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.

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice / M.A. Ghonim, K. Pyakurel, S.V. Ibba, J. Wang, P. Rodriguez, A.A. Al Khami, M.R. Lammi, H. Kim, A.H. Zea, C. Davis, S. Okpechi, D. Wyczechowska, K. Al Ghareeb, M.S. Mansy, A. Ochoa, A.S. Naura, A.H. Boulares. - In: CLINICAL SCIENCE. - ISSN 1470-8736. - 129:11(2015), pp. 951-962. [10.1042/CS20150122]

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

S.V. Ibba;
2015

Abstract

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.
T helper 2 (Th2) cytokines; eosinophilia; house dust mite; olaparib (AZD2281); poly(adenosine 5′-diphosphate-ribose)polymerase (PARP) inhibition; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme Activation; Humans; Inflammation Mediators; Lung; Lymphocyte Activation; Mice, Inbred C57BL; Mice, Knockout; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes, Regulatory; Th2 Cells; Antigens, Dermatophagoides
Settore MED/04 - Patologia Generale
CLINICAL SCIENCE
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/440724
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