A33-10 Inhibition of Mast Cell Mitigates Respiratory Syncytial Virus (RSV)-induced Airway Hyperresponsiveness and Inflammation in Guinea Pig

Background Mast cells release a range of contractile mediators, cytokines and growth factors, thereby playing a crucial role in the development, progression, and exacerbation of asthma. Many asthmatic patients achieve good symptom control with the existing treatment regimes. Despite this, they remain vulnerable to exacerbation during respiratory viral infections. Treatment options are limited due to the unclear mechanisms. Among the most common viruses that triggered asthma exacerbations, respiratory syncytial virus (RSV) has been reported to infect guinea pigs. In this study, we aimed to identify how mast cell inhibition influences the pulmonary features induced by RSV infection. Methods Guinea pigs were exposed to a vehicle or 5 × 104 PFU of RSV. In addition, one group of infected animals received food containing 1% THB001, a selective KIT inhibitor targeting mast cells, beginning ten days prior to infection. Another group received daily intraperitoneal injections of 20 mg/kg dexamethasone, starting one day before infection. Four days after infection, airway responsiveness was assessed using methacholine provocation. This was followed by the collection of bronchoalveolar lavage fluid (BALF) for differential cell count and lung tissue for histological analysis. Results No significant weight loss and symptoms was observed following RSV infection. However, infected guinea pigs exhibited increased resistance and elastance in the central airway and peripheral lung, indicating that airway hyperresponsiveness occurred, which was reversed by THB001 treatment. In contrast, dexamethasone had no beneficial effect and instead increased resistance and elastance in the peripheral lung. Dexamethasone reduced the RSV-induced increase in macrophages and eosinophils in BALF. Both THB001 and dexamethasone reduced airway inflammation caused by RSV, but only THB decreased collagen deposition and the number of mast cells in the airways (Control 5.1±0.6/100µm vs. Control+THB 0.5±0.2/100µm vs. RSV 7.5±0.7/100 µm vs. RSV+THB 0.6±0.2/100 µm vs. RSV+Dex 5.6±0.6/100 µm). Conclusions RSV induced a transient airway infection with airway hyperresponsiveness, airway inflammation, remodeling and an increase in mast cells. Mast cell inhibition effectively prevented these changes, whereas the effect of dexamethasone was limited. This abstract is funded by: Third Harmonic Bio, the Swedish Heart-Lung Foundation, and Karolinska Institutet