PhD defence S.F. Rahmawati

Novel Pharmacological targets for the inhibition of inflammation and airway remodeling in asthma

Asthma is a chronic inflammatory disease of the airways which is characterized by difficulties with breathing. Patients with severe asthma experience worsened asthma symptoms. This can be the result of changes of airway wall thickening (remodeling) as well as insensitivity to corticosteroids, which are the cornerstone medication in asthma therapy. Therefore, unraveling the pathobiology of these mechanisms will improve severe asthma therapy.

Airway remodeling is caused by inflammatory mediators, which are abundant in asthmatic airways. Indeed, the results in the thesis of Ayha Rahmawati demonstrated that airway remodeling is partly induced by inflammatory mediators such as prostaglandin D2 (PGD2) and IL-17A in cultured human airway epithelial cells; both mediators stimulate a shift towards mucus producing goblet cells. Moreover, PGD2 also moderately increased calponin, a marker for airway smooth muscle remodeling.

Airway remodeling can also affect airway neurons, which can lead to airway hyperresponsiveness (AHR) in asthma. The thesis of Rahmawati shows that allergen-induced neuronal growth is prevented by budesonide, a common corticosteroid used in asthma therapy. However the drug was unable to reverse already established remodeling. Response to corticosteroids is critical in asthma therapy, as they target persistent inflammation. Previous studies suggested that the cytokine IL-17A leads to corticosteroid insensitivity. In this thesis, we demonstrate that exposure to IL-17A during the differentiation of human airway epithelial cells increases inflammation and mucus production which were not prevented by a potent corticosteroid, dexamethasone. However, airway epithelial barrier disruption induced by IL-17A was restored by dexamethasone. This indicates that corticosteroids affect specific functional changes that are caused by IL-17A in airway epithelial cells.In conclusion, the works described in her thesis demonstrate new mechanisms of airway remodeling and corticosteroid insensitivity, which will help our collective effort to target severe asthma and improve treatment.

Promotors: Prof.dr. R. Gosens and Prof.dr. H.A.M. Kerstjens