Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis
Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis
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DOI：
10.1053/j.gastro.2007.10.001
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发表时间：
2008-01-01
期刊：
影响因子：
29.4
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
--
作者：
Ohno, Takashi;Hattori, Youichiro;Majima, Masataka
背景与目的：众所周知，胃肠道内有丰富的神经系统，其中传入神经元被报道具有保护作用。我们用CGRP基因敲除小鼠（CGRP(-/-)）检测内源性神经肽降钙素基因相关肽（CGRP）是否能预防乙醇引起的胃粘膜损伤，并促进醋酸性溃疡的愈合。方法：以1.6 mmol/L辣椒素或1 mol/L NaCl灌胃，观察50%乙醇对胃黏膜的损伤。采用酶免疫法测定灌注液中CGRP的水平。无水乙酸浆膜应用诱发胃溃疡。结果：辣椒素对损伤区有剂量依赖性的抑制作用。50%含有辣椒素的乙醇立即增加了野生型（WT）小鼠胃内CGRP的水平，尽管单独的50%乙醇没有这种作用。辣椒素对乙醇的保护作用在CGRP（-/-）中被完全消除。1 mol/L NaCl预灌注增加CGRP释放，减少乙醇灌注时粘膜损伤。而1 mol/L NaCl对CGRP（-/-）无明显抑制作用。与WT相比，乙酸诱导CGRP（-/-）小鼠溃疡的愈合明显延迟。在WT中，溃疡底部形成肉芽组织，并诱导大量新生血管形成，而CGRP（-/-）小鼠则较差。CGRP（-/-）组血管内皮生长因子的表达较WT组明显降低。结论：CGRP对胃粘膜损伤具有预防作用，并具有促进溃疡愈合的促血管生成活性。这些结果表明，cgrp依赖通路是调节胃粘膜保护和维持胃粘膜完整性的良好靶点。
Background & Aims: The gastrointestinal tract is known to be rich in neural systems, among which afferent neurons are reported to exhibit protective actions. We tested whether an endogenous neuropeptide, calcitonin gene-related peptide (CGRP), can prevent gastric mucosal injury elicited by ethanol and enhance healing of acetic acid-induced ulcer using CGRP knockout mice (CGRP(-/-)). Methods: The stomach was perfused with 1.6 mmol/L capsaicin or 1 mol/L NaCl, and gastric mucosal injury elicited by 50% ethanol was estimated. Levels of CGRP in the perfusate were determined by enzyme immunoassay. Gastric ulcers were induced by serosal application of absolute acetic acid. Results: Capsaicin inhibited injured area dose-dependently. Fifty percent ethanol containing capsaicin immediately increased intragastric levels of CGRP in wild-type (WT) mice, although 50% ethanol alone did not. The protective action of capsaicin against ethanol was completely abolished in CGRP(-/-). Preperfusion with 1 mol/L NaCl increased CGRP release and reduced mucosal damage during ethanol perfusion. However, 1 mol/L NaCl was not effective in CGRP(-/-). Healing of ulcer elicited by acetic acid in CGRP(-/-) mice was markedly delayed, compared with that in WT. In WT, granulation tissues were formed at the base of ulcers, and substantial neovascularization was induced, whereas those were poor in CGRP(-/-). Expression of vascular endothelial growth factor was more markedly reduced in CGRP(-/-) than in WT. Conclusions: CGRP has a preventive action on gastric mucosal injury and a proangiogenic activity to enhance ulcer healing. These results indicate that the CGRP-dependent pathway is a good target for regulating gastric mucosal protection and maintaining gastric mucosal integrity.