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Poly adenosine diphosphate-ribose polymerase inhibitor PJ34 abolishes systemic proinflammatory responses to thoracic
James H Black1, Patrick J Casey, Hassan Albadawi
1Department of Surgery, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Background:
Systemic inflammatory responses contribute to mortality after thoracoabdominal aneurysm repair. Poly adenosine diphosphate (ADP) ribose polymerase (PARP) activity is known to modulate inflammation in animal models of injury. The effect of the PARP inhibitor PJ34 and genetic deletion of PARP-1(PARP -/-) on the systemic inflammatory response after thoracic aortic ischemia reperfusion (TAR) is not known.
Study Design:
In one group, all mice were subject to TAR followed by 48 hours of reperfusion. Treated mice (PJ, n=24) were given PJ34 IP; untreated mice (UN, n=41) received normal saline intraperitoneally. The number of mice in each group was selected to have a similar number of survivors by 48 hours. In a second group, sham animals were subjected to mediastinotomy alone (sham, n=10) without TAR, and were compared with mice with deletion of the PARP-1 isoform (PARP-1 -/-, n=11) subjected to TAR. Tissue extracts were assayed for keratinocyte derived chemokine and granulocyte colony stimulating factor. Serum was assayed for interleukin-6.
Results:
PJ34 treatment decreased mortality throughout the experimental protocol. There were no mortalities in the sham operated mice or PARP -/- mice subjected to TAR. PJ34 treatment decreased serum levels of interleukin-6 (p=0.01) and hepatic levels of interleukin-6 mRNA when compared with untreated and PARP-/- mice (p < 0.01). Only liver and kidney cytokine levels were decreased by PJ34 treatment (p < 0.05). In PARP-/- mice subjected to TAR, tissue cytokine levels were not different from those in sham mice.
Conclusions:
PARP inhibition may represent a novel therapeutic approach to minimizing inflammatory sequelae after TAR.
Insights
Poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibition with PJ34 or PARP-1 deletion reduced mortality and systemic inflammation after thoracic aortic reperfusion (TAR) injury in mice.
Area of Science:
- Cardiovascular Surgery
- Inflammation Research
- Pharmacology
Background:
- Systemic inflammatory responses are a major cause of mortality following thoracoabdominal aneurysm repair.
- Poly adenosine diphosphate (ADP) ribose polymerase (PARP) activity is recognized for its role in modulating inflammatory responses in injury models.
- The specific impact of PARP inhibition and PARP-1 gene deletion on systemic inflammation after thoracic aortic reperfusion (TAR) remains uninvestigated.
Purpose of the Study:
- To investigate the effects of the PARP inhibitor PJ34 and genetic deletion of PARP-1 on the systemic inflammatory response and mortality following TAR.
- To evaluate the therapeutic potential of PARP inhibition in mitigating inflammatory complications after TAR.
Main Methods:
- Mice underwent TAR and were divided into groups: treated with PJ34 (PJ) or saline (UN).
- A separate group compared sham-operated mice with PARP-1 knockout (PARP-1-/-) mice subjected to TAR.
- Cytokine levels (keratinocyte-derived chemokine, granulocyte colony-stimulating factor, interleukin-6) were measured in tissue and serum.
Main Results:
- PJ34 treatment significantly reduced mortality and serum/hepatic interleukin-6 levels.
- No mortalities were observed in sham or PARP-1-/- mice subjected to TAR.
- PJ34 treatment decreased liver and kidney cytokine levels, while PARP-1-/- mice showed no significant difference in tissue cytokine levels compared to sham mice.
Conclusions:
- PARP inhibition, demonstrated by PJ34 treatment, effectively reduces mortality and systemic inflammation post-TAR.
- Genetic deletion of PARP-1 also abrogated mortality and inflammatory markers, suggesting a critical role for PARP-1 in the inflammatory cascade.
- PARP inhibition presents a promising therapeutic strategy for managing inflammatory complications after thoracic aortic repair.
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