Background: Inflammatory cytokine activity is increased in many forms of ex
perimental and clinical liver injury including alcoholic liver disease (ALD
). Monocytes and Kupffer cells produce cytokines such as tumor necrosis fac
tor (TNF), interleukin (IL)-8, and IL-G in response to stimuli such as endo
toxin (lipopolysaccharide [LPS]). This cytokine production is regulated by
the oxidative stress-sensitive transcription factor NF kappa B. Glutathione
(GSH) prodrugs such as oxathizolidine-4-carboxylic acid (OTZ) can inhibit
activation of NF kappa B and subsequent cytokine production in monocytes an
d Kupffer cells in vitro. The objective of this study was to treat stable c
irrhotic patients with OTZ in vivo to evaluate its effects on monocyte cyto
kine production (TNF, IL-8, and IL-6) and whole blood GSH levels. Methods:
Nine patients with stable cirrhosis received OTZ (70 mg/kg ni every 8 hours
) for 9 days. Peripheral blood monocytes were obtained on study days 1 and
9, using density gradient centrifugation and adherence to plastic, and were
stimulated with LPS (5 mu g/mL). TNF, IL-8, and IL-6 were measured in cult
ure supernatants by enzyme-linked serum immunosorbent assay. Whole blood GS
H levels were measured by high-performance liquid chromatography. Results:
There was a significant decrease in monocyte TNF, IL-8, and IL-6 production
after OTZ therapy. Patients with cirrhosis had significantly lower admissi
on whole blood GSH levels compared with controls and GSH normalized with OT
Z administration. Conclusions: Treatment with the GSH prodrug OTZ inhibited
monocyte cytokine production and increased whole blood GSH. This may have
important therapeutic implications for multiple cytokine-mediated disease p
rocesses.