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Nonselective inhibition of nitric oxide (NO) with NO synthase antagonists decreases hypotension but worsens outcome clinically. We investigated whether iron (III) complex of diethylenetriaminepentaacetic acid [DTPA Fe(III)], a scavenger of NO as well as other oxidant mediators, has similar divergent effects in E. coli challenged rats. Methods: Animals with venous and arterial catheters and challenged with intrabronchial or intravenous E. coli were randomized to treatment with DTPA Fe(III) in doses from 3 to 800 mg/kg or placebo. Mean blood pressure (MBP) was measured in all animals and plasma NO, cytokines, and blood and lung leukocyte and bacteria counts in animals administered intrabronchial E. coli and DTPA Fe(III) 50 mg/kg or placebo. Animals received antibiotics and were observed 168 h. Results: Independent of drug regimen or infection site, compared to placebo, DTPA Fe(III) increased MBP although this was greater with high vs. lower doses. Despite increased MBP, DTPA Fe(III) worsened the hazards ratio of survival . At 6 and 24 h DTPA Fe(III) decreased NO but not significantly and decreased four cytokines (tumor necrosis factor-?, interleukins 1 and 10, and macrophage inflammatory protein 3?) and lung lavage neutrophils. From 6 to 24 h DTPA Fe(III) increased blood bacteria. Conclusions: DTPA Fe(III) while increasing blood pressure has the potential to worsen outcome in sepsis. Further preclinical testing is required before this agent is applied clinically. [ABSTRACT FROM AUTHOR]

Presents a study which investigated whether decreases in circulating polymorphonuclear neutrophils during lethal Escherichia coli sepsis in canines are related to insufficient host granulocyte colony-stimulating factor. Methodology; Results and discussion.

We investigated the effects of either intravenous (IV) or intrabronchial (IB) treatment with transforming growth factor β1 (TGF-β1) during bacterial pneumonia in rats. Immediately following IB Escherichia coli inoculation (T0), animals (n=270) were randomized to receive a single treatment with human recombinant TGF-β1 either via IV or IB, or via both IV and IB routes, or to receive placebo (human serum albumin, HSA) only. Blood and lung analysis was done at 6 and 168 h after E. coli inoculation. Other animals (n=40) were administered IV TGF-β1 or HSA at T0 and 6, 12 and 24 h after E. coli inoculation to investigate the effects of multiple treatments also on survival rates alone. All animals received ceftriaxone daily. Route of administration did not influence TGF-β1 (p=ns for the effect of TGF-β1 comparing IV vs IB routes) and we averaged over this variable in analysis. The relative risk of death (mean±sem) was not altered by either single treatments administered at T0 (−0.18±0.25, p=0.47) or multiple treatments (0.40±0.50, p=0.66) of TGF-β1. Single treatment with TGF-β1 first decreased and then increased vascular leukocytes at 6 and 168 h, respectively, but increased alveolar leukocytes at both time points (p=0.02 comparing the differing effects of TGF-β1 on vascular and alveolar leukocytes at 6 and 168 h). Although TGF-β1 decreased blood and lung bacteria counts at 6 and 168 h, it also increased serum tumor necrosis factor levels and lung injury scores at these time points (p<0.05 for the effects of TGF-β1 on each parameter at 6 and 168 h together). Thus, while increases in lung leukocyte recruitment with TGF-β1 were associated with improved microbial clearance in this rat model of pneumonia, worsened lung injury may have negated these beneficial host defense effects, and overall survival was not significantly improved. Despite these harmful effects, additional studies may be warranted to better define the influence of exogenous TGF-β1 on host defense during acute bacterial infections. [Copyright &y& Elsevier]