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

新型SphK1抑制剂PF543在支气管肺发育不良和气道重塑治疗中的作用

• 批准号: 10224284
• 负责人: Anantha Harijith
• 金额: $ 28.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224284
• 关键词: Acute; Address; Adult; Affect; Alveolar; Animal Model; Brain; Bronchopulmonary Dysplasia; Caring; Cells; Childhood; Chronic; Clinical; Clinical Trials; Cognition; Collagen; Data; Dependence; Development; Drug Kinetics; Exposure to; Functional disorder; Gases; Generations; Growth; Home; Hyperoxia; In Vitro; Incidence; Inflammation; Inhalation; Learning Disabilities; Life; Long-Term Effects; Longevity; Lung; Magnetic Resonance Imaging; Mediating; Medical; Modeling; Morphology; Mus; Natural regeneration; Neonatal; Neonatal Hyperoxic Injury; Newborn Infant; Normalcy; North America; Oxygen; Oxygen Therapy Care; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Physiological; Plague; Play; Pregnancy; Premature Birth; Premature Infant; Production; Protein-Lysine 6-Oxidase; Pulmonary Hypertension; Reactive Oxygen Species; Recovery; Role; Route; SPHK1 enzyme; Superoxide Dismutase; Therapeutic; Therapeutic Agents; Treatment Efficacy; Ventilator; Wheezing; airway hyperresponsiveness; airway remodeling; base; cognitive function; comparative; crosslink; effective therapy; efficacy evaluation; extracellular; extreme prematurity; free radical oxygen; health disparity; human old age (65+); infancy; inhibitor/antagonist; intraperitoneal; lung development; lung volume; mouse model; neonatal mice; novel; novel therapeutics; postnatal; preterm newborn; prevent; pulmonary function; repaired; response; small molecule inhibitor; sphingosine 1-phosphate; surfactant; therapeutically effective; underserved community

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.

支气管肺发育不良(BPD)是影响早产儿的一种衰弱状态，部分原因是 呼吸机护理和吸入氧气(O2)治疗的结果。长时间的氧疗是 对于在怀孕24周时出生的极端早产儿的生存至关重要；然而，它 有害的后果。患有严重bpd的患者通常会吸氧出院。 持续数月的治疗。肺泡简化形成BPD的形态特征， 而严重的呼吸道重塑(AWRM)会导致新生儿出现顽固性喘息 舞台。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。尽管对BPD的病理生理学了解取得了进展，但有效 这种疾病的治疗仍然难以捉摸，每年影响到超过15,000名新生儿 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，PF543，作为BPD和AWRM的潜在治疗方法。PF543抑制 特异性鞘氨醇激酶(SphK)1催化形成鞘氨醇-1-磷酸 (S1P)来源于鞘氨醇，S1P在BPD(10-12)的发病机制中起关键作用。我们的 最新的初步结果显示，BPD和AWRM在 新生Sphk1-/-小鼠(但不是Sphk2-/-)暴露在高氧(HO)中。野生型(WT)新生儿 在HO期间使用PF543治疗的小鼠可改善BPD、AWRM和呼吸道 高反应性(AHR)与对照组比较。另外，我们还观察到，PF543还 抑制S1P介导的细胞内活性氧(ROS)生成。S1P/ROS也 上调赖氨酰氧化酶(Lox)。LOX促进过多的胶原蛋白交联，导致BPD。 PF543可抑制HO对LOX的诱导。基于这些令人振奋的初步数据，我们 假设“PF543对鞘氨醇激酶1的抑制具有治疗作用 BPD及其后遗症AWRM和AHR的治疗“。BPD通过两个关键的 囊状期之后的肺发育阶段。第一阶段为早期肺泡化。 早产儿发展中的BPD表现出对氧气的依赖。 第二阶段为晚期牙槽化和AWRM，与术后恢复和修复相对应 早期婴儿期和儿童期。我们将通过研究以下两个具体问题来验证我们的假设 旨在解决PF543在使用我们的 高氧-新生小鼠模型，模拟临床BPD中可见的各种病理英里结石。 具体目标#1将确定PF543在BPD牙槽早期的治疗效果 肺发育阶段(BPD早期的急性高氧血症模型)和具体目标2： PF543治疗肺泡期晚期BPD的疗效观察 发展(慢性高氧模型，如晚期BPD)。我们还将确定 PF543抑制重症患者远期脑相关认知功能异常的能力 每桶。一旦实现，拟议的工作主体将极大地增加翻译 PF543作为一种有效的BPD治疗剂的潜力。