Experimental lipid A-induced nephritis in the dog

Westenfelder, M.; Galanos, Chris

doi:10.1007/bf01641456

Cited by 27 publications

(10 citation statements)

References 9 publications

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“…It has been shown that endotoxin is distributed throughout the kidney (17). An autoradiographic study (32) showed that lipid A, the active component of endotoxin, can be recovered within the tubular cells of the renal cortex. Shands (23) has shown that endotoxin may interact with the biological membrane by edge attachment.…”

Section: Resultsmentioning

confidence: 99%

Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats

Tardif

Beauchamp

Bergeron

1990

Antimicrob Agents Chemother

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The mechanism by which endotoxin (lipopolysaccharide [LPS]) modifies the intrarenal distribution and the nephrotoxic potential of gentamicin is unknown. We studied the influence of LPS on the intracortical accumulation kinetics of gentamicin in rats infused intravenously for 6 h, during which time steady-state levels of the antibiotic in serum were achieved. We compared gentamicin accumulation rates (V) in normal rats and in rats receiving LPS (0.5 and 5 mg/kg) as levels in serum (S) varied from 0.5 to 130 ,ug/ml. The pharmacokinetic parameters of gentamicin were previously measured in the three groups of rats that were studied in order to reach and maintain in each rat the desired levels of antibiotic in serum during the 6 h of infusion. Two hours before the infusion of gentamicin, LPS was injected intravenously over a period of 15 min. In normal rats, the increase in S was associated with a nonlinear increase in V. The Michaelis-Menten kinetics, which was the best-fitting function, gave an apparent Vn,, (maximal capacity of uptake) of 195.03 + 9.75 ,g/g per h and an apparent K. (concentration in serum at Vu.m/2, an index of affinity) of 34.91 ± 4.45 ,ug/ml (linear transformation of the experimental data by the Hanes-Woolf plot: r = 0.93, n = 85). In the rats that received LPS, the increase in S was associated with a linear increase of V: for LPS at 0.5 mg/kg, V = 27.00 + 1.50 S (r = 0.94, n = 80); for LPS at 5 mg/kg, V = 22.72 + 1.48 S (r = 0.94, n = 75). We conclude that endotoxin modifies the accumulation kinetics of gentamicin in the kidney cortices of rats.The nephrotoxic potential of gentamicin has been studied extensively. Following glomerular filtration, this aminoglycoside is reabsorbed into the proximal tubular cells by pinocytosis and is accumulated in lysosomes (11,25,31), where it interferes with the normal catabolism of phospholipids, leading to cellular disturbance and necrosis (14).Previous studies done in our laboratory have shown that endotoxin which is liberated during antibiotic therapy (24) disturbs the intrarenal pharmacokinetics of gentamicin (2). In fact, endotoxin-treated animals had higher levels of drug in serum and accumulated a greater amount of gentamicin in their renal cortices and medullae than normal rats did (2). Bergeron et al. (3) have shown, using autoradiography, an increased uptake of labeled tobramycin by renal proximal tubular cells in endotoxemic animals compared with that in normal rats. More recently, it has been observed that endotoxin increased the nephrotoxic potential of gentamicin and of the combination vancomycin-gentamicin (M. Ngeleka, D. Beauchamp, D. Tardif, P. Auclair, P. Gourde, and M. G. Bergeron, J. Infect. Dis., in press).Numerous systemic effects have been observed following endotoxin injection: disturbance of the hemodynamic status of the host (7, 27), induction of vasoconstriction (26), and activation of the immunological and inflammatory processes (5). On the other hand, endotoxin can act directly on cells and organelles (16). Whether endotoxin modif...

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Section: Resultsmentioning

confidence: 99%

Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats

Tardif

Beauchamp

Bergeron

1990

Antimicrob Agents Chemother

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“…As with aminoglycoside therapy, lysosomes are also target organelles (6,7,16) of endotoxin. Endotoxin is distributed throughout the kidneys (9,18), and autoradiographic studies have shown that lipid A, the active component of endotoxin, can be recovered within the tubular cells of the renal cortex (28). Manny et al (17) observed that endotoxin induced rupture of lysosomal membranes and swelling of the mitochondria of proximal and distal tubules in the kidneys of dogs.…”

