441 - The Sphingolipid Pathway Modulator, Fingolimod, Ameliorates the Severity of Bronchopulmonary Dysplasia and Airway Remodeling in a Mouse Model

Poster Number: 441
Publication Number: 441.430

Tara Sudhadevi, Case Western Reserve University, cleveland heights, OH, United States; Prathima Basa, Case Western Reserve University School of Medicine, Cleveland, OH, United States; Jaya M. Thomas, Case Western Reserve University School of Medicine, Cleveland Heights, OH, United States; Alison W. Ha, Case Western Reserve University, Cleveland, OH, United States; Steven J. Ackerman, University of Illinois at Chicago, Chicago, IL, United States; Viswanathan Natarajan, University of Illinois College of Medicine, Frankfort, IL, United States; Anantha Harijith, Case Western Reserve University School of Medicine, Cleveland, OH, United States

Background: Rationale: We have demonstrated that Sphingosine kinase 1 (SPHK1)/sphingosine 1 phosphate (S1P) / S1P receptor 1 signaling contribute to hyperoxia induced bronchopulmonary dysplasia (BPD) like morphology in neonatal mice. SPHK 1 catalyzes formation of Sphingosine 1 phosphate (S1P) from sphingosine, which acts through G protein coupled receptors S1P1-5 and promotes formation of reactive oxygen species. We have shown that hyperoxia stimulated expression of SPHK1 and S1P1 in neonatal lungs including lung epithelium. Both Sphk1-/- and, S1pr1+/- mice pups showed protection against hyperoxic (HO) lung injury accompanied by improved alveolar formation. Increased expression of S1P receptor 1 was associated with reduced angiogenesis. Fingolimod inhibits ceramide synthase, SPHK1 and S1PRs.

Objective: Hypothesis: S1P signaling pathway modulator, fingolimod protects neonatal lungs from HO- induced BPD.

Design/Methods: Methods: Neonatal mice were administered Fingolimod (2 mg/kg/dose as intranasal injection) starting on postnatal day 3 (PN 3) and mice exposed to normoxia or HO (95% O2) from postnatal day 3 (PN 3) to day 10 (PN 10). Fingolimod injection was continued on alternate days 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. Appropriate vehicle controls were administered to control mice.

Results:

Results: Modulation of sphingolipid signaling by fingolimod caused amelioration of hyperoxia-induced alveolar simplification characterized by decreased mean linear intercept compared to controls. HO 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. Lung function also showed improvement of airway hyperreactivity to methacholine challenge.Conclusion(s):

Conclusions: Sphingolipid signaling pathway modulator, fingolimod, ameliorated the severity of HO- 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. This study was supported by NIH/NICHD grant R01 HD090887-01A1 and AHA grant #18TPA34230095 to A.H.