Sphingosine Kinase 1 Inhibitor, PF543, Blocks Inflammation and Airway Remodeling in a Murine Model of Allergic Asthma.

Asthma, a heterogeneous airway inflammatory disease, affects more than 300 million people worldwide, presenting a significant health and economic burden. Structural changes in the lung, known as airway remodeling (AWRM), as well as inflammation and airway hyperresponsiveness characterize the complex pathophysiology of severe asthma. Sphinogosine‐1‐phosphate (S1P), a bioactive sphingolipid metabolite, formed by the phosphorylation of sphingosine by either sphingosine kinase 1 or 2 (SPHK1/SPHK2) was found to be elevated in the BAL of patients with asthma. S1P signaling is involved in the pathogenesis of several lung conditions, including asthma, however, its role in the progression of the disease remains unclear. In our acute asthma model, sensitization of wild‐type C57BL/6 mice to Alum + a cocktail of allergens consisting of dust mite (D), Aspergillus (A), and ragweed (R), for 1 week, followed by challenge with DRA two weeks later, displayed an increase in inflammatory and eosinophil response, as well as goblet cell hyperplasia (Periodic acid‐Schiff staining) but no airway remodeling. In the chronic asthma model, mice were sensitized to DRA for 8 weeks, but no separate challenge was done. We observed increased pulmonary inflammation, in the absence of eosinophil response, as well as significant AWRM, as evidenced by increased subepithelial fibrosis (Masson’s trichrome staining) and smooth muscle hypertrophy (anti‐smooth muscle myosin heavy chain II staining). Furthermore, allergen challenged mice also showed increased airway hyper reactivity (AHR), as measured by methacholine challenge test. In the acute model, treatment with a specific SPHK1 inhibitor, PF543 (1 mg/kg), at 3 doses during allergen challenge, attenuated the inflammatory response, including eosinophil recruitment. In the chronic model, PF543 (1mg/kg) was administered twice weekly for three weeks after allergen challenge which reduced subepithelial fibrosis, and goblet cell hyperplasia. Decreased AHR was also observed following PF543 treatment. Together, these data suggest the significance of SPHK1/S1P signaling in the pathogenesis of asthma, as well as the therapeutic potential of PF543 in ameliorating inflammation and airway remodeling in allergic asthma. Support or Funding Information This work was supported by NIH/NICHD R01 HD090887 and AHA 18TPA34230095 to AH.