TY - JOUR
T1 - Role of PARP on iNOS pathway during endotoxin-induced acute lung injury
AU - Kiefmann, Rainer
AU - Heckel, Kai
AU - Doerger, Martina
AU - Schenkat, Sonja
AU - Kupatt, Christian
AU - Stoeckelhuber, Mechthild
AU - Wesierska-Gadek, Józefa
AU - Goetz, Alwin E.
PY - 2004/7
Y1 - 2004/7
N2 - 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.
AB - 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.
KW - AP-1
KW - Acute lung injury
KW - NF-κB
KW - Nitric oxide
KW - Poly (ADP-ribose) polymerase (PARP)
UR - http://www.scopus.com/inward/record.url?scp=3242737290&partnerID=8YFLogxK
U2 - 10.1007/s00134-004-2301-x
DO - 10.1007/s00134-004-2301-x
M3 - Article
C2 - 15197441
AN - SCOPUS:3242737290
SN - 0342-4642
VL - 30
SP - 1421
EP - 1431
JO - Intensive Care Medicine
JF - Intensive Care Medicine
IS - 7
ER -