Possible Alteration of Normal Mechanisms of Endotoxin Toxicity in Vivo by Actinomycin D

Brown, Deborah E.; Morrison, David C.

doi:10.1093/infdis/146.6.746

Cited by 17 publications

(9 citation statements)

References 18 publications

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“…Bradley and Bond (8) found that combinations of pactamycin and endotoxin administered simultaneously killed mice more rapidly than either drug alone; in vitro, the two drugs used in combination increased the in vitro fragility of renal lysosomes. Brown and Morrison (10) reported that simultaneous administration of actinomycin D to endotoxinresponsive mice increased by several orders of magnitude the susceptibility of these mice to the lethal effects of endotoxin. In contrast, Rifkind and Palmer (23) noted that three cationic cyclic polypeptide antibiotics, polymixin B sulfate, colistin sulfate, and tyrocidine hydrochloride, neutralized endotoxin lethality in chicken embryos.…”

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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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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“…Serum (225 l) was incubated at 37°C for 10 min with shaking in 96-well plates with 75 l of 2% sulfanilamine and 0.2% N-1-naphthylenediamine dihydrochloride in 1.2 N HCl. Then the nitrite concentration was determined from the optical density at 540 nm using a microplate reader and reference to a standard curve constructed with known concentrations of NaNO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Several substances have been documented to enhance by more than 1000-fold the sensitivity of mice to the lethal and hepatotoxic effects of LPS, including galactosamine [1], actinomycin D [2], and ␣-amanitin [3]. Although the mechanisms of sensitization by these metabolic inhibitors have not been elucidated in detail, blocking of protein synthesis by inhibition of RNA synthesis may be involved.…”

Section: Lipopolysaccharide (Lps)mentioning

confidence: 99%

Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

Akahori

Yamada

Takeyama

et al. 1999

Journal of Surgical Research

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“…Protein synthesis inhibition has been shown to increase LPS-induced endothelial cell detachment (Harlan et al, 1983a) and cytotoxicity (Harlan et al, 1983a;Pohlman and Harlan, 1989) in vitro. In animal models, administration of sublethal doses of protein synthesis inhibitors sensitize animals to LPS-induced mortality (Brown and Morrison, 1982;Seyberth et al, 1972;Wallach et al, 1988), whereas pretreatment with subthreshold levels of LPS desensitize animals to subsequent LPS challenge (Greisman and Hornick, 1976). These studies suggest that LPS can stimulate protein synthesis-dependent mechanismb) that can protect the endothelium against a subsequent LPS exposure.…”

Section: Mediummentioning

confidence: 99%

Bacterial lipopolysaccharide induces actin reorganization, intercellular gap formation, and endothelial barrier dysfunction in pulmonary vascular endothelial cells: Concurrent F‐actin depolymerization and new actin synthesis

Goldblum

Ding

Brann

et al. 1993

Journal Cellular Physiology

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Bacterial lipopolysaccharide (LPS) influences pulmonary vascular endothelial barrier function in vitro. We studied whether LPS regulates endothelial barrier function through actin reorganization. Postconfluent bovine pulmonary artery endothelial cell monolayers were exposed to Escherichia coli 0111:B4 LPS 10 ng/ml or media for up to 6 h and evaluated for: 1) transendothelial 14C-albumin flux, 2) F-actin organization with fluorescence microscopy, 3) F-actin quantitation by spectrofluorometry, and 4) monomeric G-actin levels by the DNAse 1 inhibition assay. LPS induced increments in 14C-albumin flux (P < 0.001) and intercellular gap formation at > or = 2-6 h. During this same time period the endothelial F-actin pool was not significantly changed compared to simultaneous media controls. Mean (+/- SE) G-actin (micrograms/mg total protein) was significantly (P < 0.002) increased compared to simultaneous media controls at 2, 4, and 6 h but not at 0.5 or 1 h. Prior F-actin stabilization with phallicidin protected against the LPS-induced increments in G-actin (P = 0.040) as well as changes in barrier function (P < 0.0001). Prior protein synthesis inhibition unmasked an LPS-induced decrement in F-actin (P = 0.0044), blunted the G-actin increment (P = 0.010), and increased LPS-induced changes in endothelial barrier function (P < 0.0001). Therefore, LPS induces pulmonary vascular endothelial F-actin depolymerization, intercellular gap formation, and barrier dysfunction. Over the same time period, LPS increased total actin (P < 0.0001) and new actin synthesis (P = 0.0063) which may be a compensatory endothelial cell response to LPS-induced F-actin depolymerization.

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Possible Alteration of Normal Mechanisms of Endotoxin Toxicity in Vivo by Actinomycin D

Cited by 17 publications

References 18 publications

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

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

Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

Bacterial lipopolysaccharide induces actin reorganization, intercellular gap formation, and endothelial barrier dysfunction in pulmonary vascular endothelial cells: Concurrent F‐actin depolymerization and new actin synthesis

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