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

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $302,393

## Abstract

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 relat...

## Key facts

- **NIH application ID:** 9939300
- **Project number:** 7R01HD090887-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Anantha Harijith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,393
- **Award type:** 7
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939300

## Citation

> US National Institutes of Health, RePORTER application 9939300, Role of novel SphK1 inhibitor, PF543 in therapy of Bronchopulmonary dysplasia and Airway remodeling (7R01HD090887-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9939300. Licensed CC0.

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