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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

基本信息

批准号：
9763604
负责人：
Anantha Harijith
金额：
$ 32.38万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763604
关键词：
Acute Address Adult Affect Age Alveolar Animal Model Brain Bronchopulmonary Dysplasia Caring Cells Childhood Chronic Clinical Clinical Trials Cognition Collagen Communities Data Dependence Development Drug Kinetics Exposure to Functional disorder Gases Generations Growth Home environment 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 Respiratory physiology Role Route SPHK1 enzyme Superoxide Dismutase Therapeutic Therapeutic Agents Treatment Efficacy Ventilator Wheezing airway hyperresponsiveness airway remodeling base cognitive function comparative crosslink effective therapy extracellular extreme prematurity free radical oxygen health disparity infancy inhibitor/antagonist intraperitoneal lung development lung volume mouse model novel novel therapeutics postnatal preterm newborn prevent repaired response small molecule inhibitor sphingosine 1-phosphate surfactant

项目摘要

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），一种影响早产儿的衰弱性疾病，是其中的一部分原因