Kjaer Marie, Russell Wayne, Schjerling Peter, Cottarelli Elena, Christjansen Kennet N, Olsen Ditte M G, Krarup Peter-Martin, Jessen Lene, Berner-Hansen Mark, Jorgensen Lars N, Ågren Magnus S
Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark.
Zealand Pharma A/S, 2600 Glostrup, Denmark.
Gastroenterol Res Pract. 2020 Oct 9;2020:8460508. doi: 10.1155/2020/8460508. eCollection 2020.
The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing.
Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) 1, and soluble collagen proteins were measured on days 3 and 5.
ZP1849 treatment increased Ki67 ( < 0.0001) and IGF-1 ( < 0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased ( = 0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels ( < 0.0001) and soluble collagen proteins ( < 0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 ( < 0.001) in both groups. ZP1849 treatment reduced TGF-1 protein levels on day 5 ( < 0.001) but did not impact MMP-7 transcription.
The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.
肠内分泌激素胰高血糖素样肽-2（GLP-2）是胃肠道中一种强大的营养因子。GLP-2受体（GLP-2R）在大肠壁基质中表达，而大肠壁基质是预防吻合口漏的主要治疗靶点区域。我们研究了长效GLP-2类似物ZP1849对结肠吻合口伤口愈合的疗效。
87只雄性Wistar大鼠被分为四组，从在第0天左半结肠进行端端吻合前一天（第-1天）开始，每天接受载体或ZP1849治疗，在第0天（切除的结肠段）、第3天和第5天，通过逆转录定量聚合酶链反应（RT-qPCR）对GLP-2R、Ki67、胰岛素样生长因子-1（IGF-1）、I型（COL1A1）和III型（COL3A1）前胶原、环氧合酶-1（COX-1）、COX-2和基质金属蛋白酶-7（MMP-7）的基因表达进行定量分析。在第3天和第5天测量抗张强度、髓过氧化物酶（MPO）、转化生长因子-1（TGF-1）和可溶性胶原蛋白水平。
与载体处理的大鼠相比，ZP1849处理在第0天非损伤结肠以及术后吻合口伤口中增加了Ki67（P<0.0001）和IGF-1（P<0.05）的mRNA水平。与载体相比，ZP1849处理的大鼠在第5天吻合口抗张强度增加（P=0.042）。在ZP1849处理的大鼠中，COL1A1和COL3A1的mRNA水平（P<0.0001）和可溶性胶原蛋白水平（P<0.05）从第3天到第5天增加，而在载体处理的大鼠中未增加。两组中COX-2 mRNA和MPO蛋白水平从第3天到第5天均下降（P<0.001）。ZP1849处理在第5天降低了TGF-1蛋白水平（P<0.001），但不影响MMP-7转录。
GLP-2类似物ZP1849增加了抗张强度、IGF-1表达和细胞增殖，这可能有利于结肠吻合口伤口愈合。
