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.

Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis.

Plasma albumin is well known to decrease in response to inflammation. The rate of albumin synthesis from both liver and plasma was measured in vivo by use of a large dose of L-[(2)H(3)-(14)C]valine in rats injected intravenously with live Escherichia coli and in pair-fed control rats during the acute-phase period (2 days postinfection). The plasma albumin concentration was reduced by 50% in infected rats compared with pair-fed animals. Infection induced a fall in both liver albumin mRNA levels and albumin synthesis relative to total liver protein synthesis. However, absolute liver albumin synthesis rate (ASR) was not affected by infection. In plasma, albumin fractional synthesis rate was increased by 50% in infected animals compared with pair-fed animals. The albumin ASR estimated in the plasma was similar in the two groups. These results suggest that hypoalbuminemia is not due to reduced albumin synthesis during sepsis. Moreover, liver and plasma albumin ASR were similar. Therefore, albumin synthesis measured in the plasma is a good indicator of liver albumin synthesis.