SOME CONCEPTS OF PLASMA PROTEIN METABOLISM, A.D. …660 CITLIN-PLASMA PROTEIN METABOLISM analogous...

AMERICAN ACADEMY OF PEDIATRICS

PROCEEDINGS

SOME CONCEPTS OF PLASMA PROTEINMETABOLISM, A.D. 1956

E. Mead Johnson Award Address

By David Gitlin, M.D.

Department of Pediatrics, Harcard Medical School, and the Children’s Medical Center, Boston

Presented at the Annual Meeting, October 10, 1956.ADDRESS: 300 Longwood Avenue, Boston 15, Massachusetts.

657

Pediatrics

VOLUME 19 APRIL 1957 NUMBER 4, PART I

[ In presenting the First E. NIead JohnsonAward for 1956 to Dr. Gitlin, Dr. Bakwin,

President of the Academy, made the following

remarks:

[“Dr. l)avid Citlin was born in New York, in

1921. He received the M.D. degree from New

York University College of Medicine in 1947.

Prior to this he was honored by being the

Naurnberg Scholar to the University of Puerto

Rico in 1940-41, �l11(l was awarded the BordenUndergraduate Research Award in Medicine in

1947.

[“l)r. Gitlin had his internship at Niorrisiana

Cit� Hospital; from there lie went to Harvard

as a Research Fellow in Pediatrics and later

served as a Fellow in Medicine; an intern on

the Medical Service, an Instructor in Pediatrics,

Assistant Physician, and an Associate in Pedi-

atrics, all at the Children’s Medical Center and

Harvard Medical School.

[“Dr. Gitlin is certified l)\ the AmericanBoard of Pediatrics and is a Fellow of the

American Academv of Pediatrics. During his

short career Dr. Gitlin has been an energetic,

tenacious, imaginative worker. He has accom-

pushed much in investigation and has published

over 30 papers.

[“To quote his Chief, Dr. Charles Janewav,

‘Dr. Gitlin’s researches represent a coherent,

progressing series of studies in which, by the use

of chemical, immunochemical, and histochemi-

cal methods, with good physiologic reasoning,

he is gradually elucidating some basic problems

of the physiology of human plasma and struc-

tural proteins and the derangements in disease.’

It is for these works that the Academy’s Com-

mittee on Awards has selected Dr. Gitlin as

the recipient of the First E. Mead Johnson

Award for 1956. Dr. Gitlin will honor us bygiving a r#{233}sum#{233}of what lie considers to be his

important works.’]

O UR SOPHISTICATED philosophers wouldhave us believe that man can never be

satisfied. A man, so they say, can be rich

although he is poor and poor although he is

rich. A paradox such as this is an excellent

rationalization to soothe one’s soul, particu-

larly if one is poor. Today I have been

given the privilege of joining the ranks of

the very rich, because of the scientific honor

associated with this Award. Yet, peculiarly

enough, this is not where the greatest satis-

faction lies. This occasion has yielded re-

wards that transcend the pride of the mo-

ment. It has given me the opportunity to

by guest on April 5, 2021www.aappublications.org/newsDownloaded from

658 GITLIN - PLASMA PROTEIN METABOLISM

appreciate more fully my friends and col-

leagues; your good will and sincere good

wishes have given me more pleasure than

the Award would have otherwise. And the

occasion serves also, in some small way, to

justify the faith and teachings of the dedi-

cated men \vilo guide my studies. Among

these: Dr. Cohn MacLeod and his associ-

ates who took me in as a medical student

and tried to instill that most important dc-

ment of research, freedom of thought; Dr.

Louis Diamond, Dr. Stewart Clifford and

Dr. Sydney Geilis who tried so valiantly to

teach me pediatrics and that life is not

necessarily as grim as it sometimes seems;

Dr. Walter Hughes and Dr. J. L. Oncleywho gave so generously and unselfishly of

their knowledge of protein chemistry; Dr.

Sidney Farber and Dr. John Craig who

have given of their sincere co-operation on

innumerable occasions.

