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

Authors: Ghonim, MA  Pyakurel, K  Ibba, SV  Wang, J  Rodriguez, P  Al-Khami, AA  Lammi, MR  Kim, H  Zea, AH  Davis, C  Okpechi, S  Wyczechowska, D  Al-Ghareeb, K  Mansy, MS  Ochoa, A  Naura, AS  Boulares, AH 
Citation: Ghonim MA, etal., Clin Sci (Lond). 2015 Dec;129(11):951-62. doi: 10.1042/CS20150122. Epub 2015 Jul 23.
Pubmed: (View Article at PubMed) PMID:26205779
DOI: Full-text: DOI:10.1042/CS20150122

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)-gamma 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.

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CRRD Object Information
CRRD ID: 11073727
Created: 2016-05-04
Species: All species
Last Modified: 2016-05-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.