Related Experiment Video
Updated: Aug 18, 2025
Pseudomonas aeruginosa Induced Lung Injury Model
Published on: October 29, 2014
Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury
Vanessa Martins1, Sidneia S Santos1,2, Larissa de O C P Rodrigues1,2
1Section of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
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.
Insights
Clinical-stage Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors show promise for treating acute lung injury (ALI). These PARP inhibitors offer cytoprotection and reduce inflammation without increasing DNA damage, supporting their repurposing for ALI therapy.
Area of Science:
- Biomedical Science
- Pharmacology
- Pulmonology
Background:
- Poly(ADP-ribose) polymerase 1 (PARP1) was identified as a therapeutic target for acute lung injury (ALI) over two decades ago.
- Clinical application was hindered by the absence of effective PARP inhibitors.
- The recent development of potent PARP inhibitors has revived interest in their therapeutic potential for ALI.
Purpose of the Study:
- To evaluate the efficacy of clinical-stage PARP inhibitors in treating acute lung injury (ALI).
- To assess the cytoprotective and anti-inflammatory effects of PARP inhibitors in vitro and in vivo.
- To investigate the underlying mechanisms of PARP inhibition in ALI models.
Main Methods:
- In vitro studies using cultured human epithelial cells and monocytes exposed to oxidative stress.
- In vivo studies utilizing a murine model of ALI.
- Assessment of cytoprotection, inflammation markers, NF-kB and caspase 3 activation, NLRP3 inflammasome activity, and DNA damage (TUNEL assay).
Main Results:
- Five clinical-stage PARP inhibitors demonstrated comparable cytoprotection in vitro.
- Olaparib and rucaparib showed beneficial effects in a murine ALI model, reducing lung extravasation and pro-inflammatory mediators.
- Mechanisms include protection against cell necrosis, inhibition of NF-kB and caspase 3, NLRP3 inflammasome suppression, and modulation of inflammatory mediators.
- PARP inhibitors did not potentiate DNA damage as assessed by TUNEL assay.
Conclusions:
- Clinically approved PARP inhibitors exhibit therapeutic potential for acute lung injury (ALI).
- These compounds offer cytoprotective and anti-inflammatory benefits in ALI models.
- PARP inhibitors represent a promising class of drugs that may be repurposed for experimental ALI therapy.
