Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

Am J Respir Cell Mol Biol. 2020 Nov;63(5):571-590. doi: 10.1165/rcmb.2020-0188TR.

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.

Keywords: cell death; coronavirus; cytokines; inflammation; olaparib.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / enzymology
  • Acute Lung Injury / virology
  • Animals
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / pathogenicity
  • COVID-19
  • COVID-19 Drug Treatment
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / enzymology
  • Coronavirus Infections / virology
  • Host-Pathogen Interactions
  • Humans
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / virology
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / enzymology
  • Pneumonia, Viral / virology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • SARS-CoV-2
  • Signal Transduction / drug effects

Substances

  • Antiviral Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1