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

Abstract

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)-α (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1β and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the treatment. Infection increased α1-acid glycoprotein (AGP), α2-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-α 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.

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

“…The fact that IL-1 neutralization prevents IGF-I inhibition caused by LPS further strengthens this interpretation . Another possibility could be that IL-6 levels, which are less affected by pentoxifylline (Voisin et al 1998), might be able to inhibit IGF-I expression. This hypothesis is suggested by recent observations showing that IL-6 is able to inhibit basal IGF-I expression in vitro (Lelbach et al 2001) and to stimulate gene expression of SOCS-3 which exerts a negative feed-back loop controlling GH action (Ram & Waxman 1999, Colson et al 2000.…”

“…Pentoxifylline, a methylxanthine which is usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit the synthesis of TNF-in several inflammatory states, in particular in LPS-treated animals (Schade 1990, Lundblad et al 1995, Staudinger et al 1996, Voisin et al 1998. Therefore, pentoxifylline represents a useful tool for exploring the role of TNF-in the decline of IGF-I induced by LPS.…”

The Role of Inflammatory Cytokines in Diabetic Nephropathy

“…120,121 In addition, PTF shows a significant effect in modulating IFN-␥, IL-1␤, and IL-6. [122][123][124] In different models of renal disease where TNF-␣ plays a central role, such as lupus nephritis and crescentic glomerulonephritis, PTF prevents or attenuates renal injury. 125,126 Regarding diabetic nephropathy, recent experimental studies show that administration of PTF prevents an increase in renal expression, synthesis, and excretion of TNF-␣ during diabetes, which was directly and significantly associated with a reduction in renal sodium retention, renal hypertrophy, and urinary albumin excretion.…”

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease

“…11,12 Pentoxifylline (PTF) is a methylxanthine derivate and nonspecific phosphodiesterase inhibitor clinically used to treat patients with occlusive peripheral vascular disorders for more than 30 years. In addition to its rheologic properties, PTF has anti-inflammatory, antiproliferative, and antifibrotic actions [13][14][15][16][17] that have been associated with beneficial effects in experimental models of renal disease progression. 18,19 We previously reported that PTF administration to diabetic patients resulted in the reduction of clinical markers of glomerular and tubulointerstitial injury.…”