Effects Of Postnatal Dexamethasone On Lung Morphogenesis And Matrix Metalloproteimase -2 And -9, And Their Tissue Inhibitors In The Deceloping Rat Lung

Objective:Postnatal glucocorticoids such as dexamethasone (DEX) can improvepulmonary function in premature newborn infants, but its long-term effects on lungdevelopment and its molecular mechanism is still unclear.MMPs and TIMPs havebeen shown to play important roles in the development of lung by maintaining thebalance between the synthesis and degradation of ECM components. To investigatethe effects of DEX on lung morphogenesis and the expression of MMP-2,MMP-9and their tissue inhibitors, newborn rat models were used to compare the effects ofvarious dosages of DEX therapy on postnatal development of rat lung.Methods:120 newborn rats were divided into three groups randomly: For the smalldosage and large dosage DEX groups, i.p with 0.2mg/(kg·d), 0.5mg/(kg·d)respectively on the 5th,6th,7th,8th and 9th day after birth. For the control group, i.pwith 0.5ml saline on the5th,6th,7th,8th and 9th day after birth. 10 rats from eachgroup were randomly chosen and sacrificed on the 10th(1 day post-Dexadministration), 14th, 21st(weaning), 45th(adolescence) day after birth. Thehistological structures of rat lungs were observed with light microscope. TheRT-PCR,Western-Blot methods were used to detect the mRNA and protein level ofMMP-2,MMP-9,TIMP-1 and TIMP-2 genes. Results:1. Under the light microscope, during the first 2 weeks, rat lung in the twoDEX groups had fewer alveolar numbers, larger alveolar space, and thinneralveolar septum compared with control group (P<0.01).On the 21st and 45th days,the airspaces of rat lungs in the two treatment groups were still enlarged, lessnumerous(P<0.01), an "emphysematous" condition of the lungs could be observedespecially in the large dosage DEX group.2. RT-PCR results: The mRNA level of MMP-9 gene was significantly enhancedin study groups compared with control on the 21st and 45th days(all P<0.05). ThemRNA level of TIMP-1 gene was significantly enhanced in study groups comparedwith control on the 21st day(all P<0.05). MMP-9/TIMP-1 ratio was significantlyenhanced on the 21st and 45th days(all P<0.05). There was no statistic difference inthe expression of MMP-2 between the DEX groups and control group at all timeintervals. The expressions of TIMP-2 was downregulated in study groups comparedwith control at all time intervals(all P<0.05). MMP-2/TIMP-2 ratio wassignificantly enhanced on the 14th and 21st days(all P<0.05).3. Western-blot results:The expressions of MMP-9 protein was significantlyenhanced in study groups compared with control on the 21st days(all P<0.05). Theexpressions of TIMP-1 protein was significantly enhanced in study groups comparedwith control on the 21st day(all P<0.05).Conclusions:1. Using DEX postnatal could promote lung development obviously, even thesmall dosage of DEX may induce the lung mature. Increasing the doses of DEX notonly improves the level of the lung development, but also has negative effect on ratlung morphogenesis. With the dose increased, the normal alveolization was inhibited,resulted in reduction of alveolar numbers, alteration of alveolar space and septum,and the impact continued well into adulthood. 2. Postnatal DEX therapy changed the expressions of the mRNA and the proteinof MMP-9,TIMP-1 and TIMP-2 genes in the developing rat lung.3. The changes of the expressions of MMP-9,TIMP-1 and TIMP-2 genes mayinvolved in the effects of DEX therapy on rat lung morphogenesis, and the imbalanceof MMP-9/TIMP-1, which may be related to the occurrence of asthma, continued toadult.