Section: Discussionmentioning

confidence: 99%

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Bergeron¹,

Bergeron²

1986

Antimicrob Agents Chemother

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Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In this study, we investigated the influence of Escherichia coli endotoxin on the renal handling of several aminoglycosides and one cephalosporin. Drug levels in the renal parenchyma, as well as several parameters of renal function and histology, were compared in rats treated with endotoxin (0.25 mg/kg) and normal rats treated with either gentamicin (10 mg/kg), netilmicin (10 mg/kg), tobramyin (10 mg/kg), amikacin (50 mg/kg), or cephalothin (100 mg/kg). Blood pressure and pulse rate were recorded. Endotoxin was associated with a decrease in the half-life and in the apparent volume of distribution of gentamnicin. The endotoxin-injected animals accumulated significantly (P < 0.05) more aminoglycosides in their kidneys than the normal animals. The amount of cephalothin recovered in the renal parenchyma was identical in both groups. Slight decreases in the glomerular filtration rate and renal plasma flow were observed after endotoxin treatment. Blood pressure and cardiac frequency were minimally affected by endotoxin. No histological lesions were observed by light microscopy in animals receiving endotoxin. Thus, endotoxin modifies the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological change. By increasing the total amount of drug within the kidneys, endotoxin might increase the nephrotoxic potential of aminoglycosides.Previous studies done in our laboratory revealed that the intrarenal distribution of gentamicin was disturbed in experimental pyelonephritis due to Escherichia coli (5). A greater accumulation of drug was observed in the cortex and medulla of pyelonephritic animals than in the kidneys of noninfected animals. Pyelonephritic kidneys were also shown to be more susceptible tp'the nephrotoxic potential of gentamicin than normal kidneys (2). Pyelonephritic animals treated with gentamicin showed signs of renal damage which were more striking than those observed in normal treated rats. We considered the possibility that endotoxin liberated during antibiotic therapy (13, 25) might have disturbed the intrarenal pharmacokinetics of gentamicin and acted concomitantly with gentamicin on tubular cells to potentiate the toxicity of this antibiotic. The purpose of the present study was to evaluate the influence of endotoxin on the intrarenal distribution of aminoglycosides.MATERIALS AND METHODS Experimental model: distribution studies. Female SpragueDawley rats weighing 175 to 200 g were used for all experiments. Sixteen groups of 5 to 11 animals were anesthetized by a single intraperitoneal injection of sodium pentobarbital (45 mg/kg), followed 2 h later by a second dose of 20 mg/kg. Four animals, two controls and two endotoxintreated rats, were used in parallel each day. Catheters were inserted into the right jugular vein for infusion of solutions. E. coli 0127:B8 endotoxin (0.25 mg/kg; Difco Laboratories, Detroit, Mich.) or normal saline was infused intr...

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“…PFC formation was easily detected in tissue culture flasks and tubes, but not in microplates. It is also possible that the state of the supporting serum could be of importance, since human sera can contain anti-LPS as well as anti-lipid A antibodies [53,541. However, we have used sera obtained from various donors and also used fetal calf serum as a supplement and not found any obvious differences (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide and lipid A‐induced human blood lymphocyte activation as detected by a protein A plaque assay

et al. 1979

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Various purified cell wall lipopolysaccharides (LPS) from gram-negative bacteria and derivatives of these LPS were tested for their stimulatory capacity for human peripheral blood cells. Immunoglobulin (Ig) production was tested by an indirect plaque-forming cell assay using Staphylococcus aureus protein A-coupled erythrocytes and specific anti-Ig as developing serum. This method allows the detection of the majority of cells secreting Ig of a single class, and the number of plaque-forming cells detected are approximately 100-1000 times the amount obtained using normal sheep red cells as targets. LPS containing the O antigen-specific chain, as well as mutant products only containing lipid A and ketodeoxyoctonate trisaccharide, could induce cell division and antibody synthesis. The polypeptide antibiotic polymyxin B was found to inhibit LPS-induced activation. Furthermore, purified lipid A, complexed with bovine serum albumin, was also found to activate human peripheral blood B cells. These findings demonstrate that human peripheral blood lymphocytes can be activated by LPS and also indicate that lipid A is the active part of these molecules.

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Experimental lipid A-induced nephritis in the dog

Cited by 27 publications

References 9 publications

Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats

Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Lipopolysaccharide and lipid A‐induced human blood lymphocyte activation as detected by a protein A plaque assay

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