EFFECTS OF PENTOXIFYLLINE ON TUMOR-NECROSIS-FACTOR PRODUCTION AND SURVIVAL DURING LETHAL ESCHERICHIA-COLI SEPSIS VS DISSEMINATED CANDIDIASIS WITH FUNGAL SEPTIC SHOCK

Lethal circulatory shock during microbial sepsis is thought to be init iated by early molecular events, including production of tumor necrosi s factor (TNF) and cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The phosphodiesteras e inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and m odulates PMN function, and has been shown to improve outcome in experi mental sepsis. We hypothesized that PTX would attentuate gram-negative and fungal septic shock by different mechanisms: reduced TNF producti on in Escherichia coli (EC) sepsis vs. enhanced PMN-mediated defense d uring Candida albicans (CA) fungemia. Conscious chronically catheteriz ed rats received PTX (25 mg/kg, i.v.) before i.v. challenge with 10(10 ) viable EC (serotype 055:B5), 10(9) viable serotype A yeast-phase CA (each the LD100 in < 24 hr in naive rats), or normal sterile saline (N SS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment contro ls received NSS before and after challenge. Serum TNF peaked 1.5 hr af ter EC infection in NSS-treated animals (1654 +/- 390 U/ml, mean t SE) , and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), bu t PTX did not improve 24 hr survival. PTX also aggravated systemic hyp otension after EC, and did not modify neutropenia, thrombocytopenia, o r microvascular permeability assessed by organ wet/dry weight (W/D) ra tios. Peak serum TNF in CA + NSS animals (130 + 45 U/ml) was delayed 8 hr compared to EC animals, and were not reduced by PTX (67 +/- 25 U/m l, P = NS). Moreover, PTX did not alter CA-induced mortality, hypother mia, hypotension, neutropenia, increased lung W/D, or interstitial and alveolar hemorrhage. We conclude that PTX-induced suppression of endo genous TNF production does not prevent gram-negative shock in this mod el, possibly due to impaired TNF-mediated antibacterial host defense. Since fungal septic shock with acute disseminated candidiasis evolves prior to significant increases in circulating TNF, PTX also appears in effective in its treatment.