BLOOD PLASMA PROTEIN PRODUCTION AND UTILIZATION

When blood plasma proteins are depleted by bleeding, with return of the washed red cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal low protein diet. These dogs are clinically normal with normal appetite, no anemia and normal nitrogen metabolism. These dogs become test subjects by which various factors relating to plasma protein production may be tested. The normal dog (10 to 13 kg.) has a substantial reserve store of plasma protein building material (10 to 60+ gm.) which requires 2 to 6 weeks plasmapheresis for its complete removal. After this period the dog will produce uniform amounts of plasma protein each week on a fixed basal diet. Dogs previously depleted by plasmapheresis and then permitted to return to normal during a long rest period of many weeks, may show much higher reserve stores of protein building material in subsequent periods of plasma depletion (see Table 1). Under uniform conditions of low protein diet intake when plasmapheresis is discontinued for 2 weeks the plasma protein building material is stored quantitatively in the body and can subsequently be recovered (Table 4) in the next 2 to 3 weeks of plasmapheresis. Given complete depletion of plasma protein building reserve stores the dog can produce very little (2± gm. per week) plasma protein on a protein-free diet. This may be related to the wear and tear of body protein and conservation of these split products. Abscesses produced in a depleted dog during a fast may cause some excess production of plasma protein which is probably related to products of tissue destruction conserved for protein anabolism. Gelatin alone added to the basal diet causes very little plasma protein production but when supplemented by tryptophane gives a large protein output, while tryptophane alone is inert.

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BLOOD PLASMA PROTEIN PRODUCTION AS INFLUENCED BY VARIOUS DEGREES OF HYPOPROTEINEMIA AND BY AMINO ACIDS

Journal of Experimental Medicine ◽

10.1084/jem.73.5.571 ◽

1941 ◽

Vol 73 (5) ◽

pp. 571-580 ◽

Cited By ~ 19

Author(s):

S. C. Madden ◽

A. P. Turner ◽

A. P. Rowe ◽

G. H. Whipple

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Protein Concentration ◽

Protein Production ◽

Dynamic Equilibrium ◽

Protein A ◽

Plasma Protein Concentration ◽

Body Protein ◽

Clinically Normal ◽

Important Amino Acid

When blood plasma proteins are depleted by bleeding with return of the washed red blood cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal low protein diet. These dogs are clinically normal but their resistance to infection is distinctly below normal. Introduction of variables into this standardized existence gives information relative to plasma protein production. Plasma protein production under these conditions with a plasma protein concentration of 3.5 to 4.2 gm. per cent is relatively constant. As the plasma protein concentration rises the plasma protein removed falls rapidly (Table 1). At 4.6 gm. per cent the protein removed is less than 50 per cent of the amount removed at a plasma protein level of 4.0 gm. per cent. Cystine appears to be an important amino acid for plasma protein formation. This shows in Table 2 and is supported by data coming from published experiments. These experiments related to the factors which control plasma protein production bear on the problems of shock, hemorrhage, and protein wastage and their treatment by plasma injections which hold the attention of surgeons and physiologists at the moment. Again we would emphasize the fluidity of body protein including plasma protein—an ebb and flow between protein depots and plasma protein—a "dynamic equilibrium" of body protein. A discussion of the passage of large protein molecules through cell borders is submitted.

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BLOOD PLASMA PROTEIN GIVEN BY VEIN UTILIZED IN BODY METABOLISM

Journal of Experimental Medicine ◽

10.1084/jem.59.3.269 ◽

1934 ◽

Vol 59 (3) ◽

pp. 269-282 ◽

Cited By ~ 27

Author(s):

