Treatment of rabbits, rats, and mice with D-galactosamine increased their sensitivity to the lethal effects of lipopolysaccharide several thousand fold. The susceptibility of the animals was highest when the lipopolysaccharide was injected together with galactosamine and decreased successively when injection was carried out 1, 2, and 3 hr later. Sensitization was absent when the lipopolysaccharide was administered 1 hr before or 4 hr after galactosamine. The onset of lethality after treatment with galactosamine and lipopolysaccharide occurred faster than with lipopolysaccharide alone; usually all animals died 5-9 hr later. The galactosamine-induced sensitization to lipopolysaccharide could be reversed by uridine which is known to inhibit the early biochemical alterations induced by the amino sugar in the hepatocytes. Although galactosamine is known to exhibit hepatotoxic activity inducing ultimate necrosis of the hepatocytes, the data so far suggests that the sensitization to lipopolysaccharide is related only to the early metabolic effects of the hexosamine.

https://www.pnas.org/content/pnas/76/11/5939.full.pdf

Galactosamine-induced sensitization to the lethal effects of endotoxin.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840010516

Endotoxin, reticuloendothelial function, and liver injury

Aberrant or defective immune responses are known to be the result of primary immunodeficiency diseases, e.g., in the DiGeorge syndrome (thymic hypoplasia) in man, or in homozygous mice with the mut...

https://www.tandfonline.com/doi/pdf/10.1080/15476910701508262

Immune suppression as related to toxicology.

This article reviews the effects of lead on genetic systems in the context of lead's various other toxic effects and its abundance and distribution in the environment. Lead is perhaps the longest used and best recognized toxic environmental chemical, yet it continued be used recklessly until only very recently. Lead is thus a lesson in the limitations and strengths of science, human conscience and common sense. Lead has been tested and found to be capable of eliciting a positive response in an extraordinarily wide range of biological and biochemical tests; among them tests for enzyme inhibition, fidelity of DNA synthesis, mutation, chromosome aberrations, cancer and birth defects. It reacts or complexes with many biomolecules and adversely affects the reproductive, nervous, gastrointestinal, immune, renal, cardiovascular, skeletal, muscular and hematopoietic systems as well as developmental processes. It is likely that lead is a selective agent that continues to act on and influence the genetic structure and future evolution of exposed plant and animal populations.

The genetic effects of environmental lead

It is generally agreed that there is an increased incidence of postoperative renal failure in patients with obstructive jaundice. The proposition that this may be due to endotoxin, and that the endotoxin may be absorbed from the patient's own bowel flora, has been investigated. The study was conducted in patients and in animals. Twenty-four patients with obstructive jaundice were studied. Sixteen had endotoxin in the portal blood at operation and 13 of these had peripheral endotoxaemia at the time of operation or developed it during the 72 hours following operation. Only 3 of the patients had a proved possible site of infective origin for the endotoxaemia, the remainder absorbing the endotoxin from their own gastro-intestinal organisms. Portal endotoxaemia occurred when the serum bilirubin was 8-5 mg/100 ml or greater. There was a highly significant decrease in mean endogenous creatinine clearance postoperatively in patients with endotoxaemia, and expression of this as a percentage postoperative fall compared with preoperative levels enhanced the significance. Jaundiced patients without endotoxaemia had no significant fall in endogenous creatinine clearance. Matched non-jaundiced control patients did not develop portal or peripheral endotoxaemia, and there was no significant fall in postoperative creatinine clearance. Experiments using animals showed that the absence of bile salts in the intestinal tract in obstructive jaundice allows endotoxin to be absorbed, and that this absorption can be prevented by the oral administration of bile salts. The therapeutic implications in patients are discussed.

Endotoxin, bile salts and renal function in obstructive jaundice

Selye, H. (Universite de Montreal, Montreal, Canada), B. Tuchweber, and L. Bertok. Effect of lead acetate on susceptibility of rats to bacterial endotoxins. J. Bacteriol. 91: 884–890. 1966.—A single, normally well-tolerated, intravenous injection of lead acetate increases the sensitivity of the rat to the endotoxins of various gram-negative bacteria about 100,000 times above normal. Under the conditions of these experiments, the mortality and organ changes normally produced by the intravenous injection of 100 μg of Escherichia coli endotoxin were essentially the same as those obtained by use of 1 nanogram in lead-sensitized rats. The sensitizing effect of lead acetate for E. coli endotoxin is greatest when the two agents are given simultaneously. However, considerable sensitization is still detectable when endotoxin is injected up to 1 hr before or 7 hr after sensitization with lead. No sensitization was noted when the endotoxin was administered 24 hr before or after lead acetate. Under our experimental conditions, the minimal dose of lead acetate which could still induce significant sensitization to E. coli endotoxin was 1 mg per 100 g of body weight. Although lead acetate induces a high degree of susceptibility to various endotoxins, other reticuloendothelial blocking agents did not acquire unusual toxicity after pretreatment with lead. Finally, none of the other metals or reticuloendothelial blocking agents tested could duplicate the pronounced decrease in endotoxin resistance induced by lead acetate. Images

Effect of Lead Acetate on the Susceptibility of Rats to Bacterial Endotoxins

SELYE, H.(Universite deMontreal, Montreal, Canada), B.TUCHWEBER, AND L. BERT6K. Effect ofleadacetate on susceptibility ofratstobacterial endotoxins. J. Bacteriol. 91:884-890. 1966.-Asingle, normally well-tolerated, intravenous injectionofleadacetate increases thesensitivity oftherattotheendotoxins ofvarious gram-negative bacteria about100,000 times abovenormal. Undertheconditions of these experiments, themortality andorganchanges normally produced bytheintravenousinjection of100,ugofEscherichia coli endotoxin wereessentially thesameas those obtained byuseof1nanograminlead-sensitized rats. Thesensitizing effect ofleadacetate forE.coli endotoxin isgreatest whenthetwoagents aregiven simultaneously. However, considerable sensitization isstill detectable whenendotoxin isinjected up to1hrbefore or7hrafter sensitization withlead. No sensitization was notedwhentheendotoxin wasadministered 24hrbefore orafter lead acetate. Underourexperimental conditions, theminimaldoseofleadacetate which couldstill induce significant sensitization toE.coli endotoxin was1mg per100gof bodyweight. Although leadacetate induces ahighdegree ofsusceptibility tovarious endotoxins, other reticuloendothelial blocking agents didnotacquire unusualtoxicity after pretreatment withlead. Finally, noneoftheothermetals orreticuloendothelial blocking agents tested couldduplicate thepronounced decrease inendotoxin resistance induced byleadacetate. Inthecourseofourinvestigations oncertain pharmacological actions ofheavy metals, itwas observed incidentally thatleadgreatly increases thesusceptibility oftherattobacterial endotoxins towhichthisspecies isotherwise notoriously resistant. Forexample, asingle intravenous injection ofleadacetate, atadosewhichnormally produces no detectable disturbance, regularly makestheratabout100,000 times moresusceptible totheconcurrent intravenous administration ofEscherichia coli endotoxin. Itisthepurpose ofthiscommunication to describe thecircumstances underwhichthis increased susceptibility canbestbeobtained. Special attention willbegiven tothepossible participation ofthereticuloendothelial

H. Selye

Papers

Effect of Lead Acetate on the Susceptibility of Rats to Bacterial Endotoxins

Effect ofLeadAcetate on theSusceptibility ofRats toBacterial Endotoxins