Matrix Metalloproteinase-9 Deficiency Worsens Lung Injury in a Model of Bronchopulmonary Dysplasia
Matrix Metalloproteinase-9 Deficiency Worsens Lung Injury in a Model of Bronchopulmonary Dysplasia
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DOI：
10.1165/rcmb.2008-0179oc
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发表时间：
2009-07-01
影响因子：
6.4
通讯作者：
Bry, Kristina
中科院分区：
文献类型：
--
作者：
Lukkarinen, Heikki;Hogmalm, Anna;Bry, Kristina
基质金属蛋白酶（MMP）-9活性升高与新生儿支气管肺发育不良（BPD）的发生有关，但MMP-9在BPD病理生理学中的作用尚不清楚。我们已经表明，围产期表达的白细胞介素-1 β（IL-1 β）在肺中足以导致BPD样疾病的婴儿小鼠。为了研究MMP-9是IL-1 β诱导的新生儿肺损伤的重要下游介质这一假设，我们比较了IL-1 β对胎儿和出生后肺部炎症和发育的影响，这些转基因小鼠具有野生型（IL-1 β/MMP-9（+/+））或无效（IL-1 β/MMP-9（-/-））MMP-9基因座的人成熟IL-1 β可调节的肺部过表达。IL-1 β可增加MMP-9（+/+）小鼠肺组织MMP-9 mRNA的表达和MMP-9蛋白的表达。IL-1 β/MMP-9（-/-）小鼠的肺中中性粒细胞比IL-1 β/MMP-9（-/-）小鼠少，但巨噬细胞比IL-1 β/MMP-9（-/-）小鼠多。MMP-9缺乏增加IL-1 β表达小鼠肺细胞死亡和死亡细胞的巨噬细胞清除。IL-1 β/MMP-9（-/-）小鼠比IL-1 β/MMP-9（+/+）小鼠具有更严重的肺泡发育不全，这意味着在没有MMP-9的情况下IL-1 β诱导的肺病恶化。这些结果表明，在发炎的新生儿肺中的MMP-9活性保护肺免受损伤。
Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 beta (IL-1 beta) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1 beta-induced lung injury in the newborn, we compared the effects of IL-1 beta on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 beta with wild-type (IL-1 beta/MMP-9(+/+)) or null (IL-1 beta/MMP-9(-/-)) MMP-9 loci. IL-1 beta increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9(+/+) mice. IL-1 beta/MMP-9(-/-) mice had fewer neutrophils but more macrophages in the lungs than did IL-1 beta/MMP-9(-/-) mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1 beta-expressing mice. IL-1 beta/MMP-9(-/-) mice had more severe alveolar hypoplasia than IL-1 beta/MMP-9(+/+) mice, implying that IL-1 beta-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.