Role of PARP on iNOS pathway during endotoxin-induced acute lung injury

Rainer Kiefmann, Kai Heckel, Martina Doerger, Sonja Schenkat, Christian Kupatt, Mechthild Stoeckelhuber, Józefa Wesierska-Gadek, Alwin E. Goetz

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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. Design: Prospective animal study. Setting: University research laboratory. Intervention: We investigated the effect of competitive PARP inhibition by 3-aminobenzamide (3-AB) on the pulmonary iNOS pathway after infusion of lipopolysaccharide (LPS). Measurements and 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-κB 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. Conclusion: PARP regulates the pulmonary NO pathway during endotoxemia via AP-1 and not NF-κB. 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.

Original languageEnglish
Pages (from-to)1421-1431
Number of pages11
JournalIntensive Care Medicine
Volume30
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

Keywords

  • AP-1
  • Acute lung injury
  • NF-κB
  • Nitric oxide
  • Poly (ADP-ribose) polymerase (PARP)

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