Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats

To explore the regulation of the acute phase response in vivo, the effects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infection) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria (Escherichia coli). PX treatment prevented the increase in plasma tumor necrosis factor (TNF)-alpha (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1beta and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the treatment. Infection increased alpha1-acid glycoprotein (AGP), alpha2-macroglobulin (A2M), and fibrinogen plasma concentrations and decreased albumin levels. PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen plasma levels only at day 6. The treatment had no effect on the albumin plasma concentration. Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of albumin were decreased. Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals. PX was ineffective in modifying those of A2M and albumin. These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sepsis. The in vivo effects of PX treatment support the hypothesis that TNF-alpha plays an important role in the regulation of AGP production, whereas other factors seem to be involved in the regulation of A2M, fibrinogen, and albumin expression.