Russell L. Holman ◽

Earle B. Mahoney ◽

George H. Whipple

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Protein Concentration ◽

Dynamic Equilibrium ◽

High Plasma ◽

The Body ◽

Food Protein ◽

Plasma Protein Concentration ◽

Body Protein ◽

Concentration Changes

Large amounts of normal blood plasma can be given intravenously to normal dogs over several weeks without causing any significant escape by way of the urine. There appears to be no renal threshold for plasma protein even with high plasma protein concentration (9.7 per cent). Dogs receiving sugar by mouth and plasma by vein can be kept practically in nitrogen equilibrium and it would seem that the injected protein must be utilized by the body. If this can happen in this emergency we may suspect that normally there is a certain amount of "give and take" between body protein and plasma protein. Plasma protein fed by mouth under identical conditions shows the same general reaction as noted with plasma by vein but the urinary nitrogen is a little higher and suggests that the injected protein is utilized a little more completely to form new protein. The difference may be explained as due to deaminization in the case of protein by mouth. During fasting periods the blood plasma proteins are used up and the total circulating protein may even decrease to one-half the normal level. The plasma protein concentration changes but little and the significant change is a shrinkage of plasma volume. All these facts point to a dynamic equilibrium between tissue protein and plasma protein depending upon the physiological needs of the moment. In the absence of food protein the body can use material coming from one body protein to fabricate badly needed protein material of different character.

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BLOOD PLASMA PROTEIN PRODUCTION AS INFLUENCED BY AMINO ACIDS

Journal of Experimental Medicine ◽

10.1084/jem.69.5.721 ◽

1939 ◽

Vol 69 (5) ◽

pp. 721-738 ◽

Cited By ~ 11

Author(s):

S. C. Madden ◽

W. A. Noehren ◽

G. S. Waraich ◽

G. H. Whipple

Keyword(s):

Blood Plasma ◽

Red Blood Cells ◽

Protein Content ◽

Plasma Protein ◽

Blood Cells ◽

Plasma Proteins ◽

Protein Production ◽

Basal Diet ◽

Liver Protein ◽

Clinically Normal

When blood plasma proteins are depleted by bleeding with return of the washed red blood cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal low protein diet. These dogs are clinically normal. By the introduction of variables into their standardized existence insight into the formation of plasma proteins can be obtained. The liver basal diet maintains health in such hypoproteinemic dogs during periods as long as a year. 17 to 27 per cent of its protein content (entirely liver protein) is presumably converted into plasma protein. Gelatin alone added to the liver basal diet causes very little if any extra plasma protein production. The addition to gelatin of cystine, or tyrosine, or tryptophane, or of both tyrosine and tryptophane has little or no effect on its potency for plasma protein production. When gelatin is supplemented by cystine and either tryptophane or tyrosine, 25 to 40 per cent of the protein content of the combination is converted into plasma protein—an efficiency equaling that of any protein hitherto tested. Preliminary experiments indicate that methionine cannot substitute for cystine nor can phenylalanine substitute for tyrosine in the efficient combination of gelatin plus cystine plus tyrosine. Laked red blood cells given by vein afford little or no material for plasma protein formation. When the reserve stores of plasma protein building material are exhausted the dog can form little if any plasma protein during protein-free diet periods.

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BLOOD PLASMA PROTEIN REGENERATION AS INFLUENCED BY INFECTION, DIGESTIVE DISTURBANCES, THYROID, AND FOOD PROTEINS

Journal of Experimental Medicine ◽

10.1084/jem.65.3.431 ◽

1937 ◽

Vol 65 (3) ◽

pp. 431-454 ◽

Cited By ~ 16

Author(s):

