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.

Public Health Relevance

Preterm birth affects nearly 500,000 babies every year in North America and its incidence has risen by 36% over the last 25 years; extreme prematurity is more common among underserved communities, contributing to health disparity. Bronchopulmonary dysplasia (and its sequela ? wheezing) is a serious lung condition for which there is no therapy yet, affecting the extreme preterm. In this proposal, we intend to develop PF543, a drug that has been shown to prevent BPD in animal models primarily by inhibiting formation of harmful oxygen free radicals within cells, thus helping the lungs regenerate to normalcy, and prevent airway changes that causes severe wheezing, as a new drug with the potential to treat not only BPD but also wheezing.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1)
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Giacoia, George
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Case Western Reserve University
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