An Endogenous Mediator of Depression of Amino Acids and Trace Metals in Serum during Typhoid Fever

Abstract

( oncentrutions, of most amino acids and of zinc in serum were depressed during periods of incubation and illness in I11 volunteers who developed symptoms after an oral dose of 105 virulent Salmonellai typhiosa. WVhen a 1.0-mi sample of sterile serum from volunteers who were ill with typhoid fever was injected into normal rats, it stimulated a prompt and significant depression of the concentration of zinc in the rats' sera and a flux of amino acids into thcir livers. These observations support the hypothesis that an endogenous factor (similar to cndogenous pyrogen released by polymorphonuclear leukocytes) was present in the blood during typhoid feve and served as a mediator for the observed depression in zinc and amino acids in serum. The magnitude and pattern of infect ion-related dep-osiion in individual amino acids in serum may he. in part, a function of the amount of endogenous mediator released and of' the rates of utilization of amino acids by tissues.[he period of symptomatic febrile illness during cantly altered in whole blood of volunteers ina ceeneralized infectiotis process is accompanied fected with Salmnone'lla I 'yphosa (S. I "vphi) [2]. A by prominent catabolic events that lead to a negasimilar depression in the total free amino acids tihe halanct ýrl nitrogen and other elements in the in whole blood or serum has been observed durbo~dy 111. Hosi~ever. many other infection-related ing prospective studies in volunteers infected with biochemical changes in the host appear ty-develop Pastettrella tilare'nsis 131, live, attenuated (vaclong before the onset of fever and symptoms of cine strain) Venezuelan equine encephalitis illness and to he anabolic rather than catabolic (VEE) virus 141, or sandfly-fever virus 151. in nature. Little is known about the role of these Serum zinc was also depressed during the periods \er\ early biochemical responses of the host or of incubation and clinikal illness of several bacthe tinderlying mechanisms that initiate them.terial and viral infections, while serum copper f'otal concentrations of amino acids were signifivalues became elevated during the latter stages of the same illnesses 15. 6].Recent studies in experimental animals sug- tissues. The use of a 1 'C-labeled. nonmetabolizable I \periP'w.,s invok~ing humans reported in this paper amino-acid analog, Il-aminocyclopentane-lI-car%kcr : L'oserned b% the principle%. policies, and rules for boxylic acid (cycloleucine) in rats exposed to

Pathological and Biochemical Features of Legionella Pneumophila Infection in Guinea-pigs

“…The decreases in zinc may have been associated with the decrease in free amino acids observed in the later stages of the disease; a similar association is often observed in experimental infections of man and other animals (Wannemacher et al, 1972a(Wannemacher et al, , 1975. This may be related to the synthesis of acute-phase proteins (Powanda et al, 1975;Berendt et al, 1977;, although the latter may not necessarily result in a measurable decrease in amino acids (Hambleton et al, 1977(Hambleton et al, , 1978.…”

“…In guinea-pigs striking changes occurred in serum trace metals, amino acids and proteins, resembling those induced by other acute bacterial and viral infections of man and animals (Wannemacher et al, 1972a;Powanda et al, 1975;Hambleton et al, 1977Hambleton et al, , 1978. The decreases in zinc may have been associated with the decrease in free amino acids observed in the later stages of the disease; a similar association is often observed in experimental infections of man and other animals (Wannemacher et al, 1972a(Wannemacher et al, , 1975.…”

“…These changes may be initiated by circulating substances elaborated by leucocytes in response to inflammatory processes (Wannemacher et al, 1972a); they include early changes in the concentrations of serum trace metals (Wannemacher et al, 1972a;Powanda et al, 1975;Hambleton et al, 1977Hambleton et al, , 1978 and amino acids that may be concerned with the subsequent synthesis of acute-phase proteins (Wannemacher et al, 19726;Powanda et al, 1975). Increases in the serum phenylalanine to tyrosine ratio also often precede inflammatory changes (Wannemacher et al, 1976;Hambleton et al, 1978).…”

Zinc, Copper, and Parenteral Nutrition in Cancer. A Review

“…These include decrease in serum Zn and iron concentrations, an increase in serum Cu concentration, movement of serum Zn and iron into the liver, increased uptake of serum amino acids (AA) by the liver, increased synthesis of serum (XI and (X2 acute phase globulins, and accelerated release of neutrophils from the bone marrow. [83][84][85][86][87][88][89][90] The available data suggest that the depression of serum Zn and iron in the acute infection of inflammatory processes does not result from decreased intake or absorption of those metals at the gastrointestinal tract or from enhanced excretion into the urine," but are due to enhanced movement into the liver so as to be used for the accelerated synthesis of acute phase globulins. This Zn-Iowering mediator, LEM, is heat-labile (inactivated in 30 min at 9Q°C), is a low molecular weight (20,000-30,000 daltons) proteinaceous substance, and appears to be released into serum before the onset of acute infections or the appearance of fever.…”

Protein Metabolism in Response to Injury and Other Pathological Conditions

“…An early change is a selective depression of free amino acid concentrations in the plasma which can occur before the onset of the rise in temperature. This effect has been traced to release of a factor (leukocytic endogenous mediator, LEM) from the phagocytic leukocytes which acts on liver cells to cause not only increased uptake of amino acids, but also of iron and zinc, whose levels in the plasma consequently also undergo a reduction ( WANNEMACHER et al 1972). In addition to these effects on transport into the liver, LEM stimulates liver RNA and protein synthesis, and is responsible for the release of extra ceruloplasmin and new alphaglycoproteins (acute phase reactant proteins) into the circulation.…”