IL-33 is a key mediator of airway hyper-responsiveness in a murine model of allergic airway disease

Jane Fox1, Samantha Peel1, Jillian Barlow2, Bo Liu1, Ian Sayers1, Ian Hall1. 1University of Nottingham, Nottingham, United Kingdom, 2Molecular Biology Laboratory, Cambridge, United Kingdom.

Asthma is characterised by airway remodelling and increases in airway resistance. A greater understanding of the mechanisms involved in airway inflammation and hyper-responsiveness may highlight therapeutic opportunities. This study aimed to explore the mechanisms involved in airway smooth muscle contraction and the pathogenesis of hyper-reactivity implicated in airway inflammation using a murine model of allergic airway disease.

BALB/c mice underwent sensitisation by intraperitoneal administration of ovalbumin (OVA) on days 0 and 12. Mice received a 3 day challenge with aerosolised OVA 1%, repeated every 7 days for up to 3 weeks depending on length for acute, mid-chronic and chronic sensitisation protocols. Control mice received PBS. Agonist induced contractile responses in peripheral airways were measured ex vivo using the precision cut lung slice technique. To investigate the influence of the inflammatory environment, naïve murine lung slices were incubated with selected inflammatory mediators.

OVA sensitisation lead to progressive structural remodelling and airway hyper-responsiveness to 10μM methacholine (MCh) (39.5 + 4.8 % contraction (n = 15, 11 mice) for control vs. 66.0 + 5.6 % contraction (n = 15, 10 mice) for OVA sensitised). However, this hyper-responsiveness was decreased 48 hours post lung removal. Of the inflammatory mediators selected for lung slice incubation, IL-33 significantly increased airway hyper-responsiveness to MCh (35.0 + 2.8 % contraction in control (n = 25, 12 mice) vs. 56.5 + 5.1 % contraction for IL-33 incubated airways (n = 17, 11 mice)). In lung slices prepared from ST2 (IL-33 receptor) KO mice IL-33 was unable to sensitise contractile response.

This study suggests the inflammatory environment promotes airway hyper- responsiveness and disassociates this airway sensitivity from structural remodelling. Importantly, this study implicates a role for IL-33 in mediating airway hyper-responsiveness in this murine model.