| Objectives: Mechanical ventilation with high oxygen concentration is an important treatment to neonate respiratory distress syndrome (NRDS). However, prolonged high concentration oxygen therapy can result in lung oxygen toxicity damage, pulmonary interstitial fibrosis as well as lung developmental disorders. It is also one of the main etiological factors of bronchopulmonary dysplasia. Present researches show that extracellular matrix (ECM) metabolism disturbance participates in pathophysiological process of acute and chronic lung injury. Matrix metalloproteinase (MMPs), most important protein hydrolytic enzyme degradating ECM component, and its tissue inhibitor (TIMPS) may play an important role in this process. In present study, we investigated the dynamic change regularity, the significance of the expressions of MMPs and TIMPs in hyperoxia-induced lung injury through establishing the animal model of acute and chronic hyperoxia-induced lung injury.Methods: Thirty-two juvenile Wistar rats were randomly divided into breathing room-air group (n=8) and hyperoxia exposure group (n=8 at 3, 7 and 14days respectively). The rats in hyperoxia group were kept in lucide chambers with an O2 concentration ≥95%, CO2 concentration ≤5%, temperature at 21℃-25℃ and humidity at 60%-70%. The room air group was kept under similar conditions in the same room (O2 concentration = 21%). After 3, 7, 14 days of continuous exposure to high concentration oxygen, the distribution of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the lung tissues were detected by immunohistochemistry and their expressions were measured by reverse transcription-polymerase chain reaction (RT-PCR). In addition, the ratio of lung wet weight to lung dry weight (W/D weight ratio), the protein content of bronchoalveolar lavage fluid (BALF), lung permeability coefficient, histological changes of oxygen induced lung injury were measured respectively. Results: Light microscopic findings in the hyperoxia group including edema, hemorrhage and extensive inflammatory cells in the lungs were observed. In contrast, there were no such changes in the room-air group. The lung W/D weight ratio in hyperoxia group(5.19±0.19 at 3d, 5.60±0.25 at 7d and 5.46±0.30 at 14d) was significantly higher than that in room air groups(4.92±0.38), with statistical differences at 7d and 14d(P<0.05). The permeability coefficient at 3d(6.61±2.05), 7d(10.88±1.54) and 14d(12.75±2.20) was much higher than that of the room-air group(2.99±1.27, P<0.05). The protein content in BALF at 3d(0.45±0.10), 7d(0.66±0.08)and 14d(0.79±0.14)was much higher than that of the room-air group (0.18±0.08,P<0.05). Weak positive expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 were detected in alveolar and tracheal epithelial cells in the room-air group, while strong positive expressions were observed in alveolar epithelial cells, macrophages, neutrophils, interstitial cells and tracheal epithelial cells in hyperoxia group, especially at 7d and 14d. The expressions of MMP-2 mRNA in the lungs were significantly increased in 3 days of hyperoxia-exposure, maximized at 7d and declined from 14d (0.553±0.072, 0.789±0.085, 0.719±0.067, respectively, vs 0.242±0.064 in room air group, P <0.05). The expression of MMP-9 mRNA was similar too(0.523±0.098, 0.698±0.104, 0.686±0.084 vs 0.283±0.063,respectively, P <0.05), while the expressions of TIMP-1 and TIMP-2 mRNA continuously enhanced and didn't decline even at 14d (TIMP-1 : 0.487±0.089, 0.621±0.135, 0.661±0.124 vs 0.312±0.081,P<0.05; TIMP-2: 0.376±0.070, 0.446±0.069, 0.483±0.088 vs 0.261±0.050, P<0.05). The ratio of MMP-2/TIMP-2 and MMP-9/TIMP-1 were significantly enhanced after 3 days of hyperoxia-exposure and maximized on the 7th day, but declined on the 14th (MMP-2/TIMP-2: 1.502±0.193, 1.781±0.152, 1.529±0.217 vs 0.933±0.105,respectively, P <0.05; MMP-9/TIMP-1: 1.115±0.317, 1.220±0.207, 1.072±0.237 vs 0.870±0.182, respectively ).Conclusions: High concentration oxygen exposure can result... |
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