Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice.

ABSTRACT

BACKGROUND/AIMS: We have investigated the role of the nitric oxide (NO) and prostaglandins (PGs), respectively, synthesized by nitric oxide synthase 2 (NOS-2) and cyclooxygenase-2 (COX-2), in the outcome of liver regeneration after partial hepatectomy (PH). METHODS: Liver mass recovery and molecular parameters related to cell proliferation and apoptotic death have been determined. RESULTS: NOS-2 and COX-2 are normally both expressed in the remnant liver after PH, and inhibition of either one delays regeneration. We found, however, that simultaneous suppression of the activities of NOS-2 (by gene knockout) and COX-2 (by pharmacological inhibition) resulted in animal death between 24 and 72 h after PH. Analysis of liver mass recovery and molecular parameters related to cell proliferation and apoptotic death revealed increased liver-cell apoptosis and an insufficient proliferative response. Broad-specificity caspase inhibitors, such as z-Val-Ala-Asp.fmk (z-VAD), or administration of NO-donors, rescued animals from death, revealing a critical apoptotic bias at this stage of proliferation. CONCLUSIONS: These findings demonstrate that simultaneous signaling by NO and prostaglandins plays an important role in the mechanism of liver regeneration after PH by protecting the remnant tissue from apoptotic death.