Steeb C B, Trahair J F, Read L C
Cooperative Research Center for Tissue Growth and Repair, North Adelaide, South Australia.
Gut. 1995 Nov;37(5):630-8. doi: 10.1136/gut.37.5.630.
It has previously been shown that longterm administration of insulin-like growth factor-I (IGF-I) or the analogue Long R3 IGF-I (LR3IGF-I) selectively stimulate growth of the gastrointestinal tract in gut resected, dexamethasone treated, and normal rats. In this study, the short-term effects of IGF-I administration on intestinal proliferation have been investigated. Female rats (110 g, five-six/group) were infused for three days with 2.5 mg/kg/day of either IGF-I or LR3IGF-I and compared with vehicle treated or untreated control rats. LR3IGF-I but not IGF-I increased body weight and wet tissue weight of the small and large intestine (+20%), compared with controls. Tissue weight responses were independent of food intake and were reflected in the histology of the tissue. In LR3IGF-I treated animals, duodenal and ileal crypts length were increased by 13 and 22%, respectively, associated with an increase in crypt cell number. No such histological changes were seen in IGF-I treated rats. Tritiated thymidine labelling indices were significantly increased after administration of either IGF-I or LR3IGF-I (up to 14%) in both the duodenum and ileum. In IGF-I treated rats, increased nuclear labelling was not associated with an increase in the crypt compartment. In contrast, LR3IGF-I induced proportional increments in thymidine labelling and crypt size, suggesting that LR3IGF-I is not only more potent than the native peptide but also induced proliferative events more rapidly. In the colon, the thymidine labelling index was low, however, a non-significant increase in the number of cells labelled with thymidine was seen. These results suggest that within a three day treatment period intestinal mitogenesis is more advanced in animals treated with LR3IGF-I. The differences in proliferative response between the two peptides may be accounted for by variations in pharmacokinetics, clearance rates, and interactions with circulating and tissue specific binding proteins.
先前的研究表明，长期给予胰岛素样生长因子-I（IGF-I）或类似物长效R3 IGF-I（LR3IGF-I）可选择性刺激肠道切除、地塞米松处理的大鼠以及正常大鼠的胃肠道生长。在本研究中，对给予IGF-I的短期肠道增殖效应进行了研究。雌性大鼠（110 g，每组5 - 6只）连续三天以2.5 mg/kg/天的剂量输注IGF-I或LR3IGF-I，并与给予赋形剂处理的或未处理的对照大鼠进行比较。与对照组相比，LR3IGF-I而非IGF-I使小肠和大肠的体重及湿组织重量增加（+20%）。组织重量反应与食物摄入量无关，并在组织学上有所体现。在接受LR3IGF-I处理的动物中，十二指肠和回肠隐窝长度分别增加了13%和22%，同时隐窝细胞数量增加。在接受IGF-I处理的大鼠中未观察到此类组织学变化。给予IGF-I或LR3IGF-I后，十二指肠和回肠中的氚标记胸腺嘧啶核苷标记指数均显著增加（高达14%）。在接受IGF-I处理的大鼠中，核标记增加与隐窝区室增加无关。相比之下，LR3IGF-I诱导胸腺嘧啶核苷标记和隐窝大小成比例增加，这表明LR3IGF-I不仅比天然肽更有效，而且能更快地诱导增殖事件。在结肠中，胸腺嘧啶核苷标记指数较低，然而，观察到胸腺嘧啶核苷标记细胞数量有不显著的增加。这些结果表明，在三天的治疗期内，接受LR3IGF-I处理的动物肠道有丝分裂更为显著。两种肽之间增殖反应的差异可能是由药代动力学、清除率以及与循环和组织特异性结合蛋白的相互作用的差异所导致的。
