PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

Our laboratory established a role for poly(ADP-ribose)polymerase (PARP) in asthma. To increase the clinical significance of our studies, it is imperative to demonstrate that PARP is actually activated in human asthma, to examine whether a PARP inhibitor approved for human testing such as olaparib blocks already-established chronic asthma traits in response to house dust mite (HDM), a true human allergen, in mice and to examine whether the drug modulates human cluster of differentiation type 4 (CD4+) T-cell function. To conduct the study, human lung specimens and peripheral blood mononuclear cells (PBMCs) and a HDM-based mouse asthma model were used. Our results show that PARP is activated in PBMCs and lung tissues of asthmatics. PARP inhibition by olaparib or gene knockout blocked established asthma-like traits in mice chronically exposed to HDM including airway eosinophilia and hyper-responsiveness. These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-γ or interleukin (IL)-10. PARP inhibition prevented HDM-induced increase in overall cellularity, weight and CD4+ T-cell population in spleens of treated mice whereas it increased the T-regulatory cell population. In CD3/CD28-stimulated human CD4 +T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 ( gata-3)/IL-4 expression while moderately affecting T-cell proliferation. PARP inhibition inconsistently increased IL-17 in HDM-exposed mice and CD3/CD28-stimulated CD4+ T cells without a concomitant increase in factors that can be influenced by IL-17. In the present study, we provide evidence for the first time that PARP-1 is activated in human asthma and that its inhibition is effective in blocking established asthma in mice. * AHR, : airway hyper-responsiveness; BAL, : bronchoalveolar lavage; BALF, : BAL fluids; CD4+, : cluster of differentiation type 4; CFSE, 5,6-carboxyfluorescein diacetate succinimidyl ester; FoxP3, : forkhead box P3; gapdh, : glyceraldehyde-3-phosphate dehydrogenase; gata-3 , : GATA binding protein-3; GM-CSF, : granulocyte macrophage colony-stimulating factor; HDM, : house dust mite; H&E, : Hematoxylin and eosin; i.p., intraperitoneal; IFN, : interferon; IL, : interleukin; IP-10, : interferon gamma-induced protein-10; KC, : keratinocyte chemoattractant; NF-κB, : nuclear factor kappa-light-chain-enhancer of activated B cells; OVA, ovalbumin; PAR, : poly (ADP-ribose) moiety; PARP-1, : poly(ADP-ribose)polymerase-1; PAS, : periodic acid–Schiff; PBMC, : peripheral blood mononuclear cell; Penh, : enhanced pause; STAT-6, : signal transducer and activator of transcription-6; t-bet , : T-box transcription factor; TCR, : T-cell receptor; T-reg, : CD4+ T-regulatory cell; TGF, : transforming growth factor; Th2, : T helper cells 2; WT, : wild-type