Rationale: VR588 is a potent, selective pan-JAK inhibitor. Viral
infection is regarded as an important trigger of airway inflammation.
This study investigates VR588 by the inhaled and oral routes in a
murine model of viral lung inflammation
Methods: Male BALB/c mice were administered Poly(I:C) 1 mg/ml
intranasally (i.n) 1 hour after VR588 administration and again 16 hours
later. VR588 was given (i.n 1.5, 7.5, 15 mg/kg and p.o 15 mg/kg; n¼6
per group). Lung tissue and bronchoalveolar lavage fluid (BALF) was
harvested 40 hours after the initial Poly(I:C) challenge. Inflammatory
cell count from BALF (FACS analysis), JAK-STAT activation
(pSTAT1, 3 & 5) (ELISA) and BAL inflammatory cytokines (Luminex
immunoassay) were measured. Fluticasone propionate (FP) (i.n 1.5 mg/
kg) and tofacitinib (T) (p.o 15 mg/kg) were positive controls.
Results: Poly(I:C) increased total BAL cell count which was reduced
in a dose-related manner by i.n VR588; oral VR588 was ineffective. Poly
(I:C)-elevated BAL cytokines (eotaxin, MIP-1a & b, IP-10, KC, TNF-a
and MCP-1) were all reduced by i.n VR588. pSTAT1 and pSTAT5 (but
not pSTAT3) were increased by Poly(I:C) and subsequently attenuated
by VR588. Intranasal VR588 activity was typically greater than that seen
for oral and at least as great as that with FP or T.
Conclusions: VR588 attenuation of Poly(I:C) induced inflammatory
cell accumulation, cytokines and STAT phosphorylation supports
its possible use in the treatment of viral induced airway inflammation.