A Phosphodiesterase III Inhibitor Protects Rat Liver From Sinusoidal Obstruction Syndrome Through Heme Oxygenase-1 Induction

Abstract

In Brief 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. Sinusoidal obstruction syndrome induced by chemotherapy is of concern in hepatectomy for patients with hepatic colorectal metastases. We succeeded in inhibiting the occurrence of sinusoidal obstruction syndrome in a rat model through induction of heme oxygenase-1 by pretreatment with olprinone, a phosphodiesterase III inhibitor.