Targeting viral induced TSLP - an airway treatment opportunity

Abstract: Respiratory viral infections cause exacerbations of asthma and COPD that cannot be effectively treated today. Thymic Stromal Lymphopoietin (TSLP) is an upstream epithelial cytokine linking the innate and adaptive immune system. Viral stimuli induce epithelial overexpression of TSLP in asthma and COPD. We hypothesise that TSLP switches on Th2-type inflammation in severe asthma/COPD. A deficient antiviral interferon-response has also been showed in asthmatic epithelium. The aim of this thesis was to study effects of selected compounds on viral induced epithelial TSLP and antiviral proteins. We show that capsazepine, a small airway relaxant, inhibits TSLP induced by the viral infection surrogate dsRNA in human bronchial epithelial cells (HBECs) from asthmatic and healthy donors. Surprisingly, simvastatin, a cholesterol-lowering compound with pleiotrophic effects, inhibits dsRNA-induced IRF3 phosphorylation and TSLP but not NFkB in HBECs from COPD-patients, healthy smokers and asthmatics. TSLP-inhibitory effects of capsazepine and simvastatin are superior to effects produced by the glucocorticoid dexamethasone. However, simvastatin, but not dexamethasone, inhibits antiviral interferon-beta (IFNβ) and IL-32. We developed a method by which repeated topical nasal dsRNA for the first time induces effects in vivo on human respiratory mucosa. We found that IFNβ, IFNλ and IL-32 were upregulated by dsRNA during but not outside birch pollen season. dsRNA challenges were below threshold for TSLP induction. In conclusion, using HBEC we discovered that different classes of compounds were effective inhibitors of viral induced TSLP. With pharmacological tools we discovered that IRF3 phosphorylation is involved in TSLP production meaning also that difficulties arise regarding the aim of inhibiting TSLP without inhibiting interferons. For future studies we devise novel human in vivo methods for study of pharmacology of airway antiviral protein production.