Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1–30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1–10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production—both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI.

The role of inflammatory factors and T‐cell subsets in the diagnosis of recurrence in epithelial ovarian cancer patients and the effect of olaparin treatment on them

“… 32 Without changing IκBα phosphorylation, olaparib can passivate the phosphorylation of P65 in Ser 536, and reduce elastase induced lung inflammation and emphysema in mice. 33 , 34 This study found that the serum IL‐6 and TNF‐α level of patients receiving olaparib maintenance treatment was lower than that of patients receiving conventional treatment, while the serum IFN‐γ level was increased, indicating olaparib maintenance treatment can significantly inhibit the inflammatory response of patients with ovarian cancer, which was in agreement with previous reports.…”

When DNA-damage responses meet innate and adaptive immunity

“…Rat models of acute lung injury (ALI) have verified this. By blocking the NF-κB pathway, PARP inhibitors shield the ALI rat from inflammatory extravasation and prevent cell malfunction and necrosis [ 182 ]. Therefore, through interaction with the NF-κB pathway, DDR components may function as immunological modulators in some immune disorders (Fig.…”