To Dr. Charles A. Janeway, however, re-

mained the most severe task of all-the in-

tegnation of these teachings and the forma-

tion of an individual. He has been my

guide, my critic, my advisor, and my

teacher, in personal matters as well as sci-

entific, and to him I owe my pediatric

career. In all candidness, the work for

which this Award has been given was due to

his efforts as much as to mine.

In accepting this Award, then, I accept

it in the names of these men and our col-

labonators and friends of many different in-

stitutions.

I have been asked to select highlights

from our work upon which this Award has

been based. Because of the many namifica-

lions of our studies and depending upon

the work of so many other investigators, this

is as heartless as asking a student to con-

dense an encyclopedia to an essay. And

how to select the highlights when we are

not sure just what they are? What may be

the important factors to us today may be

the nonsense of tomorrow. However, as the

title states, we should like to discuss some

simple aspects of human plasma protein

metabolism.

Just as man’s nature and emotions are in

a continuous state of flux, so is his body

chemistry; the plasma proteins share in this

general unrest. The individual plasma pro-

teins are synthesized or born at certain rates

and they are catabolized or die at certain

rates. The amount of a specific plasma pro-

tein present in the body at any given time,

therefore, represents the brief existence of

a group of its molecules between the times

of their synthesis and degradation. For the

amount of this protein in the body to re-

main constant, then, the rate of synthesis

must equal the rate of loss of that protein

from the body whether by catabolism or by

any other route of loss.

When we measure concentrations of a

particular plasma protein, we are localizing

a group of its molecules in a given place at

a given time. The individual protein mole-

cules, however, are in constant activity.

A molecule is synthesized, eventually ne-

leased into the circulation and remains in-

tact as an individual molecule for a variable

period of time. Theoretically, a molecule

may be catabolized immediately after syn-

thesis or it may remain in the body fluids

for months. Taken as a whole, however, a

given proportion or fraction of the total

body pool is catabolized per unit time. This

fraction of the total body pool may be

termed the fractkrnal rate of cataboli,sin

while the actual amount catabolized per

unit of time, expressed for example in grams

per day, is the rate of catabolirm.

Our studies until now have been con-

cenned with the peregrinations of some of

the plasma protein molecules. It is possible,

as you know, to label a gnoup of protein

molecules in a variety of ways-with radio-

active iodine, sulfur, carbon, or even with

certain dyes. When a trace amount of a

plasma protein is injected into the vascular

system, the plasma concentration of the in-

jected protein ordinarily follows a definite

cunve.14 Initially, the concentration falls

relatively rapidly and then, after a period

of some days, the decline in concentration

follows a logarithmic or exponential func-

tion. The rate of exponential decline is a

measure of the catabolism of the tracer pro-


PLAJM’A D/JAPPEAPANCf a�Z’&,41&al/// IA’ A //O#4�AL C/#Li�

LOA vJ

AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 659

Fic. 1. The plasma disappearance curve of a tracer dose of radio-iodinated albumin

given intravenously to a normal child. To calculate the half-life, t3�, a concentration(e.g., 0.4) at a given time was taken and the time required for half of this to dis-

appear (to 0.2) was determined.

tein being studied. The initial rapid fall in

concentration which occurs after distribu-

tion within the blood is due to the diffusion

of the protein from the vascular system.

Let us take a specific example. In Figure

1 is plotted the plasma-disappearance curve

for radio-iodinated human serum albumin

in a normal child. In this instance, during

the logarithmic phase, the concentration of

labeled albumin fell at a rate such that 50%,

or half, of a given number of labeled al-

bumin molecules was catabolized about

every 15 days. The latter value may be

termed the half-life of albumin due to Ca-

tabolism and, when applied to the child’s

endogenously synthesized albumin. states

that half of the child’s total body albumin

was catabolized every 15 days.

