Lethal circulatory
shock during microbial
sepsis is thought to be initiated by early molecular events, including production of
tumor necrosis factor (TNF) and
cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The
phosphodiesterase inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and modulates PMN function, and has been shown to improve outcome in experimental
sepsis. We hypothesized that PTX would attenuate gram-negative and fungal
septic shock by different mechanisms: reduced TNF production in Escherichia coli (EC)
sepsis vs. enhanced PMN-mediated defense during Candida albicans (CA)
fungemia. Conscious chronically catheterized 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 (NSS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment controls received NSS before and after challenge. Serum TNF peaked 1.5 hr after EC
infection in NSS-treated animals (1654 +/- 390 U/ml, mean +/- SE), and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), but PTX did not improve 24 hr survival. PTX also aggravated systemic
hypotension after EC, and did not modify
neutropenia,
thrombocytopenia, or microvascular permeability assessed by organ wet/dry weight (W/D) ratios. 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/ml, P = NS). Moreover, PTX did not alter CA-induced mortality,
hypothermia,
hypotension,
neutropenia, increased lung W/D, or interstitial and alveolar
hemorrhage. We conclude that PTX-induced suppression of endogenous TNF production does not prevent gram-negative
shock in this model, 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 ineffective in its treatment.