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-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. CONCLUSION: 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.
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-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. CONCLUSION: 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: Helder Mota-Filipe; Bruno Sepodes; Michelle C McDonald; Salvatore Cuzzocrea; Rui Pinto; Christoph Thiemermann Journal: Med Sci Monit Date: 2002-11
Authors: Rosanna Vaschetto; Jan W Kuiper; Shyh Ren Chiang; Jack J Haitsma; Jonathan W Juco; Stefan Uhlig; Frans B Plötz; Francesco Della Corte; Haibo Zhang; Arthur S Slutsky Journal: Anesthesiology Date: 2008-02 Impact factor: 7.892
Authors: Adam I Kaplin; Deepa M Deshpande; Erick Scott; Chitra Krishnan; Jessica S Carmen; Irina Shats; Tara Martinez; Jennifer Drummond; Sonny Dike; Mikhail Pletnikov; Sanjay C Keswani; Timothy H Moran; Carlos A Pardo; Peter A Calabresi; Douglas A Kerr Journal: J Clin Invest Date: 2005-09-22 Impact factor: 14.808