Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome
✍ Scribed by Laurie D. Deleve; Xiangdong Wang; Gary C. Kanel; Yoshiya Ito; Nancy W. Bethea; Margaret K. McCuskey; Zoltan A. Tokes; Jeffrey Tsai; Robert S. McCuskey
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 979 KB
- Volume
- 38
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vim microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in uitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion. (HEPATOLOGY 2003;38:900-908.) inusoidal obstruction syndrome (SOS) is a major cause of morbidity and mortality in patients who S undergo myeloablative hematopoietic stem cell transplantation for malignancy. The published incidence