Heme arginate pretreatment attenuates pulmonary NF-kappaB and AP-1 activation induced by hemorrhagic shock via heme oxygenase-1 induction.
Hemorrhagic shock followed by resuscitation (HSR) induces oxidative stress that leads to acute lung injury. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to play an important role in the protection from oxidative tissue injuries. We previously demonstrated that HO-1 induction by heme arginate (HA), a strong inducer of HO-1, ameliorated HSR-induced lung injury and inflammation. Cellular redox state is known to modulate the DNA biding activity of the transcription factors; nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In the present study, we treated rats with HA (30 mg/kg of hemin) 18 h prior to HSR and examined its effect on the DNA binding activity of NF-kappaB and AP-1 at 1.5 h after HSR. HSR significantly increased the DNA binding activity of NF-kappaB as well as AP-1, while HA pretreatment markedly attenuated the activities of these transcription factors. In contrast, administration of tin mesoporphyrin, a specific competitive inhibitor of HO activity, to HA-pretreated animals abolished the suppressive effect of HA on the activities of NF-kappaB and AP-1, and increased these activities to almost the same level as those in HSR animals. Our findings indicate that HA pretreatment can significantly suppress the increased activity of NF-kappaB and AP-1 induced by HSR by virtue of its ability to induce HO-1. Our findings also suggest that HO-1 induced by HA pretreatment ameliorates HSR-induced lung injury at least in part mediated through the suppression of the activities of these transcription factors.
Sasaki
T
T
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine and Dentistry, Japan.
Takahashi
T
T
Maeshima
K
K
Shimizu
H
H
Toda
Y
Y
Morimatsu
H
H
Takeuchi
M
M
Yokoyama
M
M
Akagi
R
R
Morita
K
K
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D006418:Heme; D001120:Arginine; D006419:Heme Oxygenase (Decyclizing); C048849:heme arginate