Role of novel SphK1 inhibitor, PF543 in therapy of Bronchopulmonary dysplasia and Airway remodeling

支气管肺发育不良（BPD）是一种影响早产儿的衰弱性疾病， 呼吸机护理和吸入氧气（O2）治疗的结果。长期氧疗是 对于妊娠24周时出生的极端早产儿的生存至关重要;然而， 有害的后果。患有严重BPD的患者通常会在吸氧后出院回家 治疗持续数月。肺泡简化形成了BPD的形态学标志， 而严重气道重塑（AWRM）导致新生儿出现顽固性喘息， 阶段喘息、肺动脉高压和学习障碍等后遗症困扰着BPD 成人生活中的病人尽管在BPD的病理生理学的理解方面取得了进展，但有效的 在美国，每年有超过15，000名新生儿患有这种疾病， 仅美国就有262亿美元的医疗负担。在这方面，我们已经确定了一个小的 分子抑制剂PF 543作为BPD和AWRM的潜在治疗药物。PF 543抑制 特别是催化鞘氨醇-1-磷酸形成的鞘氨醇激酶（SphK）1 (S1P)S1 P在BPD的发病机制中起关键作用（10-12）。我们 最近的初步结果显示，BPD和AWRM都显着改善， 新生Sphk 1-/-小鼠（但不是Sphk 2-/-）暴露于高氧（HO）。野生型（WT）新生儿 在HO期间用PF 543治疗的小鼠导致BPD、AWRM和气道改善。 高反应性（AHR）。在相关的说明中，我们还观察到PF 543也 抑制S1 P介导的细胞内活性氧（ROS）的产生。S1P/ROS 上调赖氨酰氧化酶（Lox）。Lox促进过量胶原交联，导致BPD。 PF 543可抑制HO对Lox的诱导。基于这些令人兴奋的初步数据，我们 假设“PF 543对鞘氨醇激酶1的抑制在 BPD及其后遗症AWRM & AHR的治疗”。BPD通过两个关键的 囊状阶段之后的肺发育阶段。第一阶段是早期牙槽骨化 和AWRM，在此期间，患有BPD的早产儿表现出氧依赖性。 第二阶段是晚期肺泡化和AWRM，对应于 早期婴儿期和儿童期。我们将通过以下两个具体问题来验证我们的假设： 目的是利用我们的研究，探讨PF 543在中度和重度BPD中的疗效。 模拟临床BPD中观察到的各种病理学里程碑的高氧新生小鼠模型。 具体目标#1将确定PF 543在BPD的早期肺泡炎期间的治疗效果。 肺发育阶段（如早期BPD中的急性高氧模型）和具体目标#2： PF 543治疗肺泡晚期BPD的疗效观察 发展（慢性高氧模型，如晚期BPD）。我们还将确定 PF 543抑制严重脑损伤患者长期脑相关认知异常的能力 波士顿警局一旦实现，拟议的工作将大大增加翻译 PF 543作为BPD的有效治疗剂的潜力。

Bronchopulmonary Dysplasia (BPD), a debilitating condition affecting preterm newborns, is in part a consequence of ventilator care and inhaled oxygen (O2) therapy. Prolonged oxygen therapy is essential for survival of an extreme preterm born at 24 weeks gestation; however, it has deleterious consequences. Patients with severe BPD are often discharged home on oxygen therapy lasting many months. Alveolar simplification forms the morphological hallmark of BPD, while severe airway remodeling (AWRM) leads to intractable wheezing right from the neonatal stage. Sequelae such as wheezing, pulmonary hypertension and learning disabilities plague BPD patients in adult life. Despite advances in the understanding of pathophysiology of BPD, effective therapy remains elusive for this condition affecting more than 15,000 newborns per year in the US alone with a medical burden of $26.2 billion. In this context, we have identified a small molecule inhibitor, PF543, as a potential therapy for both BPD and AWRM. PF543 inhibits specifically sphingosine kinase (SphK) 1 that catalyzes formation of sphingosine-1-phosphate (S1P) from sphingosine, and S1P plays a critical role in the pathogenesis of BPD (10-12). Our recent preliminary results revealed that both BPD and AWRM were significantly ameliorated in neonatal Sphk1-/- mice (but NOT Sphk2-/-) exposed to hyperoxia (HO). Wild type (WT) newborn mice treated with PF543 during HO resulted in ameliorated BPD, AWRM and airway hyperreactivity (AHR) compared to controls. On a related note, we also observed that PF543 also inhibits S1P-mediated intracellular reactive oxygen species (ROS) generation. S1P/ROS also upregulate Lysyl oxidase (Lox). Lox promotes excess collagen cross-linking leading to BPD. Induction of Lox by HO was inhibited by PF543. Based on these exciting preliminary data, we hypothesized that “Inhibition of sphingosine kinase 1 by PF543 has a therapeutic role in the treatment of BPD and its sequela of AWRM & AHR”. BPD evolves through two critical stages of lung development following the saccular stage. The first stage is early alveolarization and AWRM during which the preterm neonate with developing BPD shows oxygen dependency. The second stage is late alveolarization and AWRM corresponding to recovery and repair during early infancy and childhood. We will validate our hypothesis by pursuing the following two specific aims that address the efficacy of PF543 in moderate and severe forms of BPD using our hyperoxia-neonatal mouse model that mimcs various pathology mile stones seen in clinical BPD. Specific Aim #1 will determine the therapeutic efficacy of PF543 in BPD during the early alveolar stage of lung development (acute hyperoxia model as in early stage BPD) and specific Aim #2: Determine the therapeutic efficacy of PF543 in BPD during late alveolar stage of lung development (chronic hyperoxia model as in advanced stage BPD). We will also determine the ability of PF543 to suppress the long term brain related cognition abonormalities seen in severe BPD. Once realized, the proposed body of work will dramatically increase the translational potential of PF543 as an effective therapeutic agent against BPD.