Poly(ADP)Ribose Polymerase inhibition by gene knockout or pharmacologically by olaparib restores steroid sensitivity in murine model of steroid-resistant Asthma

Abstract

Abstract Background Asthma is a serious health issue worldwide and a common treatment for the disease is a combination of steroids with β2-agonist; however, many patients are refractory to steroid treatment. Individuals with steroid-resistant asthma have limited therapeutic options; some can die by status asthmaticus. steroid-resistant asthma is intimately associated with neutrophilic inflammation. Our laboratory has established a critical role for PARP-1 in asthma and neutrophile-based inflammation. Thus we hypothesize that PARP-1 may restores steroid sensitivity in murine model of steroid-resistant asthma. Objective To investigate whether PARP-1 inhibition could restore steroid sensitivity in steroid-resistant asthma model. Methods Murine model of steroid-resistant asthma and cell culture system were used. Results OVA challenge promotes eosinophilic-Th2 mediated response that is blocked by dexamethasone treatment. OVA priming with LPS/IFNγ results in class switching into neutrophile with developing resistance to the treatment with dexamethasone. PARP inhibition by gene knockout or by olaparib reversed the established steroid-resistant asthma manifestation in mice. This is attributed to marked reduction in the inflammatory cells infiltrating the airways and the significant reduction in the Th2 cytokines production, AHR, and the OVA-specific IgE secretion in both BALF and serum of the mice. The reversal of steroid resistance is explained by marked increase in the expression of Glucocorticoid Receptors (GR). Conclusion Our findings demonstrate a critical role for PARP-1 in steroid resistance and support the potential of PARP inhibition as a viable therapeutic strategy for treatment of steroid-resistant asthma.