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

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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.

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Acknowledgement

The writers thank K. Messmer and K. Peter for their helpful support. The technical assistance of Alke Schropp, Elke Schütze, Silvia Münzing, and Anne-Marie Allmeling are acknowledged

Author information

Authors and Affiliations

  1. Department of Anesthesiology, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany

    Rainer Kiefmann, Kai Heckel & Alwin E. Goetz

  2. Institute for Surgical Research, University of Munich, Munich, Germany

    Martina Doerger & Sonja Schenkat

  3. Department of Medicine, University of Munich, Munich, Germany

    Christian Kupatt

  4. Institute for Anatomy II, University of Munich, Munich, Germany

    Mechthild Stoeckelhuber

  5. Institute for Cancer Research, University of Vienna, Austria

    Józefa Wesierska-Gadek

Authors
  1. Rainer Kiefmann
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  2. Kai Heckel
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  3. Martina Doerger
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  4. Sonja Schenkat
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  5. Christian Kupatt
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  6. Mechthild Stoeckelhuber
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  7. Józefa Wesierska-Gadek
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  8. Alwin E. Goetz
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Corresponding author

Correspondence to Alwin E. Goetz.

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Conflict of interest statement: all authors state that there are no conflicts of interest

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Kiefmann, R., Heckel, K., Doerger, M. et al. Role of PARP on iNOS pathway during endotoxin-induced acute lung injury. Intensive Care Med 30, 1421–1431 (2004). https://doi.org/10.1007/s00134-004-2301-x

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  • DOI: https://doi.org/10.1007/s00134-004-2301-x

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