Valencia Arwin M, Cai Charles L, Tan Jeffrey, Duggan Thomas J, Valencia Gloria B, Aranda Jacob V, Beharry Kay D
a Department of Pediatrics, Division of Neonatal-Perinatal Medicine , State University of New York, Downstate Medical Center , Brooklyn , New York , USA.
b Department of Pediatrics, Division of Neonatal-Perinatal Medicine , Sumerlin Hospital Medical Center, Valley Healthcare System , Las Vegas , Nevada , USA.
Exp Lung Res. 2017 Apr;43(3):120-133. doi: 10.1080/01902148.2017.1306897. Epub 2017 Apr 14.
Purpose/Aim: Intravitreal bevacizumab (Avastin) is an irreversible vascular endothelial growth factor (VEGF) inhibitor used off-label to treat severe retinopathy of prematurity in extremely low gestational age neonates. VEGF and matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) participate in lung maturation. We tested the hypothesis that intravitreal bevacizumab enters the systemic circulation and has long-lasting effects on lung MMPs.
Neonatal rats were exposed to: (1) hyperoxia (50% O); (2) intermittent hypoxia (IH) (50% O with brief episodes of 12% O); or (3) room air (RA) from birth (P0) to P14. At P14, the time of eye opening in rats, a single dose of Avastin (0.125 mg) was injected into the vitreous cavity of the left eye. A control group received equivalent volume saline. At P23 and P45, lung MMP-2 and MMP-9, and TIMP-1, and TIMP-2 were assessed in the lungs.
At P23, Avastin increased MMP-2, MMP-9, and TIMP-1 levels in the hyperoxia group but decreased TIMP-1 levels in the IH group. The ratios of MMP-2/TIMP-1 and MMP-9/TIMP-1 were significantly elevated at P23 in the IH group treated with Avastin. At P45, the levels of MMP-2 and MMP-9 remained elevated in the hyperoxia and IH groups treated with Avastin, while a rebound increase in TIMP-1 levels was noted in the IH group.
Avastin treatment in IH has lasting alterations in the balance between MMPs and their tissue inhibitors. These changes may lead to impaired alveologenesis and tissue damage consistent with bronchopulmonary dysplasia/chronic lung disease.
目的/目标：玻璃体内注射贝伐单抗（阿瓦斯汀）是一种不可逆的血管内皮生长因子（VEGF）抑制剂，被用于极低孕周新生儿的早产视网膜病变的非标签治疗。VEGF、基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）参与肺成熟过程。我们检验了玻璃体内注射贝伐单抗进入体循环并对肺MMPs有长期影响的假说。
新生大鼠出生后（P0）至P14暴露于：（1）高氧环境（50%氧气）；（2）间歇性低氧（IH）（50%氧气，伴有短暂12%氧气发作）；或（3）室内空气（RA）。在P14，即大鼠睁眼时，将单剂量阿瓦斯汀（0.125毫克）注入左眼玻璃体内。对照组接受等量生理盐水。在P23和P45，评估肺组织中的MMP-2、MMP-9、TIMP-1和TIMP-2。
在P23时，阿瓦斯汀使高氧组的MMP-2、MMP-9和TIMP-1水平升高，但使IH组的TIMP-1水平降低。在接受阿瓦斯汀治疗的IH组中，P23时MMP-2/TIMP-1和MMP-9/TIMP-1的比值显著升高。在P45时，接受阿瓦斯汀治疗的高氧组和IH组中MMP-2和MMP-9水平仍升高，而IH组中TIMP-1水平出现反弹升高。
IH组接受阿瓦斯汀治疗后，MMPs与其组织抑制剂之间的平衡发生了持久改变。这些变化可能导致肺泡形成受损和与支气管肺发育不良/慢性肺病一致的组织损伤。
