WS13.2 The role of PGE2 in cystic fibrosis (CF) lung inflammation and the potential association with ivacaftor therapy and treatment response

Abstract

Listen

Translate article

Objectives CF causes recurrent lung infections and inflammation which causes lung damage and pulmonary decline. The cyclooxgenase signalling pathway and its major metabolite PGE 2 have been shown to increase lung inflammation. PGE 2 signals through four different receptor subtypes, EP1–EP4. Exact mechanisms underpinning mode of action of new therapies such as ivacaftor may be multifactorial with potential downstream signaling consequences. Methods PGE 2 plasma levels were detected in clinically stable CF patients (n = 25) with a G551D mutation pre and post ivacaftor treatment. CF bronchial epithelial cells (DF508 homozygote, CFBE41o-) and human bronchial epithelial cells (16HBEo-) were seeded at2×10 5 cells/ml. EP1 receptor expression was determined by qRT-PCR. Cells were stimulated with PGE 2 or EP1 receptor antagonist and cell supernatant harvested. Cell proliferation was determined and changes in cytokine levels of IL-6, IL-8 and TNFa following PGE 2 stimulation and IL-6 following EP1 receptor antagonism were detected by ELISA. Results Treatment of CF patients with ivacaftor significantly reduced PGE 2 plasma levels (p 2 stimulation significantly increased expression of IL-6, IL-8 and TNFα in CFBE41o-cells compared to 16HBEo- in vitro. EP1 receptor antagonism significantly reduced IL-6 secretion in CFBE41o- cells. No significant change in cell proliferation was detected. Conclusion The findings underscore the value of unravelling the mechanisms regulating PGE 2 signalling, potentially advancing our understanding of the mechanisms of action of existing novel therapies in CF.