title: PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice.
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.
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ghonim
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Kusma
authors.initials: K
authors.lastname: Pyakurel
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Salome V
authors.initials: SV
authors.lastname: Ibba
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodriguez
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Al-Khami
authors.affiliation: Pulmonary and Critical Care Section, School of Medicine, Louisiana State University; New Orleans, LA 70112, U.S.A.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lammi
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Hogyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Zea
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Christian
authors.initials: C
authors.lastname: Davis
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Samuel
authors.initials: S
authors.lastname: Okpechi
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Dorota
authors.initials: D
authors.lastname: Wyczechowska
authors.affiliation: Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
authors.forename: Kamel
authors.initials: K
authors.lastname: Al-Ghareeb
authors.affiliation: Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
authors.forename: Moselhy S
authors.initials: MS
authors.lastname: Mansy
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Naura
authors.affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. hboulr@lsuhsc.edu.
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D039741:Antigens, Dermatophagoides; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
chemical_list: D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D039741:Antigens, Dermatophagoides; D016207:Cytokines; D018836:Inflammation Mediators; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011948:Receptors, Antigen, T-Cell; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: T helper 2 (Th2) cytokines; eosinophilia; house dust mite; olaparib (AZD2281); poly(adenosine 5′-diphosphate-ribose)polymerase (PARP) inhibition