Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia.
Molecular Imaging and Therapy Research Unit (MITRU), South Australian Health and Medical Research Institute, Adelaide, Australia.
Sci Rep. 2020 Nov 23;10(1):20372. doi: 10.1038/s41598-020-77390-7.
Intestinal fibrosis is a common complication of inflammatory bowel disease but remains difficult to detect. Matrix metalloproteases (MMPs) have key roles in fibrosis and are therefore potential targets for fibrosis detection. We determined whether immunoPET of F(ab') antibody fragments targeting MMPs detects colitis induced colonic fibrosis. Mice were administered 2% dextran sulfate sodium treated water for 1 cycle (inflamed) or 3 cycles (fibrotic), or were untreated (control). Colonic and kidney collagen, innate cytokine, MMPs and fecal MPO concentrations were analyzed by multiplex/ELISA. α-pro-MMP-9 F(ab') fragments were engineered and conjugated to Zr for PET imaging, ex-vivo Cherenkov analysis and bio-distribution. Colonic innate cytokine concentrations and fecal myeloperoxidase were increased in inflamed mice but not fibrotic mice, while collagen concentrations were increased in fibrotic mice. MMPs were increased in inflamed mice, but only pro-MMP-9 remained increased in fibrotic mice. Zr-pro-MMP-9 F(ab') uptake was increased in the intestine but also in the kidney of fibrotic mice, where collagen and pro-MMP-9 concentrations were increased. Zr-pro-MMP-9 F(ab') detects colitis induced intestinal fibrosis and associated kidney fibrosis.
肠道纤维化是炎症性肠病的常见并发症，但仍难以检测。基质金属蛋白酶 (MMPs) 在纤维化中起关键作用，因此是纤维化检测的潜在靶点。我们确定了针对 MMP 的 F(ab') 抗体片段的 immunoPET 是否可以检测结肠炎诱导的结肠纤维化。给小鼠给予 2% 葡聚糖硫酸钠处理水 1 个周期（发炎）或 3 个周期（纤维化），或不处理（对照）。通过多重/ELISA 分析结肠和肾脏胶原、先天细胞因子、MMPs 和粪便 MPO 浓度。设计了 α-pro-MMP-9 F(ab') 片段并与 Zr 缀合用于 PET 成像、体外切伦科夫分析和生物分布。发炎小鼠的结肠先天细胞因子浓度和粪便髓过氧化物酶增加，但纤维化小鼠没有增加，而纤维化小鼠的胶原浓度增加。发炎小鼠的 MMPs 增加，但只有 pro-MMP-9 在纤维化小鼠中持续增加。Zr-pro-MMP-9 F(ab') 在纤维化小鼠的肠道和肾脏中摄取增加，其中胶原和 pro-MMP-9 浓度增加。Zr-pro-MMP-9 F(ab') 可检测结肠炎诱导的肠道纤维化和相关的肾脏纤维化。
