NITRIC OXIDE/CYCLIC GMP CASCADE IN NEONATAL PULMONARY HYPERTENSION

（改编自申请人摘要） 循环，以实现或维持肺循环的正常减少， 出生时的血管阻力（PVR）对 产后适应的两个主要临床问题的病理生理学： 肺透明膜病（HMD）与持续性临床肺 新生儿高血压（PPHN）虽然表面活性剂治疗是 在许多患有严重HMD的早产儿中有效， 有几种疾病，其特征是PVR升高， 高死亡率。在PPHN中，大多数足月新生儿的临床综合征 高PVR引起右向左肺外分流和几种低氧血症。 早产儿肺血管功能障碍的机制 与严重HMD的了解甚少，但反映了不成熟的影响， 以及对出生后急性肺损伤的反应。相比之下， 重症急性肺损伤新生儿肺血管反应性和结构的研究 PPHN常因慢性宫内应激所致。在这两种疾病中， 肺循环不能适应出生后的生活， PVR降低，导致严重低氧血症和不良结局。 实验研究表明，内源性一氧化氮（NO）-cGMP 级联（包括至少3种酶系统的活性：NO 合成酶（NOS）、可溶性鸟苷酸环化酶（sGC）和cGMP特异性（V型） 磷酸二酯酶调节肺血管张力和反应性 在子宫内，并有助于出生时PVR的正常下降。以来 NO-cGMP级联的成熟变化发生在胎儿期， 早产和肺损伤对肺血管反应性的影响， 与正常发育变化的中断密切相关， 内皮和平滑肌功能。是否改变了NO-cGMP活性， 例如NO 5和PDE 5活性之间不平衡， 与治疗失败相关的疾病中的PVR和异常血管反应性 肺转移是未知的。此外，吸入的NO 成功治疗了许多患有几种PPHN的新生儿， 严重的HMD，对其潜在毒性知之甚少，非血管扩张剂 对发育中的肺的影响，反应性差的潜在机制 在某些患者中，或对内源性NO-cGMP级联的可能影响。 检查导致围产期异常的机制， 为了更好地理解吸入NO治疗， 提出了一系列平行实验， 正常发育肺中NO-cGMP级联反应的病理生理学 建立胎羊HMD和PPHN模型。这些 研究将检验以下假设：1）严重早产和血管性 急性出生后肺损伤或慢性高血压所致损伤 子宫改变肺血管NO-cGMP级联反应，引起异常 出生后血管反应性和PVR持续升高;和2） 增加肺NO活性的策略，如吸入NO治疗， 抑制PDE 5或两者，将降低PVR并改善氧合 而不会对发育中的肺产生不良影响。

(Adapted from the Applicant's Abstract) Failure of the pulmonary circulation to achieve or sustain the normal decrease in pulmonary vascular resistance (PVR) at birth contributes significantly to the pathophysiology of two major clinical problems of post-natal adaptation: hyaline membrane disease (HMD) and persistent clinical pulmonary hypertension of the newborn (PPHN). Although surfactant therapy is effective in many premature neonates with severe HMD, patients who fail to respond have several disease which is characterized by elevated PVR and high mortality. In PPHN, a clinical syndrome of mostly full-term neonates high PVR causes right-to-left extra-pulmonary shunt and several hypoxemia. Mechanisms underlying pulmonary vascular dysfunction in premature neonates with sever HMD are poorly understood, but reflect the effect of immaturity and the response to acute post-natal lung injury. In contrast, altered pulmonary vascular reactivity and structure in mature neonates with severe PPHN are often due to chronic intrauterine stress. In both diseases, the pulmonary circulation fails to adapt to post-natal life with adequate reduction in PVR, causing profound hypoxemia and poor outcome. Experimental studies suggest that the endogenous nitric oxide (NO)-cGMP cascade (which includes activities of at least 3 enzyme systems: NO synthase (NOS), soluble guanylate cyclase (sGC) AND cGMP-specific (Type V) phosphodiesterase; PDE 5) modulates pulmonary vascular tone and reactivity in utero and contributes to the normal fall in PVR at birth. Since maturational changes in the NO-cGMP cascade occur during fetal life, the effects of premature birth and lung injury on pulmonary vasoreactivity are closely linked with disruption of normal developmental changes in endothelial and smooth muscle function. Whether altered NO-cGMP activity, such as an imbalance between NO5 and PDE5 activities, contribute to high PVR and abnormal vascoreactivity in diseases associated with failure of the pulmonary transition is unknown. In addition, inhaled NO has successfully treated many neonates with several PPHN, prematures with severe HMD, little is known about its potential toxicity, non-vasodilator effects in the developing lung, mechanisms underlying poor responsiveness in some patients, or possible effects on the endogenous NO-cGMP cascade. To examine mechanisms contributing to abnormalities of the perinatal pulmonary circulation and to better understand inhaled NO therapy, they propose a series of parallel experiments which examines the biochemistry and pathophysiology of the NO-cGMP cascade in the normal developing lung circulation and established models of HMD and PPHN in fetal lambs. These studies will test the hypothesis that: 1) severe prematurity and vascular injury due to acute post-natal lung injury or chronic hypertension in utero alter the pulmonary vascular NO-cGMP cascade, causing abnormal vasoreactivity and sustained elevations of PVR after birth; and 2) strategies which increase lung NO activity, such as inhaled NO therapy, inhibition of PDE5, or both, will lower PVR and improve oxygenation without adverse effects in the developing lung.