rhIGF-1 Therapy: A Silver Bullet for Bronchopulmonary Dysplasia Prevention?
rhIGF-1 Therapy: A Silver Bullet for Bronchopulmonary Dysplasia Prevention?
复制标题
rhIGF-1 疗法：预防支气管肺发育不良的灵丹妙药？
DOI：
10.1164/rccm.202002-0287ed
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发表时间：
2020
影响因子：
24.7
通讯作者：
Benjamin,JohnT
中科院分区：
文献类型：
--
作者：
Plosa,ErinJ;Benjamin,JohnT
过去二十年新生儿护理的进步提高了极早产儿的生存率，但支气管肺发育不良（BPD）仍然是困扰这些婴儿的棘手问题。 “新”BPD 最初在前表面活性剂时代被描述为一种与肺损伤和纤维化相关的疾病，其特点是未成熟肺中肺泡化减少和微血管发育受损 (1)。尽管它被认为是新生儿期的疾病，但患有 BPD 的婴儿在成年后仍会继续遭受其后果 (2)。产前损伤（例如暴露于绒毛膜羊膜炎和母亲吸烟）以及机械通气和高氧引起的产后损伤都会增加 BPD 的风险 (3)。 BPD 的多因素病因使治疗方法的开发成为一个独特的挑战，目前尚无有效的治疗方法可以预防或治愈这种使人衰弱的疾病。 IGF-1（胰岛素样生长因子-1）是一种与胰岛素原结构同源的肽激素，在体内多种组织中表达，包括肺 (4)。 IGF-1 与其受体 IGFR-1（IGF 受体-1）结合并促进细胞生长和分化 (4)。循环中的 IGF-1 与七种 IGFBP（IGF 结合蛋白）之一结合，其中 IGFBP-3 的含量最丰富 (5)。胎儿中的 IGF-1 水平很高，并在妊娠晚期（快速生长发育期）迅速增加 (6, 7)。出生后的新生儿早期，IGF-1 的血清水平会下降。 IGF-1 水平的下降在早产后尤其明显，这使得早产婴儿相对缺乏 IGF-1 (5)。与其他组织一样，IGF-1 调节胎儿肺中对形态发生至关重要的多种功能，包括 VEGF 依赖性内皮细胞增殖、上皮细胞增殖和分化，以及细胞外基质成分的间充质产生。 IGFR-1 缺失小鼠出现肺发育不全和膈肌缺陷，并死于呼吸衰竭 (8)。此外，阻断 IGF-1 信号传导可防止人胎肺外植体的离体分支 (9)。因此，IGF-1对于正常的肺部发育是必不可少的，其缺乏可能导致早产儿的肺部疾病。事实上，产后早期血清 IGF-1 水平降低与早产儿后期 BPD 的发生有关 (5,10,11)。鉴于 IGF-1 在肺部发育中至关重要，以及较低的血清 IGF-1 水平与 BPD 之间已确定的联系，早产后补充 IGF-1 是预防 BPD 的可行策略，需要进一步研究。在本期杂志报道的一项研究中，Seedorf 及其同事（第 1120-1134 页）测试了 rhIGF-1/BP3（重组人 IGF-1/IGFBP-3）在三种已充分描述的 BPD 小鼠模型中保持正常肺生长的功效 (12)。使用两种产前模型（分别在羊膜腔内注射 sFlt1 或内毒素来模拟先兆子痫和绒毛膜羊膜炎）和产后高氧模型来检验 IGF-1 治疗将保留 BPD 患者肺生长和功能的假设。出生后对幼鼠腹腔注射 rhIGF-1/BP3，可改善所有三种模型中远端肺的肺泡化和微血管密度，并防止右心室肥大（肺动脉高压的征兆）的发展。此外，rhIGF-1/BP3可增加胎儿II型肺泡上皮细胞和内皮细胞的体外增殖，表明IGF-1可能作为有丝分裂原和促血管生成因子，促进正常的肺生长。不同的煽动性侮辱可以激活不同的……
Advancements in neonatal care over the past two decades have improved survival of extremely premature infants, yet bronchopulmonary dysplasia (BPD) continues to be a vexing problem that plagues these infants. Initially described in the presurfactant era as a disorder associated with lung injury and fibrosis, the “new” BPD is characterized by reduced alveolarization and impaired microvascular development in the immature lung (1). Although it is considered a disease of the neonatal period, infants with BPD continue to suffer from its consequences well into adulthood (2). Both prenatal insults, such as exposure to chorioamnionitis and maternal smoking, and postnatal injury from mechanical ventilation and hyperoxia increase the risk of BPD (3). The multifactorial etiology of BPD has made the development of therapies a unique challenge, and currently no effective treatment exists to prevent or cure this debilitating disease. IGF-1 (insulin-like growth factor-1) is a peptide hormone with structural homology to proinsulin that is expressed in various tissues in the body, including the lung (4). IGF-1 binds to its receptor, IGFR-1 (IGF receptor-1) and promotes cellular growth and differentiation (4). Circulating IGF-1 is bound to one of seven IGFBPs (IGF-binding proteins), of which IGFBP-3 is the most abundant (5). IGF-1 levels are high in the fetus and increase rapidly in the third trimester of pregnancy, a period of rapid growth and development (6, 7). Serum levels of IGF-1 then decrease after birth, in the early neonatal period. The decrease in IGF-1 levels is especially pronounced after preterm birth, which leaves prematurely born infants relatively IGF-1 deficient (5). As in other tissues, IGF-1 regulates numerous functions in the fetal lung that are critical for morphogenesis, including VEGF-dependent endothelial cell proliferation, epithelial cell proliferation and differentiation, and mesenchymal production of extracellular matrix components. IGFR-1–null mice develop pulmonary hypoplasia and diaphragmatic defects and die of respiratory failure (8). In addition, blocking IGF-1 signaling prevents ex vivo branching in human fetal lung explants (9). Thus, IGF-1 is indispensable for normal lung development and its deficiency could contribute to lung disease in preterm infants. Indeed, reduced serum IGF-1 levels in the early postnatal period are associated with later development of BPD in preterm infants (5, 10, 11). Given its critical importance in lung development, and the established link between lower serum IGF-1 levels and BPD, replenishment of IGF-1 after preterm birth represents a viable strategy to prevent BPD that requires further investigation. In a study reported in this issue of the Journal, Seedorf and colleagues (pp. 1120–1134) tested the efficacy of rhIGF-1/BP3 (recombinant human IGF-1/IGFBP-3) in preserving normal lung growth in three well-described murine models of BPD (12). Two antenatal models (intraamniotic administration of sFlt1 or endotoxin to model preeclampsia and chorioamnionitis, respectively) and a postnatal hyperoxia model were used to test the hypothesis that IGF-1 therapy would preserve lung growth and function in BPD. Postnatal administration of rhIGF-1/BP3 intraperitoneally to rat pups improved alveolarization and microvascular density in the distal lung in all three models and prevented the development of right ventricular hypertrophy, a sign of pulmonary hypertension. Furthermore, rhIGF-1/BP3 increased in vitro proliferation of fetal type II alveolar epithelial cells and endothelial cells, suggesting that IGF-1 may act as a mitogen and proangiogenic factor and promote normal lung growth. Different inciting insults can activate distinct …