TNF-alpha and cyclooxygenase metabolites do not modulate C. albicans septic shock with disseminated candidiasis

Abstract

We analyzed differences in host regulation of tumor necrosis factor-alpha (TNF-alpha) production and pathophysiological responses in conscious rats after infection with two strains of pathogenic Candida albicans spp. (CA-1 and CA-2) compared with Escherichia coli serotype 055:B5 (EC). The hypothesis was tested that, in contrast to EC, hypotension, organ injury, and mortality after candidemia are not obligatorily dependent on TNF-alpha or TNF-alpha-induced cyclooxygenase pathway metabolites. Dose, viability, and strain-specific dependencies were established after intravenous 10(6) or 10(9) viable CA, as well as heat-killed (HK) or Formalin-inactivated (FI) CA blastospores, compared with live EC at the 24-h LD25 [10(9) colony-forming units (CFU)] and LD100 (10(10) CFU). Shock without endotoxemia developed 4-8 h after 10(9) live CA-1 or CA-2 (LD100 at 24 h) with disseminated yeast-mycelial transformation and increased microvascular permeability in multiple organs but not after HK or FI CA-1. Peak serum TNF-alpha after an LD100 of CA-1 or CA-2 was < 3% of LD25 EC values and was < 1% of peak values during lethal bacteremia. Similar pathogen-specific differences were found in liver- and lung-associated TNF. Production of functionally inactive TNF-alpha during candidemia was excluded by enzyme-linked immunosorbent assay and sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting. Passive immunization against TNF-alpha 2 h before microbial challenge was not protective against CA but prevented otherwise lethal EC sepsis. Cyclooxygenase inhibition also failed to attenuate candidemic shock. We conclude that the magnitude and kinetics of TNF-alpha production and TNF-alpha-dependent immunophysiological responses are differentially regulated after lethal fungal vs. gram-negative bacterial infection. Thus TNF-alpha is not a pivotal mediator of the acute Candida septic shock syndrome with disseminated candidiasis.

Acute lung injury during bacterial or fungal sepsis

“…If host defense is impaired or inappropriately regulated, these microbiological features synergize with, or are amplified by, host-derived in-flammatory responses, thereby predisposing to the ALI and multiple organ injury seen in the septic shock syndrome (Dinarello, 1991;Marshall et al, 1988;Natanson et al, 1989). The results described here, combined with supporting hemodynamic, hematological, and microbiological data reported elsewhere (Lechner et al, 1992(Lechner et al, , 1993Matuschak et al, 1993), necessitate revision of this paradigm by demonstrating that the type, severity, and timing of ALI differ between bacteria and fungi. These striking differences in ALI were found despite many physiological similarities in the shock syndromes induced by each organism.…”

An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

“…The present study demonstrated that inhalation of ONO-1714 reduced the tissue injury caused by peroxynitrite and suppressed the production of iNOS locally in the lung. Our results for the W/D ratio conflict with the finding of Okamoto et al (37) was injected into mice intravenously (1,26,32). Our results agree with those of a study by Kristof et al (23), using mice lacking the iNOS gene.…”

Cytokines and fungal infections

“…The role of TNF‐ α in the development of protective Th1 responses was demonstrated in animal models of candidiasis, aspergillosis and cryptococcosis (Mencacci et al , 2000a; Bauman et al , 2003). Interestingly, and in contrast to what happens in gram‐negative bacterial infections, TNF‐ α is not a pivotal mediator of the acute septic shock syndrome associated with disseminated candidiasis (Matuschak et al , 1993).…”