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A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction.

Authors: Narita, M  Hatano, E  Ikai, I  Miyagawa-Hayashino, A  Yanagida, A  Nagata, H  Asechi, H  Taura, K  Uemoto, S 
Citation: Narita M, etal., Ann Surg. 2009 May;249(5):806-13.
Pubmed: (View Article at PubMed) PMID:19387321
DOI: Full-text: DOI:10.1097/SLA.0b013e3181a38ed5

OBJECTIVE: The aim of study was to investigate pharmacological treatment for sinusoidal obstruction syndrome (SOS). BACKGROUND: SOS is associated with oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. Patients with SOS have increased postoperative morbidity after major hepatectomy, but a method for effective prevention of SOS has not been established. METHODS: Male Sprague-Dawley rats were treated with cobalt protoporphyrin IX (CoPP) or olprinone (OLP), a phosphodiesterase III inhibitor, and hepatic HO-1 expression and HO enzymatic activity were determined. Monocrotaline (MCT) was given to rats to induce SOS, and blockage of SOS by CoPP or OLP-induced hepatic HO-1 was examined in these rats. Zinc protoporphyrin IX (ZnPP), a competitive HO inhibitor, was given to MCT-treated rats together with OLP to clarify the mechanism of protection against SOS. We also examined if OLP preserved remnant liver function after 70% hepatectomy in MCT-treated rats. RESULTS: OLP up-regulated hepatic HO-1 protein expression and HO enzymatic activity, and activated Akt protein. Administration of ZnPP to OLP-treated rats resulted in inhibition of HO activity and inactivation of Akt. Induction of HO-1 by pretreatment with CoPP led to amelioration of SOS in histologic findings and blockage of elevation of serum liver enzymes. Pretreatment with OLP gave a similar result and preserved remnant liver function, as indicated by improved survival after hepatectomy. ZnPP completely abolished the protective effects of OLP. CONCLUSIONS: Protection of the liver from drug-induced injury by prior up-regulation of HO-1 using OLP may have potential as a therapeutic strategy for prevention of SOS.


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CRRD Object Information
CRRD ID: 4145318
Created: 2010-10-29
Species: All species
Last Modified: 2010-10-29
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.