Lyle L. Moldawer

Glutamine or fiber supplementation of a defined formula diet: Impact on bacterial translocation, tissue composition, and response to endotoxin

Despite provision of adequate calories, defined formula diets in rats lead to bacterial translocation (BT), fatty infiltration of the liver, and an increased susceptibility to endotoxin. These deleterious effects may be due in part to a loss of intestinal barrier integrity resulting from bowel atrophy. Defined formula diets lack both glutamine and fiber, substances which may help maintain intestinal mass. To determine whether supplementation of defined formula diets with either glutamine or fiber might prevent bowel atrophy and, thus, BT, hepatic steatosis, and the altered response to endotoxin, Wistar rats were fed (1) defined formula diet ad libitum (DFD), (2) (DFD + 2% (w/v) glutamine, (GLUT), or (3) DFD + 2% (w/v) psyllium (FIBER). Rats given standard food isocalorically pair-fed to DFD were used as controls. Nutritional status was assessed by daily weight gain, as well as the ability to maintain serum albumin, hematocrit and white blood counts. After 2 weeks of these feeding regimens, animals were sacrificed, and organ weights and composition were determined, with rates of bacterial translocation determined by mesenteric lymph node, abdominal viscera, and cecal cultures. Additional animals receiving the same experimental diets were subsequently challenged with endotoxin and observed for mortality with rates of post-endotoxin BT and the responses of acute phase proteins and cytokines measured. All dietary regimens resulted in equivalent weight gain and other nutritional parameters. Both glutamine and fiber supplementation maintained small bowel mass, but only GLUT preserved normal jejunal mucosal architecture. Neither fiber nor glutamine supplementation prevented cecal bacterial overgrowth or BT, resulting from the DFD.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-1 TNFα and Their Naturally Occurring Antagonists in Sepsis

Recent evidence has demonstrated that specific inhibitors of the proinfiammatory cytokines, IL-1 and TNFα, circulate in the blood of healthy individuals and concentrations of these inhibitors are elev

The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock

Human neutrophil azurophilic granules contain an ∼55-kDa protein, known as bactericidal/permeabilityincreasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). Thein vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethalEscherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 μg/kg/min BPI infusion over 4 hr), while four additional animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Both wild-type rhBPI and NCY103 significantly (P<0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bacterial challenge. Two hours followingE. coli administration, LPS levels peaked in the controls, at 6.86±3.22 ng/ml, whereas LPS levels were 3.39±2.1 ng/ml in the BPI group and 2.04±1.18 ng/ml in the NCY103 group. Tumor necrosis factor-alpha (TNF-α) and interleukin-6 levels likewise were attenuated in the treatment groups, whereas circulating sTNFR I was significantly (P<0.05) reduced only in the BPI group. Leukocytopenia and granulocytopenia were significantly (P<0.02) lessened in the BPI group, by an average of 59% leukocytopenia and 65% granulocytopenia, respectively. This study supports the concept ofE. coli LPS neutralization by BPIin vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.

Effect of prostaglandin E in multiple experimental models. IV. Effect on resistance to endotoxin and tumor necrosis factor shock

Administration of a long-acting prostaglandin E, 16,16-dimethyl-PGE (dPGE), to rats improves their survival of bacterial peritonitis. We examined the mechanism of this protective effect with reference to its interaction with the release of cachectin (TNF). Sixty rats received saline, 20 micrograms/kg dPGE, or 80 micrograms/kg dPGE 12 hr prior to endotoxin and continuing for 48 hr. Survival rates for the saline, 20 micrograms/kg dPGE, and 80 micrograms/kg dPGE groups were 0, 40, and 85%, respectively. Forty rats received saline or 80 micrograms/kg dPGE, with the initial dose being 3 hr following endotoxin challenge and continuing for 48 hr. Survival rates for both groups were 0%. Sixty rats received saline or 80 micrograms/kg dPGE at 12 and 1 hr prior to endotoxin. Two hours after challenge, they were sacrificed and plasma TNF levels were assayed. The plasma TNF level in saline-treated rats was 22.72 +/- 0.83 ng/ml and in the dPGE-treated group, 16.03 +/- 1.13 ng/ml (P less than 0.001).