Gyömber E, Vattay P, Szabo S, Rainsford K D
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Int J Exp Pathol. 1996 Feb;77(1):1-6. doi: 10.1046/j.1365-2613.1996.955094.x.
Early vascular injury is a key element in the pathogenesis of gastric haemorrhagic mucosal lesions which develop rapidly after intragastric (i.g.) administration of ethanol, HCl or NaOH. The sequence of vascular events leading to gastric lesions has not, however, been investigated in detail with ulcerogenic non-steroidal anti-inflammatory drugs such as indomethacin (IND). Accordingly, experiments were performed in rats using the vascular tracer Monastral blue to assess whether vascular lesions precede and are subsequently associated with mucosal lesions induced by oral (p.o.) or subcutaneous (s.c.) administration of IND. Fasted female Sprague-Dawley rats (150-180 g) were given IND either at 100 mg/kg, p.o. or 200 mg/kg s.c. and killed 15, 30, 120 or 240 minutes later. Monastral blue, 3% saline 1 ml/kg, was injected intravenously under ether anaesthesia 3 minutes before autopsy and the formalin fixed, glycerol cleared stomachs were examined microscopically for deposition of the dye particles on damaged blood vessels. The percentage area of Monastral blue labelled vessels (measured by stereomicroscopic planimetry) at 15 minutes after oral IND was 10.1 +/- 1.5% (mean +/- s.e.m.) of glandular stomach and increased progressively to 64.5 +/- 3.0% at 240 minutes. Gastric haemorrhagic lesions (also measured by stereomicroscopic planimetry) were first evident at 30 minutes (0.2 +/- 0.03%; mean +/- s.e.m.), and developed progressively to 2.0 +/- 0.3% total area of glandular mucosa at 240 minutes. Subcutaneous injection of IND resulted in a delayed time of onset for the appearance and the extent of mucosal lesions (first appearing at 120 minutes, 0.1 +/- 0.03% area) compared with that from oral administration of the drug, but as with oral IND the vascular damage (first appearance at 15 minutes, 7.5 +/- 3.6%) clearly preceded the occurrence of gastric lesions. The observations of microvascular dye labelling were paralleled by observations of the electron-microscopic appearance of endothelial cell disruption in the region adjacent to superficial mucous cells and accumulation of red blood cells in the interstitium at 20-60 minutes. We conclude that vascular injury precedes haemorrhagic mucosal damage in the pathogenesis of IND-induced acute gastric mucosal lesions.
早期血管损伤是胃出血性黏膜病变发病机制中的关键因素，此类病变在胃内给予乙醇、盐酸或氢氧化钠后迅速发展。然而，对于诸如吲哚美辛（IND）等致溃疡非甾体抗炎药导致胃病变的血管事件序列尚未进行详细研究。因此，在大鼠中进行了实验，使用血管示踪剂酸性媒介蓝来评估血管损伤是否先于口服（p.o.）或皮下（s.c.）给予IND诱导的黏膜损伤，并在随后与之相关。禁食的雌性斯普拉格 - 道利大鼠（150 - 180克）分别以100毫克/千克口服或200毫克/千克皮下给予IND，并在15、30、120或240分钟后处死。在尸检前3分钟，于乙醚麻醉下静脉注射1毫升/千克的3%酸性媒介蓝生理盐水，对用福尔马林固定、甘油透明处理的胃进行显微镜检查，以观察染料颗粒在受损血管上的沉积情况。口服IND后15分钟，酸性媒介蓝标记血管的面积百分比（通过体视显微镜平面测量法测量）为腺胃的10.1±1.5%（平均值±标准误），并在240分钟时逐渐增加至64.5±3.0%。胃出血性病变（同样通过体视显微镜平面测量法测量）在30分钟时首次明显出现（0.2±0.03%；平均值±标准误），并在240分钟时逐渐发展至腺黏膜总面积的2.0±0.3%。与口服给药相比，皮下注射IND导致黏膜损伤出现的时间延迟且程度较轻（首次出现在120分钟，面积为0.1±0.03%），但与口服IND一样，血管损伤（首次出现在15分钟，7.5±3.6%）明显先于胃病变的发生。微血管染料标记的观察结果与电子显微镜观察结果一致，即在20 - 60分钟时，浅表黏液细胞相邻区域的内皮细胞破坏以及间质中红细胞的积聚。我们得出结论，在IND诱导的急性胃黏膜病变发病机制中，血管损伤先于出血性黏膜损伤。
