570 - Sphingosine 1 Phosphate Receptor modulator, Fingolimod, Reduces the Severity of Bronchopulmonary Dysplasia by Protecting the Mitochondrial Structure in a Mouse Model

Poster Number: 570
Publication Number: 570.1436

Background: We have demonstrated that Sphingosine kinase 1 (SPHK1)/sphingosine 1 phosphate (S1P) / S1P receptor 1 (S1PR1) signaling contribute to hyperoxia (HO)-induced bronchopulmonary dysplasia (BPD) like morphology in neonatal mice. S1pr1+/- mice pups showed protection against hyperoxic (HO) lung injury accompanied by improved alveolar formation. Fingolimod, an FDA approved drug for multiple sclerosis (MS) protects against relapse of MS primarily by downregulating S1PR1.

Objective: 1. Study the role of fingolimod in protecting neonatal lungs from alveolar simplification in a murine model of BPD. 2. Investigate the role of fingolimod in the possible protection of mitochondrial structure in the lung tissue upon exposure to HO or HO & LPS.

Design/Methods: Neonatal mice were exposed to normoxia or HO (95% O2) and LPS or vehicle from postnatal day (PN) 3 to PN 10. Neonatal mice were administered fingolimod (2 mg/kg/dose as intranasal injection) or vehicle starting on PN 3 till PN10 and the animals were sacrificed on PN 10 or PN 56. Bronchoalveolar lavage fluid and lung tissue were collected to investigate markers of inflammation and lung histology. Lung function tests were done using flexiVent ventilator. Transmission electron microscopy (TEM) was used to study the morphology of mitochondria in animal lung tissues.

Results: Modulation of S1PR signaling by fingolimod caused amelioration of HO & LPS-induced alveolar simplification characterized by decreased mean linear intercept compared to controls (Fig.1). HO & LPS exposed but fingolimod treated pups when allowed to grow as adults showed decreased airway remodeling characterized by reduced airway smooth muscle thickening and peribronchial fibrosis compared to controls (Fig.2). Lung function also showed improvement of airway hyperreactivity to methacholine challenge following fingolimod therapy. TEM studies showed that, HO as well as HO & LPS induced a significant pathological hyperfusion of mitochondria in alveolar type 2 pneumocytes which was prevented by fingolimod (Fig.3). Hyperfusion tends to precede mitochondrial fragmentation.

Conclusion(s): Sphingolipid signaling pathway modulator, fingolimod, ameliorated the severity of HO & LPS- induced lung injury in a mouse model of BPD. These results show that fingolimod can be used as a potential therapeutic agent to treat BPD. Fingolimod probably exerts its protection by protecting the mitochondrial structure and hence preserving the potential for the energy surge required for lung development and regeneration.