TY - JOUR
T1 - Poly Adenosine Diphosphate-Ribose Polymerase Inhibitor PJ34 Abolishes Systemic Proinflammatory Responses to Thoracic Aortic Ischemia and Reperfusion
AU - Black, James H.
AU - Casey, Patrick J.
AU - Albadawi, Hassan
AU - Cambria, Richard P.
AU - Watkins, Michael T.
N1 - Funding Information:
Funding sources for this work included a Merit Award from the Research Service of the Veterans Administration, the VA Department of Defense Combat Casualty Care Project; the Department of Surgery, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital; and the Pacific Vascular Research Foundation.
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jamcollsurg.2006.04.004
DO - 10.1016/j.jamcollsurg.2006.04.004
M3 - Article
C2 - 16798486
AN - SCOPUS:33745213325
SN - 1072-7515
VL - 203
SP - 44
EP - 53
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 1
ER -