S. C. Madden ◽

P. M. Winslow ◽

J. W. Rowland ◽

G. H. Whipple

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Plasma Proteins ◽

Protein Production ◽

Building Materials ◽

Basal Diet ◽

The Body ◽

Potency Ratio ◽

Blood Plasma Protein ◽

Diet Intake

When blood plasma proteins are depleted by bleeding, with return of washed red cells (plasmapheresis), it is possible to bring dogs to a steady state of low plasma protein in the circulation and a uniform plasma protein production on a basal diet. Such dogs become test subjects by which the effect of various factors on plasma protein regeneration can be measured. Dogs previously the subjects of plasmapheresis, during long rest periods appear to increase their stores of plasma protein building materials and their blood plasma protein concentrations above former normal levels. A sterile abscess (turpentine) induces a marked reduction in plasma protein regeneration in these test dogs consuming an ample basal diet. The sharp reduction during the initial 24 hours may in part reflect an extravasation of plasma protein into the injured tissue but there also appears to develop a true disturbance of the mechanism which produces plasma proteins. Digestive disturbances interfere seriously with plasma protein production. Whereas large quantities of live yeast upset digestion and form no plasma protein, autoclaved yeast is well utilized, having a potency ratio of 4.4. Amino acids have been tested inadequately. A mixture of cystine, glutamic acid, and glycine does seem to have a definite effect upon protein metabolism and plasma protein production. Iron, under the conditions of these experiments, does not influence the output of plasma proteins. Liver extract (parenteral) is also inert. The proteins of red blood cells when added to the diet are poorly utilized for plasma protein formation and show a potency ratio of only 10.1. Kidney protein added to the kidney basal diet shows a potency ratio of about 5 as compared with 4.6 for that basal diet. A digest of beef stomach and rice polishings shows a potency ratio of about 7.9. Dried powdered serum shows a potency ratio of 3.5, which is much less than fresh serum (2.6). Powdered thyroid fed in doses sufficient to accelerate body metabolism shows no distinct effect upon plasma protein production not attributable to the protein in the thyroid powder itself. Long periods (25 to 30 weeks) of plasma depletion and basal diet intake remove much protein from body fluids and tissues. Associated with this protein depletion the dog loses its appetite and may vomit some food. There is loss of hair, a tendency to skin ulceration, and a distinct lowering of resistance to infection. The plasma protein output may fall to fasting levels in spite of food intake sufficient to maintain weight. We believe this condition to be a deficiency state related to severe depletion of the essential protein matrix of the body cells.

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CASEIN DIGESTS PARENTERALLY UTILIZED TO FORM BLOOD PLASMA PROTEIN

Journal of Experimental Medicine ◽

10.1084/jem.73.6.727 ◽

1941 ◽

Vol 73 (6) ◽

pp. 727-743 ◽

Cited By ~ 6

Author(s):

S. C. Madden ◽

L. J. Zeldis ◽

A. D. Hengerer ◽

L. L. Miller ◽

A. P. Rowe ◽

...

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Plasma Proteins ◽

Protein Production ◽

Basal Diet ◽

Clinically Normal ◽

Blood Plasma Proteins ◽

Resistance To Infection ◽

Protein Output ◽

Uniform Plasma

When blood plasma proteins are depleted by bleeding with return of the washed red cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal diet limited in protein. Such dogs are clinically normal but have a lowered resistance to infection and certain intoxications. Casein digests given by vein or subcutaneously to such plasma depleted dogs are effective in promoting abundant new plasma protein production. Casein digest L by vein is equivalent to whole liver of like protein equivalence by mouth. The ratio of new plasma protein production to protein intake is 20 to 25 per cent in both instances. Casein digest L by vein gives the same response in plasma protein output as the same digest by mouth. Protein digest X by vein requires addition of tryptophane and cysteine to be effective in plasma protein production. The added cysteine sulfur is more than 95 per cent retained by the dog. The speed of digest injection has no effect on its utilization, within the range tested. Casein digest L given by vein to non-depleted dogs is less well utilized than in dogs depleted of plasma protein.

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BLOOD PLASMA PROTEIN REGENERATION CONTROLLED BY DIET

Journal of Experimental Medicine ◽

10.1084/jem.61.2.261 ◽

1935 ◽

Vol 61 (2) ◽

pp. 261-282 ◽

Cited By ~ 29

Author(s):

W. T. Pommerenke ◽

H. B. Slavin ◽

D. H. Kariher ◽

G. H. Whipple

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Plasma Proteins ◽

Protein Production ◽

Protein A ◽

Basal Diet ◽

Food Protein ◽

Potency Ratio ◽

Health And Disease ◽

Clinical Conditions

When blood plasma proteins are depleted by bleeding, with return of washed red cells (plasmapheresis) it is possible to bring the dog to a steady state of low plasma protein and uniform plasma protein production on a basal diet. Such dogs are excellent test subjects by which the potency of various diet factors for plasma protein regeneration can be measured. To regenerate plasma proteins in any significant amount the depleted dog requires food protein. Some proteins are very potent for new plasma protein production and others are utilized poorly. Beef serum is very potent and its proteins (2.6 gm.) will produce 1 gm. of new plasma protein in the depleted dog—a potency ratio of 2.6. Kidney protein stands at the bottom of our list and the dog needs 21 gm. of kidney protein to regenerate 1 gm. of plasma protein—a potency ratio of 21.0. Some grain proteins approximate the potency of beef serum and may show potency ratios of 2.7 to 4.6. Some of these grain proteins appear to favor the production of globulin more than albumin in the plasma. Skeletal muscle, gizzard (smooth muscle), lactalbumin and egg white fall into a favorable group with a potency ratio of 5.3 to 6.0. Whole liver, liver fractions, casein, and beef heart are a little less potent and present potency ratios of 6.5 to 8.0. Many of these food substances favor the production of albumin more than globulin. Pancreas and salmon muscle show less favorable potency ratios of 19.0 and 15.0 respectively. Fasting periods indicate that these depleted dogs can produce little if any new plasma protein. Iron feeding in some unexplained manner will influence body metabolism so that an excess of plasma protein will be produced. These observations have a bearing on clinical conditions associated with hypoproteinemia and give suggestions for diet aid or control in some of these abnormal states. The make-up of the diet is obviously of great interest and it is possible that protein combinations may be more potent than a single protein or that food potency ratios may differ in health and disease.

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Marker changes of blood plasma proteinogram in rats with toxic hepatitis

Regulatory Mechanisms in Biosystems ◽

10.15421/022055 ◽

2020 ◽

Vol 11 (3) ◽

pp. 360-366

Author(s):

V. A. Gryshchenko ◽

V. S. Minina

Keyword(s):

Blood Plasma ◽

Plasma Protein ◽

Total Protein ◽

Toxic Hepatitis ◽

Diclofenac Sodium ◽

The Body ◽

Laboratory Animals ◽

Total Protein Content ◽

Protein Spectrum ◽

G Ratio

In recent years, there has been a pronounced tendency to increase in the incidence of drug-induced liver damage due to the growing expansion of the pharmaceutical market, which is also observed in the case of incorrect administration of nonsteroidal anti-inflammatory drugs (NSAIDs). In this case, the violation of the functional state of the body has a negative effect on synthetic processes, which in combination with the protein system of tissues significantly affects the metabolic homeostasis of the body. Therefore, the aim of the study was to determine marker changes in the plasma protein spectrum in laboratory rats with diclofenac-induced hepatitis and the effectiveness of reparative therapy based on milk phospholipids. The drug form of toxic hepatitis in laboratory animals was induced according to the author’s model by oral administration of diclofenac sodium (NSAID group) at a dose of 12.5 mg/kg, once a day for 14 days. Thus, in rats with toxic hepatitis there was a probable decrease in plasma total protein content by 15.6% compared with control, indicating a violation of protein-synthesizing function of the liver. With the introduction into the body of clinically healthy and sick animals of the liposomal form of the bioadditive "FLP-MD" based on milk phospholipids, the level of total protein in blood plasma corresponded to control values. As a result of the study of the plasma protein spectrum of Wistar rats, the four most sensitive indicators, which undergo significant probable changes in absolute and relative units of measurement with the development of toxic diclofenac-induced hepatitis, are protein fractions with molecular weights of 180–190, 150–170, 60 and 54–58 kDa and four markers of the effectiveness of restoring the protein-synthesizing function of the liver with the use of corrective therapy, in particular, bioadditives "FLP-MD" – 900, 180–190, 68–70 kDa and the value of A/G ratio, which is important for implementation in applied veterinary medicine, especially in the diagnosis of NSAID hepatopathy, supplementing the picture of its pathogenesis at the molecular level and testing the effectiveness of newly created drugs of hepatoprotective profile.

