892:
Administration of the CXCR2 inhibitor reparixin in sensitized mice inhibits allergen-challenge induced allergic inflammation.
Monday, March 5, 2018
South Hall A2 (Convention Center)
Koa Hosoki, MD PhD, Sanjiv Sur, MD
RATIONALE: Inhibiting allergenic extract-induced neutrophil recruitment in mice by administration of SB225002 CXCR2 inhibitor attenuates allergic sensitization. Unexpectedly, even though the CXCR2 inhibitor AZD5069 was safe in humans and reduced the level of neutrophils in sputum and blood, its administration failed to improve asthma control in subjects with severe uncontrolled asthma. We hypothesized that the role of airway neutrophils may be different in uncontrolled asthma vs. allergen-induced neutrophil recruitment. To test this hypothesis, here we examined the role of administration of reparixin, a human-safe CXCR2 inhibitor, in inhibiting allergic inflammation in naïve and allergen-sensitized mice.

METHODS: Wild-type naïve mice were challenged once with cat dander extract (CDE) to stimulate innate inflammation, or five multiple times to sensitize the mice, prior to a final CDE challenge to elicit allergic inflammation. Reparixin was administered intraperitoneally in a subset of each of these models prior to CDE challenge, and innate and allergic lung inflammation was quantified.

RESULTS: Administration of reparixin in the single challenge model suppressed CDE-induced innate neutrophil recruitment into the lungs. Furthermore, administration of reparixin in the multiple challenge model inhibited CDE-induced allergic inflammation. Reparixin inhibited levels of eosinophil numbers, IL-4, IL-13, IL-33, and TSLP in BALF, levels of mucin in airway epithelial cells, lung mRNA expression of Th2-inflammation-associated genes Periostin and Muc5ac, and serum levels of total IgE and CDE specific IgE.

CONCLUSIONS: Inhibiting CXCR2 suppresses allergen-induced innate and allergic airway inflammation in mice. CXCR2 may be a novel target for attenuating allergen-induced allergic airway inflammation in humans.