title: The poly(adenosine diphosphate-ribose) polymerase inhibitor PJ34 reduces pulmonary ischemia-reperfusion injury in rats.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Go
authors.initials: G
authors.lastname: Hatachi
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Takuro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Okita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nanashima
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D004260:DNA Repair; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy*; D013908:Thoracotomy; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000975:Antioxidants; D015850:Interleukin-6; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate