PARP-1 inhibitor, DPQ, attenuates LPS-induced acute lung injury through inhibiting NF-κB-mediated inflammatory response.

Abstract

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Poly (ADP-ribose) polymerase-1 has been demonstrated to be involved in tissue inflammation and one of its inhibitors, 3, 4-Dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline (DPQ), exerts anti-inflammatory effect. However, it is still unclear whether the DPQ possesses the protective effect on ALI and what mechanisms are involved. In this study, we tested the effect of DPQ on the lung inflammation induced by lipopolysaccharide (LPS) challenge in mice. We found that 6 h-LPS challenge induced significant lung inflammation and vascular leakage in mice. Treatment with DPQ at the dose of 10 μg/kg markedly reduced the neutrophil infiltration, myeloperoxidase activity and up-regulation of pro-inflammatory mediators and cytokines. LPS-elevated vascular permeability was decreased by DPQ treatment, accompanied by the inhibition of apoptotic cell death in mice lungs. In addition, we isolated mice peritoneal macrophages and showed pretreatment with DPQ at 10 μM inhibited the production of cytokines in the macrophages following LPS stimulation. DPQ treatment also inhibited the phosphorylation and degradation of IκB-α, subsequently blocked the activation of nuclear factor (NF)-κB induced by LPS in vivo and in vitro. Taken together, our results show that DPQ treatment inhibits NF-κB signaling in macrophages and protects mice against ALI induced by LPS, suggesting inhibition of Poly (ADP-ribose) polymerase-1 may be a potential and effective approach to resolve inflammation for the treatment of ALI.

• Authors: Gang Wang, Xiaojia Huang, Yongjin Li, Kangkang Guo, Pengbo Ning, Yanming Zhang
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e79757 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24278171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoquinolines
• Lipopolysaccharides
• NF-kappa B
• Piperidines
• Poly(ADP-ribose) Polymerase Inhibitors
• 3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone
• Peroxidase
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1

Topics

• Acute Lung Injury (drug therapy, metabolism)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cells, Cultured
• Inflammation (drug therapy, metabolism)
• Isoquinolines (therapeutic use)
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Peroxidase (metabolism)
• Piperidines (therapeutic use)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Real-Time Polymerase Chain Reaction
• Sepsis (drug therapy)