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 eff ects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infecti on) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria (Escherichia coli). PX trea tment prevented the increase in plasma tumor necrosis factor (TNF)-alp ha (peak 1.5 h after the infection) and resulted in an 84 and 61% inhi bition of plasma interleukin (IL)-1 beta and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the trea tment. Infection increased alpha(1)-acid glycoprotein (AGP), alpha(2)- macroglobulin (A2M), and fibrinogen plasma concentrations and decrease d albumin levels. PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen pla sma levels only at day 6. The treatment had no effect on the albumin p lasma concentration. Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of alb umin were decreased. Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals. PX was ineffective i n modifying those of A2M and albumin. These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sep sis. The in vivo effects of PX treatment support the hypothesis that T NF-a plays an important role in the regulation of AGP production, wher eas other factors seem to be involved in the regulation of A2M, fibrin ogen, and albumin expression.