity of Tryp-1 at diagnosis is lower when compared to that of patients with a more benign disease course.
研究基质金属蛋白酶-9（MMP-9）或胰蛋白酶原是否可以作为儿科溃疡性结肠炎（UC）侵袭性病程的组织学标志物。
我们鉴定了 24 例儿科发病（≤16 岁）的 UC 患者，他们在芬兰赫尔辛基儿童医院的诊断后中位数 2.1 年（范围 0.1-7.4 年）接受了手术（1990 年至 2008 年之间）。我们还鉴定了 27 例接受保守治疗的 UC 患者，并根据诊断时的年龄和中位数 6 年（范围 3-11 年）的随访将他们匹配为疾病对照组。由于内镜检查排除了炎症性肠病（IBD）的 20 名儿童作为非 IBD 对照组。在开始治疗前通过诊断性内镜检查采集结肠活检标本，使用免疫组织化学染色研究 MMP-9、胰蛋白酶原-1（Tryp-1）、胰蛋白酶原-2（Tryp-2）和胰蛋白酶抑制剂（TATI）的表达。在诊断时，比较手术组、保守治疗 UC 患者和非 IBD 对照组之间这些蛋白酶和抑制剂的特征。
在诊断时，研究组之间结肠上皮细胞和结肠基质炎症细胞中 Tryp-1 和 Tryp-2 阳性样本的比例相当。有趣的是，与保守治疗的 UC 患者（中位数 2；范围 0-3；P=0.03）和非 IBD 对照组（中位数 2；范围 0-3；P=0.04）相比，接受手术的儿科 UC 患者结肠上皮细胞中的 Tryp-1 免疫阳性率（中位数 1；范围 0-3）明显更低。对于 Tryp-2，没有这种差异。在结肠基质的炎症细胞中，在诊断时，研究组之间 Tryp-1 和 Tryp-2 的免疫阳性率相当。在结肠上皮细胞中，研究组之间 TATI 的阳性样本比例和免疫阳性率也相当。在结肠基质的炎症细胞中未检测到 TATI。与非 IBD 患者相比，UC 患者的结肠基质炎症细胞中 MMP-9 阳性样本更多，免疫阳性率更高（P=0.006 和 P=0.002）；免疫阳性率与炎症组织学分级相关（95%CI：0.22-0.62；P=0.0002），但与其他疾病活动标志物无关。通过上皮染色检查时，免疫阳性率或 MMP-9 阳性样本的比例没有差异。在研究的所有标志物中，研究组之间回肠活检的染色特征相当。
对于需要手术的儿科 UC 患者，与疾病进程更良性的患者相比，诊断时 Tryp-1 的免疫阳性率较低。
