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

Abstract

BackgroundAn 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.MethodsWe 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.ResultsAdministration 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.ConclusionsOur 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.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…Although the clear focus with olaparib -both preclinically and clinically -has been the therapy of various cancers, several groups have started conducting preclinical studies with olaparib in the context of various non-oncological applications, with an eye on future therapeutic repurposing. These efforts, so far, have demonstrated (1) protective effects of olaparib in vitro against NMDA receptor stimulation induced or oxygen-glucose deprivation induced death in differentiated human neurons (Xu et al, 2016) and in retinal pigment epithelial cell lines exposed to H 2 O 2 (Jang et al, 2017) and in cisplatin-induced injury in chronic myeloid leukaemia cells (Xiao and Kan, 2017), (2) protective effects of olaparib in a mouse model of transient middle cerebral artery occlusion and reperfusion (Teng et al, 2016), (3) protective effects of olaparib in various models of model of lung injury/lung inflammation, either induced by endotoxin (Kapoor et al, 2015) or in asthma models elicited by senzitization to ovalbumin (Ghonim et al, 2015a) or to house dust mites (Ghonim et al, 2015b), (4) protective effects of olaparib in various models of multiple organ dysfunction, either elicited by bacterial lipopolysaccharide (Kapoor et al, 2015) or by third-degree thermal injury (Ahmad et al, 2018), and (5) protective effects of olaparib in rodent models of acute and chronic liver failure Mukhopadhyay et al, 2017). The current data confirm and extend these findings and demonstrate the protective effect of olaparib in oxidant-challenged cardiac myocytes and in transplanted rat hearts.…”

Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target

“…For the OVA‐induced asthma model, mice were sensitized by intraperitoneal injection of 50 μg grade V chicken OVA (Sigma‐Aldrich) mixed with 2 mg aluminium hydroxide in saline once a week for 2 weeks. After two weeks, mice were challenged with aerosolized 3% OVA for 30 minutes . Mice were left untreated or treated with intraperitoneal injection of the CPT1 inhibitor etomoxir (Sigma‐Aldrich, St. Louis, MO) or the HADHA inhibitor ranolazine (Sigma‐Aldrich) at 50 mg/kg (both diluted in saline) 30 minutes after challenge.…”

Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis

“…CD4 + T cells in ex vivo studies of mice treated with olaparib, 30 could have a synergistic effect with the robust immunogenic response seen in POLE mutant tumors. Such hypotheses in this disease site require investigation.…”