Note that this particular curve was con-

structed by plotting plasma concentration

versus time. We can demonstrate that the

plasma volume was constant during the

course of the study. If the plasma concen-

trations are multiplied by the plasma vol-

ume (a constant value), this does not change

the shape of the curve, but now the or-

dinates indicate the total amount of labeled

albumin in the vascular on plasma compart-

ment and the value at zero time represents

the total amount of tracer given to the

child. Extrapolating the catabolism portion

of the plasma-disappearance curve to zero

time, one can obtain that fraction of the

total body pool of the tracer that is in the

plasma during the steady state, or after the

tracer was distributed throughout the body

fluids.

Thus, from the catabolism curve of radio-

iodinated albumin, only 50% of the labeled

albumin can be accounted for in the plasma

compartment after the protein has been

distributed throughout the body. It is ap-

parent that approximately 50% of the in-

jected tracer left the vascular system within

the first 5 to 7 days. If endogenous albumin

behaves as does nadio-iodinated albumin,

then in the steady state, about half of an

individual’s total body albumin should be

present extravascularly.

In the presence of edema or in the pres-

ence of very rapid catabolism of the plasma

protein being studied, this type of graphic

analysis of plasma-disappearance curves is

not applicable to the body pool of endoge-

nous plasma protein.5 Under these circum-

stances, the specific activity of the tracer in

the various body fluids, i.e., amount of

tracer per unit amount of unlabeled


660 CITLIN - PLASMA PROTEIN METABOLISM

analogous I)r�tt’iii, �votikI not be equal, a

condition essential to this method of analy-

sis.�, 6 There are a number of other, but

more difficult, ways of estimating that frac-

tion of the total body content of a specific

plasma protein that is in the plasma, and

hence that fraction present extravascu-

larly’ but it is not possible to discuss them

at this time.

skin and muscle, at least, the amount of al-

bumin present outside the vascular system

is equal to or greater than that within the

vascular system of these tissues.’#{176}’ ‘�

The rapidly falling portion of the radio-

iodinated-albumin curve, then, is attribut-

able to two factors: 1) migration of the

tracer from the vascular system, and 2)

catabolism. The rate of extravascular diffu-

FIG. 2. Sctiuns of human tissue stained for various plasma pro-tciiis liv tht fliiorcscent-antibodv niethod. The white areas indicatefluoreseeIIc(’ 111(l hence localize the given plasma protein. (All

x210.) A. y-Clobiilin in the sinusoids of the liver. Note the generalLl)Sc1iC(’ of this protein froni the hepatic cells. B. y-Clobulin in

tl��’ (OIInctiV�’ tissue of nornial niuscle. C. The absence of ?-glob-

tiliti in tli coiiiiectiv#{128}’ tissue of a niuscle biopsy froiii a child �vithcongenital againinaglobulineinia. D. Fibrinogen in the connective

tissue of the same muscle biopsy as in C.

That there are large quantities of plasma

l)r�tei11s extravascularly has been demon-strate(1 by the fluorescent antibody method

of Coons. � � \Vith this technique one can find

albumin, ‘i’-globulin, iron-binding globulin,

�-lipoproteins and other plasma proteins in

all interstitial fluids (Fig. 2), and even small

amounts within certain cells.’ In addition,

it has been possible, by the use of a very

simple technique, to demonstrate that, in

sion is much greater than the rate of catab-

olism.

From the definition of half-life and froni

the mathematical characteristics of the

phase of catabolism the following equation

can be derived:

Half-life due to catabolism = 0.693�

Total amount of albumin in the body (T�)

Amount of albumin catabolized per day (Ar)

The catabolic half-life for albumin has al-


ready i)een estimated as 15 days in the

example given. Then to determine the nate

of catabolism, A(., it is necessary to know

the total amount of albumin in the body,

T�. The plasma concentration of albumin in

this child \V15 3.5 gm/100 ml and the

plasiu�t volunie was 1500 ml; thus, the3.5gm

vascular system contained X 1500lOOmi

nil 52.5 gm. However, the vascular sys-

tern contains about 50% of the total body al-

bumin in this case and hence the total body

all)umin can be calculated:

52.5 gin 0.50 � or TA � 105 gm.

0.693 X 105gm

The rate of catabolism, A(�

= 4.85 gm/day.

