title: Role of PARP on iNOS pathway during endotoxin-induced acute lung injury.
abstract: OBJECTIVE
  Excessive nitric oxide (NO) and especially peroxynitrite may cause pulmonary tissue damage, e.g., through lipid peroxidation and/or exhaustion of cellular energy depletion induced by activation of poly (ADP-ribose) polymerase (PARP). Furthermore, PARP seems to aggravate tissue destruction by regulating the expression of respective genes.
  
  
  METHODS
  Prospective animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  We investigated the effect of competitive PARP inhibition by 3-aminobenzamide (3-AB) on the pulmonary iNOS pathway after infusion of lipopolysaccharide (LPS).
  
  
  RESULTS
  The pretreatment of rabbits with 3-AB attenuated the LPS-induced iNOS mRNA and protein expression analyzed by RT-PCR and Western blot, and plasma nitrite concentrations quantified by Griess reaction (71+/-6%, 93+/-6% vs baseline). Electromobility shift assay showed an enhanced NF-kappaB and attenuated AP-1 activation after 3-AB vs LPS alone. Lipid peroxidation determined as levels of thiobarbituric acid reactive substances in plasma and lung tissue was reduced by 50% in the LPS+3-AB in comparison to LPS alone. Simultaneously, 3-AB was able to inhibit correspondingly the LPS-induced extravasation of gold-labeled albumin and increase of alveolo-arterial oxygen difference.
  
  
  CONCLUSIONS
  PARP regulates the pulmonary NO pathway during endotoxemia via AP-1 and not NF-kappaB. Thus, pharmacological inhibition of PARP might be an effective intervention to prevent endotoxin-induced lung injury, interrupting the vicious circle of NO production and PARP activation.
authors.affiliation: Department of Anesthesiology, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kiefmann
authors.forename: Kai
authors.initials: K
authors.lastname: Heckel
authors.forename: Martina
authors.initials: M
authors.lastname: Doerger
authors.forename: Sonja
authors.initials: S
authors.lastname: Schenkat
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.forename: Mechthild
authors.initials: M
authors.lastname: Stoeckelhuber
authors.forename: Józefa
authors.initials: J
authors.lastname: Wesierska-Gadek
authors.forename: Alwin E
authors.initials: AE
authors.lastname: Goetz
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D001549:Benzamides; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C025160:3-aminobenzamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases