Abman Steven H
Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, CO 80218-1088, USA.
Neonatology. 2007;91(4):283-90. doi: 10.1159/000101343. Epub 2007 Jun 7.
Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by failure of the lung circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth. Past laboratory studies identified the important role of nitric oxide (NO)-cGMP signaling in the regulation of the perinatal lung circulation, leading to the development and application of inhaled NO therapy for PPHN. Although inhaled NO therapy has improved the clinical course and outcomes of many infants, pulmonary hypertension can be refractory to inhaled NO, suggesting the need for additional approaches to severe PPHN. To develop novel therapeutic strategies for PPHN, ongoing studies continue to explore basic mechanisms underlying the pathobiology of PPHN in experimental models, including strategies to enhance NO-cGMP signaling. Recent studies have demonstrated that impaired vascular endothelial growth factor (VEGF) signaling may contribute to the pathogenesis of PPHN. Lung VEGF expression is markedly decreased in an experimental model of PPHN in sheep; inhibition of VEGF mimics the structural and functional abnormalities of PPHN, and VEGF treatment improves pulmonary hypertension through upregulation of NO production. Other studies have shown that enhanced NO-cGMP activity through the use of cGMP-specific phosphodiesterase inhibitors (sildenafil), soluble guanylate cyclase activators (BAY 41-2272), superoxide scavengers (superoxide dismutase), and rho-kinase inhibitors (fasudil) can lead to potent and sustained pulmonary vasodilation in experimental PPHN. Overall, these laboratory studies suggest novel pharmacologic strategies for the treatment of refractory PPHN.
新生儿持续性肺动脉高压（PPHN）是一种临床综合征，其特征为肺循环在出生时未能达到或维持正常的肺血管阻力（PVR）下降。过去的实验室研究确定了一氧化氮（NO）-环磷酸鸟苷（cGMP）信号通路在围产期肺循环调节中的重要作用，从而促成了吸入NO治疗PPHN的研发与应用。尽管吸入NO治疗改善了许多婴儿的临床病程及预后，但肺动脉高压对吸入NO可能无效，这表明对于重度PPHN需要其他治疗方法。为了开发PPHN的新型治疗策略，正在进行的研究继续在实验模型中探索PPHN病理生物学的基本机制，包括增强NO-cGMP信号通路的策略。最近的研究表明，血管内皮生长因子（VEGF）信号通路受损可能导致PPHN的发病机制。在绵羊PPHN实验模型中，肺VEGF表达显著降低；抑制VEGF可模拟PPHN的结构和功能异常，而VEGF治疗可通过上调NO生成来改善肺动脉高压。其他研究表明，通过使用cGMP特异性磷酸二酯酶抑制剂（西地那非）、可溶性鸟苷酸环化酶激活剂（BAY 41-2272）、超氧化物清除剂（超氧化物歧化酶）和 Rho激酶抑制剂（法舒地尔）增强NO-cGMP活性，可在实验性PPHN中导致强效且持续的肺血管舒张。总体而言，这些实验室研究提示了治疗难治性PPHN的新型药物策略。
