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Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept
Csaba Szabo1, Vanessa Martins1, Lucas Liaudet2
1Chair of Pharmacology, Section of Medicine, University of Fribourg, Fribourg, Switzerland; and.
Abstract:
PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.
Insights
Poly(ADP-ribose) polymerase 1 (PARP1) is activated in acute lung injury (ALI). PARP inhibitors, effective in cancer, show promise for treating ALI, including viral causes like COVID-19.
Area of Science:
- Biochemistry
- Molecular Biology
- Pathology
Background:
- Poly(ADP-ribose) polymerase 1 (PARP1) regulates DNA repair, transcription, and cell death.
- PARP1 activation in acute lung injury (ALI) has been recognized for over two decades.
- Pharmacological inhibition or genetic deletion of PARP1 may offer therapeutic benefits in ALI.
Purpose of the Study:
- To review the cellular mechanisms of PARP1 in ALI pathogenesis.
- To summarize preclinical data supporting PARP inhibitor efficacy in ALI.
- To explore the potential repurposing of approved PARP inhibitors for ALI treatment, including viral etiologies like COVID-19-associated ALI.
Main Methods:
- Review of existing literature on PARP1 function in ALI.
- Analysis of preclinical studies on PARP inhibitors in ALI models.
- Examination of recent clinical approvals and preclinical efficacy of PARP inhibitors in ALI.
Main Results:
- PARP1 plays a significant role in the cellular mechanisms underlying ALI.
- Preclinical data consistently support the therapeutic potential of PARP inhibition in ALI.
- Recently approved potent PARP inhibitors demonstrate efficacy in animal models of ALI.
Conclusions:
- PARP inhibitors represent a promising therapeutic strategy for ALI.
- Repurposing of approved oncology PARP inhibitors for ALI is a viable translational approach.
- PARP inhibition may be beneficial for viral ALI, such as that associated with COVID-19.
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