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The Poly(Adenosine Diphosphate-Ribose) Polymerase Inhibitor PJ34 Reduces Pulmonary Ischemia-Reperfusion Injury in Rats

Hatachi, Go1; Tsuchiya, Tomoshi1; Miyazaki, Takuro1; Matsumoto, Keitaro1; Yamasaki, Naoya1; Okita, Naoyuki2; Nanashima, Atsushi1; Higami, Yoshikazu2; Nagayasu, Takeshi1,3

doi: 10.1097/TP.0000000000000305
Basic and Experimental Research

Background: Ischemia-reperfusion (I/R) injury after lung transplantation causes alveolar damage, lung edema, and acute rejection. Poly(adenosine diphosphate-ribose) polymerase (PARP) is a single-stranded DNA repair enzyme that induces apoptosis and necrosis after DNA damage caused by reactive oxygen species. We evaluated tissue protective effects of the PARP inhibitor (PARP-i) PJ34 against pulmonary I/R injury.

Methods: Rats (total n=45) underwent a thoracotomy with left hilar isolation and saline administration (sham group) or thoracotomy with hilar clamping and saline administration (I/R group) or PJ34 administration (PARP-i group). Parameters were measured for 7 days after reperfusion.

Results: Pathologic analysis revealed that reperfusion injury was drastically suppressed in the PARP-i group 2 days after reperfusion. Terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling–positive cells were significantly decreased in the PARP-i group compared to the I/R group (P<0.05). Accordingly, the wet-to-dry lung ratio in the I/R group was significantly higher compared with the PARP-i group (P=0.025). Four hours after reperfusion, serum tissue necrosis factor-α and interleukin-6 were significantly suppressed in the PARP-i group compared with the I/R group (P<0.05). Serum derivatives of reactive oxygen metabolites increased quickly and remained high in the I/R and PARP-i groups from 4 hr until 7 days after reperfusion. Interestingly, the serum biologic antioxidant potential in the PARP-i group was significantly higher than that in the I/R group from day 2 until day 7.

Conclusion: The PARP-i decreased inflammation and tissue damage caused by pulmonary I/R injury. These beneficial effects of the PARP-i may be correlated with its antioxidative efficacy.

1 Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

2 Section of Pharmacology, Drug Metabolism & Molecular Pathology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan.

3 Address correspondence to: Takeshi Nagayasu, M.D., Ph.D., Division of Surgical Oncology, Department of Surgery Nagasaki University Graduate School of Biomedical Sciences 1-7-1 Sakamoto Nagasaki City, Nagasaki 852-8501, Japan.

The present study, ‘Poly(adenosine diphosphate-ribose) Polymerase Inhibitor (PJ34) Reduces Pulmonary Ischemia-Reperfusion Injury in Rats’, was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 23592066).

The authors declare no conflicts of interest.

E-mail: nagayasu@nagasaki-u.ac.jp

G.H. participated in research design, performance of research, and writing of the article. T.T. participated in financial support, research design, and writing of the article. T.M. participated in the performance of the research. K.M. participated in the performance of the research. N.Y. participated in the performance of the research. N.O. participated in research design. Y.H. participated in research design and evaluation of the research. A.N. participated in the performance of the research. T.N. participated in research design and evaluation of the research.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 16 August 2013. Revision requested 10 September 2013.

Accepted 7 May 2014.

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