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PROTEOSE INTOXICATIONS AND INJURY OF BODY PROTEIN

Journal of Experimental Medicine ◽

10.1084/jem.25.3.479 ◽

1917 ◽

Vol 25 (3) ◽

pp. 479-494 ◽

Cited By ~ 14

Author(s):

G. H. Whipple ◽

J. V. Cooke ◽

T. Stearns

Keyword(s):

Total Nitrogen ◽

Duodenal Obstruction ◽

The Body ◽

Intestinal Loop ◽

Base Line ◽

General Reaction ◽

Protein Nitrogen ◽

Body Protein ◽

Nitrogen Elimination ◽

Elimination Curve

Dogs with isolated loops of small intestine show many evidences of intoxication. A study of the total nitrogen elimination shows a great rise above the normal base-line minimum of the fasting period (Table II). This means that the intoxication is associated with a great destruction of body protein, and explains the high non-protein nitrogen of the blood which was observed and reported previously (2). Injection of a proteose obtained from a closed intestinal loop will cause a similar rise in the nitrogen elimination curve. This furnishes more evidence that the intoxication observed in association with a closed intestinal loop is in reality a proteose intoxication. Dogs injected with sublethal doses of proteose will show a definite tolerance to subsequent injection, and will show much less acute intoxication after the isolation of a closed intestinal loop (Table 1). These immune or tolerant dogs show a much less pronounced rise in the nitrogen elimination curve during proteose intoxication of any type. This indicates that the tolerance or immunity to proteose gives more protection for the body proteins against the injury which these toxic proteoses inflict upon the body cells. Complete duodenal obstruction combined with a gastrojejunostomy gives a chronic type of intestinal obstruction associated with little vomiting, which is peculiarly suited to metabolism study (Table IV). Such duodenal obstructions show a definite and sustained rise in the curve of nitrogen elimination above the normal base-line level. These dogs, too, are tolerant to injections of standard toxic proteoses. Control ether anesthesia experiments show little if any rise in the curve of nitrogen elimination (Table VI). Control laparotomy experiments show a definite rise in the curve of nitrogen elimination, but a rise which is small compared with the rise noted in the intoxication of duodenal obstruction or of isolated intestinal loops. It is probable that the tissue injury and disintegration associated with the wound reaction are responsible for the general reaction. We may assume that protein split products from the wound area are absorbed and are responsible for the general reaction observed. We propose to assume that the intoxications here studied are associated with a definite proteose intoxication, which is capable of initiating and continuing a profound injury of tissue protein. One index of this protein injury is the great and sustained rise in the curve of total nitrogen elimination.

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ANEMIA AND HYPOPROTEINEMIA

Journal of Experimental Medicine ◽

10.1084/jem.85.3.267 ◽

1947 ◽

Vol 85 (3) ◽

pp. 267-275 ◽

Cited By ~ 10

Author(s):

L. L. Miller ◽

F. S. Robscheit-Robbins ◽

G. H. Whipple

Keyword(s):

Amino Acids ◽

Body Weight ◽

Plasma Protein ◽

Nitrogen Balance ◽

Essential Amino Acids ◽

The Body ◽

Liver Protein ◽

Food Proteins ◽

Positive Nitrogen Balance ◽

Maintain Body Weight

Dogs with sustained anemia and hypoproteinemia due to bleeding and a continuing low protein or protein-free diet with abundant iron are used to test the value of food proteins as contrasted with mixtures of pure amino acids. The stimulus of double depletion (anemia and hypoproteinemia) drives the body to use every source of protein and all protein-building materials with the utmost conservation. Raiding of body tissue protein to produce plasma protein and hemoglobin is a factor when protein-building factors are supplied in small amounts. In this severe test (double depletion) the good food proteins in adequate amounts are able to maintain body weight, a strongly positive nitrogen balance, and produce considerable amounts of new hemoglobin and plasma protein. Casein, lactalbumin, whole egg protein, liver protein are all adequate in amounts of 150 to 250 gm. protein per week. Under comparable conditions mixtures of pure amino acids (essential for growth) do produce large amounts of new hemoglobin and plasma protein and a positive nitrogen balance but do not maintain body weight. The loss of weight is conspicuous even with large amounts of amino acids (200 to 300 gm. protein equivalent per week). Methionine, threonine, and phenylalanine are related to nitrogen conservation in growth mixtures of essential amino acids (Paper I) but when these three are given together they have little influence on the doubly depleted dog (Table 3). Some unidentified substance or compound present in certain proteins but absent in mixtures of the essential amino acids may be responsible for these differences in the response of the doubly depleted dog.

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