PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4(+) T cell function.

Autor: Ghonim MA; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. mghoni@lsuhsc.edu.; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. mghoni@lsuhsc.edu., Pyakurel K; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. kpyaku@lsuhsc.edu., Ibba SV; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. sibba@lsuhsc.edu., Al-Khami AA; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. aalkh@lsuhsc.edu.; Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt. aalkh@lsuhsc.edu., Wang J; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. jwang4@lsuhsc.edu., Rodriguez P; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. prodri1@lsuhsc.edu., Rady HF; Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. hrady@lsuhsc.edu., El-Bahrawy AH; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. alipharma2006@yahoo.com., Lammi MR; Pulmonary and Critical Care Section, School of Medicine, Louisiana State University, New Orleans, LA, USA. mlammi@lsuhsc.edu., Mansy MS; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. moselhysalah@gmail.com., Al-Ghareeb K; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. kamelalghareeb2000@gmail.com., Ramsay A; Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. aramsay@lsuhsc.edu., Ochoa A; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. aochoa@lsuhsc.edu., Naura AS; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. anaura@pu.ac.in.; Department of Biochemistry, Panjab University, Chandigarh, India. anaura@pu.ac.in., Boulares AH; The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. hboulr@lsuhsc.edu.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2015 Jul 14; Vol. 13, pp. 225. Date of Electronic Publication: 2015 Jul 14.
DOI: 10.1186/s12967-015-0583-0
Abstrakt: Background: An important portion of asthmatics do not respond to current therapies. Thus, the need for new therapeutic drugs is urgent. We have demonstrated a critical role for PARP in experimental asthma. Olaparib, a PARP inhibitor, was recently introduced in clinical trials against cancer. The objective of the present study was to examine the efficacy of olaparib in blocking established allergic airway inflammation and hyperresponsiveness similar to those observed in human asthma in animal models of the disease.
Methods: We used ovalbumin (OVA)-based mouse models of asthma and primary CD4(+) T cells. C57BL/6J WT or PARP-1(-/-) mice were subjected to OVA sensitization followed by a single or multiple challenges to aerosolized OVA or left unchallenged. WT mice were administered, i.p., 1 mg/kg, 5 or 10 mg/kg of olaparib or saline 30 min after each OVA challenge.
Results: Administration of olaparib in mice 30 min post-challenge promoted a robust reduction in airway eosinophilia, mucus production and hyperresponsiveness even after repeated challenges with ovalbumin. The protective effects of olaparib were linked to a suppression of Th2 cytokines eotaxin, IL-4, IL-5, IL-6, IL-13, and M-CSF, and ovalbumin-specific IgE with an increase in the Th1 cytokine IFN-γ. These traits were associated with a decrease in splenic CD4(+) T cells and concomitant increase in T-regulatory cells. The aforementioned traits conferred by olaparib administration were consistent with those observed in OVA-challenged PARP-1(-/-) mice. Adoptive transfer of Th2-skewed OT-II-WT CD4(+) T cells reversed the Th2 cytokines IL-4, IL-5, and IL-10, the chemokine GM-CSF, the Th1 cytokines IL-2 and IFN-γ, and ovalbumin-specific IgE production in ovalbumin-challenged PARP-1(-/-)mice suggesting a role for PARP-1 in CD4(+) T but not B cells. In ex vivo studies, PARP inhibition by olaparib or PARP-1 gene knockout markedly reduced CD3/CD28-stimulated gata-3 and il4 expression in Th2-skewed CD4(+) T cells while causing a moderate elevation in t-bet and ifn-γ expression in Th1-skewed CD4(+) T cells.
Conclusions: Our findings show the potential of PARP inhibition as a viable therapeutic strategy and olaparib as a likely candidate to be tested in human asthma clinical trials.
Databáze: MEDLINE
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