The septic shock syndrome that complicates severe infection is thought to result from inappropriate regulation of a cytokine network, in which overexpression of tumor necrosis factor a (TNF) plays a central role. Interactions between inflammatory responses mediated by TNF and TNF-induced interleukin-1 (IL-1), IL-8, eicosanoids, nitric oxide (NO), and neutrophils (PMNs), on the one hand, and changes in cardiovascular performance, microcirculatory patency, and coagulation/fibrinolytic cascades, on the other, determine sepsis-related tissue injury.'1' However, a dynamic balance between TNF-mediated predisposition to critical organ injury versus enhanced host defense suggests that either an excess or a deficiency of this cytokine is detrimental during sepsis. Accordingly, there is much interest in novel immunoadjuvant therapies with the potential to tissue factor gene in endotoxin-activated human monocytes,'5' and this may be independent of changes in IL-6 levels.'6' These consistent effects of PTX on the TNF signaling pathway that suppress TNF biosynthesis are shared by other PDEs, with the exception of theophylline,'7' in proportion to their enzymatic inhibition of PDE.With respect to the modulation of neutrophil functions relevant to host defense during sepsis, PTX has a number of complex effects that for the most part have been defined in vitro using recombinant cytokines, bacterial organisms, or their products. These include inhibitory effects on neutrophil adherence: such antiinflammatory effects of PTX could be of therapeutic value inasmuch as adherence of microbially activated and TNF-activated neutrophils to the vascular endothelium is a critical first step in pathological cellular interactions and sepsis-related tissue injury.'" The hemodynamic consequences during sepsis and effects on survivorship resulting from the actions of PTX remain unclear. In part, this seems related to differences among models, dosing regimens, and use of purified microbial products (e.g., lipopolysaccharide) versus viable organisms. Oral PTX decreases neither circulating TNF levels nor the hyperdynamic cardiovascular response in normal humans given endotoxin,'8' but cytokine levels were reduced in models of group B Streptococcus spp. neonatal sepsis and Escherichia coli septic shock.'9-10' An array of cardiovascular, microcirculatory, and immunomodulatory effects induced by PTX in such models beneficially influence organ function and outcome. These include (1) increased cardiac output, (2) induction of prostacyclin in vascular endothelium, (3) reduction in PMN adhesiveness, pulmonary leukostasis, and lung extravascular protein accumulation, (4) improved capillary patency, (5) decreased hepatic and splenic sinusoidal damage, (6) restoration of TNF-a-induced depression of PMN chemotactic activity, and (7) downregulation of superoxide radical production. Nonetheless, a causal relation with suppression of TNF remains unproved.We previously showed that the magnitude and kinetics of TNF production and TNF-dependent immunophysiological r...