Effects of pentoxifylline on tumor necrosis factor production and survival during lethal E. coli sepsis vs. disseminated candidiasis with fungal septic shock.
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.
Lechner
A J
AJ
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, MO 63104.
Rouben
L R
LR
Potthoff
L H
LH
Tredway
T L
TL
Matuschak
G M
GM
D000818:Animals; D016470:Bacteremia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D016469:Fungemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline