title: Administration of poly(ADP-ribose) polymerase inhibitor into bronchial artery attenuates pulmonary pathophysiology after smoke inhalation and burn in an ovine model.
abstract: Poly(ADP-ribose) polymerase (PARP) is well known to be an enzyme that repairs damaged DNA and also induces cell death when overactivated. It has been reported that PARP plays a significant role in burn and smoke inhalation injury, and the pathophysiology is thought to be localized in the airway during early stages of activation. Therefore, we hypothesized that local inhibition of PARP in the airway by direct delivery of low dose PJ-34 [poly(ADP-ribose) polymerase inhibitor] into the bronchial artery would attenuate burn and smoke-induced acute lung injury. The bronchial artery in sheep was cannulated in preparation for surgery. After a 5-7 day recovery period, sheep were administered a burn and inhalation injury. Adult female sheep (n=19) were divided into four groups following the injury: (1) PJ-34 group A: 1h post-injury, PJ-34 (0.003mg/kg/h, 2mL/h) was continuously injected into the bronchial artery, n=5; (2) PJ-34 group B: 1h post-injury, PJ-34 (0.03mg/kg/h, 2mL/h) was continuously injected into bronchial artery, n=4; (3) CONTROL GROUP: 1h post-injury, an equivalent amount of saline was injected into the bronchial artery, n=5; (4) Sham group: no injury, no treatment, same operation and anesthesia, n=5. After injury, all animals were placed on a ventilator and fluid resuscitated equally. Pulmonary function as evaluated by measurement of blood gas analysis, pulmonary mechanics, and pulmonary transvascular fluid flux was severely deteriorated in the control group. However, the above changes were markedly attenuated by PJ-34 infusion into the bronchial artery (P/F ratio at 24h: PJ-34 group A 398±40*, PJ-34 group B 438±41*†‡, Control 365±58*, Sham 547±47; * vs. sham [p<0.05], † vs. control [p<0.05], ‡ vs. PJ-34 group A [p<0.05]). Our data strongly suggest that local airway production of poly(ADP-ribose) polymerase contributes to pulmonary dysfunction following smoke inhalation and burn.
authors.affiliation: Tokyo Woman's Medical University, Department of Plastic and Reconstructive Surgery, Tokyo, Japan. a.hamahata@gmail.com
authors.forename: Atsumori
authors.initials: A
authors.lastname: Hamahata
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shimoda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakazawa
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001981:Bronchial Arteries / Q000187:drug effects; D002056:Burns / Q000188:drug therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D008168:Lung / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012129:Respiratory Function Tests; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors