Effect And Mechanism Of Gastric Mucosa In Rats Induced By Clopidogrel Combine Aspirin

Objective:To investigate the effect of the gastral mocusa and expression of TNF-α,VEGF in rats which was induced by clopidogrel or clopidogrel combine aspirin. And further to realize the specific pathophysiology process of the injury.Materials and Methods:192 SPF grade male adult Spraguc-Dawley rats weighing from 190 to 210g were randomly allocated into four groups:there experiment groups to give clopidogrel (7.81 mg/kg.d, n=48), aspirin (10.41 mg/kg.d, n=48) and clopidogrel combined aspirin(n=48) respectively. Each experiment group had the intragastric administration once daily, blank group will give normal saline(n=48), meanwhile.4 groups of rats in administration were killed before and after administration 3d,7d,14d,21d and 28d, then took the stomach to observe and determine ulcer index with sliding caliper, scored in full refer to Guth. Then had ordinary pathology test (HE dyeing) and examined the expression of TNF-a and VEGF on gastric mucosal cell by immunohistochemistry. All the time points were eight.Result1. General observation of the stomach mucosa:Gastric mucosal injury occurred in the experiment group at the third day after administration of clopidogrel and the seventh day reached the peak. The score of ulcer index was higher than which of control group (P<0.05). Gastric mucosal injury occurred in the experiment group at the third day after administration of low dose aspirin and the fourteenth day reached the peak. The score of ulcer index was higher than which of control group (P<0.01). Gastric mucosal injury occurred in the experiment group at the third day after administration of clopidogrel combined aspirin and the fourteenth day reached the peak. The score of ulcer index was higher than which of control group (P<0.01). The scores of ulcer index after administration of aspirin were higher than which of clopidogrel group (P<0.01). The scores of ulcer index with clopidogrel and aspirin were higher than the group of clopidogrel or aspirin alone (P<0.01).2. Change of histological anatomy under light microscope:The membrane structure of the control group was complete. We could sometimes see epithelium defected and a small quantity of inflammatory cell infiltrate.All the stomach mucosa of the experiment groups were damaged differently. They showed mucosa anabrosis, necrosis, diastem augmentation, lamina propria cutaneous dropsy obviously with inflammatory cell infiltration, cellula epithelialis apomorphosis, cellular necrosis, and even cellular necrosis, defluvium, defect leading to exposure of the lamina propria. Most of mucosal injury of clopidogrel group was gradeⅠandⅡ, seldom was gradeⅢ. Most part of mucosal injury of aspirin group was gradeⅠandⅡ, the others was gradeⅢ. Most part of mucosal injury of clopidogrel and aspirin group was gradeⅢandⅣ, the others was gradeⅠandⅡ. The difference had statistical significance when compared with control group (P<0.05).3. TNF-αand VEGF expression:The difference of expression of TNF-αbetween each experiment group and control group had statistical significance (P<0.05). TNF-αbegan to express at the third day, and reached peak level the seventh day and declined at the fourteenth day in the clopidogrel group. TNF-αshowed positive correlation with injury index (rs=0.691, P<0.01).TNF-αbegan to express at the third day, and reached peak level the fourteenth day and declined at the twenty-first day in the aspirin group. TNF-αshowed positive correlation with injury index (rs=0.704, P<0.01). TNF-αbegan to express at the third day, and reached peak level the fourteenth day and declined at the twenty-first day in the clopidogrel combined aspirin group. TNF-αshowed positive correlation with injury index (rs=0.732, P<0.01)The difference of expression of VEGF between each experiment group and control group had statistical significance (P<0.05). There was a certainty expression in contral group. At the third day after administration the expression of VEGF reached rock bottom and it begain to come-back from the seventh day slowly in the clopidogrel group. But at twenty-eighth day, it was still lower than contral group. In the aspirin group, at the third day after administration the expression of VEGF reached peak level(P<0.05)) and it began to decline at the seventh day and fourteenth day (P>0.05). VEGF intensified the expression at the twenty-first day and twenty-eighth day again. In the clopidogrel and aspirin group, the expression of VEGF reached rock bottom at the third day and it began to come-back from the seventh day.Conclusions:General dose clopidogrel may induce gastric mucosal injury in rats. After administration the expression of VEGF is declined and TNF-αincreased. VEGF and TNF-αmay play significant role in the pathogenesis of gastric mucosal injury induced by clopidogrel. General low-dose aspirin may induce gastric mucosal injury. And the injury is serious than which induced by clopidogrel. The expression of TNF-αis increased. The expression of VEGF is increased firstly, and then decreased, and increased finaly. The change of the expression of VEGF induced by aspirin in rats gastric mucosa injury considered is the self-protection of endothelial growth factor. The gastric mucosal injury induced by clopidogrel and aspirin was serious than the group of clopidogrel or aspirin alone. The gastric mucosal injury in rats is relatcd to decreasing VEGF expression and increasing TNF-αexpression. One of the mechanisms of gastric mucosal injury induced by clopidogrel might relate to the reduction of gastric mucosal blood flow and weakended gastric mucosal protection factors by regulating the expression of VEGF in the gastric mucosa, and then result in gastric mucosal damage and its repair delayed. It need more work to explore its mechanism.