Valsartan Impact On The Expression Of MMP-2 And MMP-9 In Acute Hyperoxia-induced Lung Injury In Neonatal Rats

Objective: To establish the model of hyperoxia lung injury in neonatal SD rats; we explored the expression and activity of MMP-2, MMP-9 in acut and subacute hyperoxia lung injury. And to investigate whether valsartan, a selective inhibitor of AT1 receptors for angiotansinⅡ(AT-Ⅱ),can reduce the expression of MMP-2,MMP-9 in acute lung injury induced by hyperoxia .Methods: seventy-two SD rats aged from three days to five days were randomly devided into three groups:Ⅰair(air group): the rats were exposed to air in the same room;Ⅱhyperoxia+valsartan ( treated group): the rats were exposed continuously to 85%～95% oxygen, douched valsartan (30mg/kg) on day 2;Ⅲhyperoxia+saline ( hperoxia group ):the rats were exposed continuously to 85%～95% oxygen, while were given equivalent volume of normal saline. Half animals of every group were lavaged at 3,7 days after douched, the others were killed and the lung was removed. The left lung was used for histologic examination. The expression and activity of MMP-2 and MMP-9 in bronchoalveolar lavage fluids (BALF) and lung tissues were studied by gelatin zymography and immunohistochemistry; the right lung(100mg) was made into homogenate ,then measured the level of malondialdehyde(MDA) and total protein content (TP);the remaining was weighed ,then heated in 60℃. The W/D lung weight ratio was calculated.Results:1. Pathologic changes in lung: at 3rd day, we could find obvious bleeding and inflammatory cells in alveolar space in hyperoxia group; and at 7th day, the damage was more serious: the lung compartment was enlarged, and the framework was disordered. In valsartan-treated group, there were less inflammatory changes and no significant enlargement of lung compartment. 2. Lung wet weight/dry weight rate: At 3rd day, the ratio was higher in hyperoxia group than air groups; and at 7th day, it was more higher in hyperoxia group (p<0.01), while in valsartan-treated group, it was lower than in hyperoxia groups.3. TP: At 3rd day, the TP content was higher in hyperoxia group than other groups; and at 7th day, it was more higher in hyperoxia group (p<0.05), while in valsartan-treated group, it was little lower than in hyperoxia group at 3rd day (p>0.05), and at 7th day it was significantly lower (p<0.01).4. MDA: At 3rd day, the MDA content was higher in hyperoxia group than air groups; and at 7th day, it was more higher in hyperoxia group (p<0.01), while in valsartan-treated group, it was lower than in hyperoxia groups.5. Expression of MMP-2 and MMP-9 protein in mice lung tissue: The expression of MMP-2 in airw ay epithelial cells vascular smooth muscle cells and macrophages was the higher at 3rd day of hyperoxia (P<0.O1),later itsexpression get to the peak at 7th day. The level of MMP-9 protein was not increased significantly until at 7th day (p<0.01). In valsartan-treated groups, MMP-2 and MMP-9 were not inhibited until 7th day (p<0.01).6. Results for Gelatinase Zymogram:The zymogram of BALF in air groups displayed vague gelatinolytic bands. The level of MMP-2 protein increased significantly at 3rd and 7th day of hyperoxia,at the same time. MMP-9 protein(92 kD)didn't become clear until 7th day of hyperoxia. In valsartan-treated groups the level of two gelatinases were inhibited significantly at 7th day (p<0.01).Conclusions: MMP-2 and MMP-2 play an important role in the development of hyperoxia-induced acute lung injury in rats. In hyperoxia-induced lung injury, valsartan can relieve inflammatory reaction and lung edema, and slow the development of lung injury by inhibiting the expression of MMP-2 and MMP-9.