Since the child was in a steady state

with respect to all)umin metal)olism, that is,

the total concentration of albumin was

neither rising nor falling, then the rate of

synthesis must have been equal to the rate

of catabolism. Therefore, the rate of syn-

thesis of albumin in this instance was also

4.85 gm/day. The behavior of newly syn-

AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINCS 661

ALBUMIN METABOLISM IN A

30 P�G. CHILD

CAP, LLARI ES

CaL,s .,.�-.* � -� CELLSSYNThESIS CATABOLISM

46�m� 48.�

LVMPHATCS

26 os /12 � - . � #{149}MS/i�

BODY POOL = 105 GMS. 3.5 �s �l4ALF-LIFE� 15 DAYS

FI(;. :3. A simplified diagram of the metabolism of albumin in a child weighing:3() kg. Tlii’ introduction of tracer into the pi�isiiia conipartiiient �vouId behave

as newly synthesized endogenous albumin entering the sanie conipartinent from

the cells.

thesized albumin entering the vascular

system directly on indirectly from the sites

of synthesis would be that already de-

scnibed by the injection of iodinated albumin

into the vascular system (Fig. 3).

We have pointed out that molecules of

the various plasma proteins continuously

diffuse from the vascular system into the

interstitial fluids. That the extravascular

plasma proteins return to the vascular

system also appears to be true.’2 To test

this experimentally, normal rabbits were

given a concentrated solution of rabbit

antipneumococcai antibodies intravenously

(Fig. 4). This was a passive transfer; the

recipient rabbits were not synthesizing15 days these specific antibodies. As was to be cx-

pected, initially there was a rapid fall in the

plasma concentration of antibody followed

by the characteristic exponential decline.

During the latter phase, when the antibody

was in a steady state with respect to its

relative distribution in the body fluids, most

of the antibody present in the plasma was

removed by exchange transfusion on by a

reaction with specific antigen. The plasma


DyN,ui/c EQii,L/o/�veii.i -�4�445�3/T AN17-/�v&’4,t�r2rt:’uJ �

4’V7DOLVEJ //t/ RAB�.&’TJ

, �XC/�44�7-24NJrw/ON

I 2 4 j� 6 7


Fic. 4. The plasma concentration curve of rabbit antibodies against pneumococcus

type 3 passively transferred intravenously to non-immune rabbits.

I

concentration of antibody fell precipitously,

then nose rapidly from the low values at-

tamed and then resumed the phase of

logarithmic fall. The rapid rise was due to

the shift of antibody from the extravascu-

ian compartment. Thus, extravascular

plasma protein is in dynamic equilibrium

with intravascular plasma protein and a de-

crease in the mass of a specific plasma pro-

tein in one compartment results in the

movement of plasma protein to that com-

partment until a steady state is once again

attained. The clinical importance of this

large extravascular reservoir of preformed

plasma protein in homeostasis should not

be underestimated. Thus, after an acute

hemorrhage, for example, extravasculan

plasma protein would rapidly ne-enter the

circulation and maintain oncotic pressure.

Actually, the extravascular plasma protein

is not truly a reservoir in the sense of a stag-

nant reserve, but instead represents simply

that plasma protein which is outside the

vascular compartment at any given mo-

ment. The individual protein molecules are

in constant motion, going into or leaving

the extravascular areas.

From what has been discussed thus far

and from additional evidence obtained in

animals, it will be noted that the catabolism

of a given plasma protein is a first-order

chemical reaction. Under these cincum-

stances: 1) the half-life of a given plasma

protein due to catabolism is independent of

the total body pool on plasma concentration;

e.g., the normal half-life of albumin would

be about 15 days, whether the plasma con-

centration were 3.5 gm on 0.35 gm/100 ml,

and 2) the rate of catabolism of a given

plasma protein in terms of amount catabo-


/0a:Q0t�07

0s5

�Q4JMA

CI., � � d /�? /6- it:� � � J2 id � 44 ‘�1 �? JO �50 64

D,4vJFic. 5. The plasma disappearance curve of unlabeled normal y-globulin given

intravenously to a child with congenital agammaglobulinemia. Estimations of

?-globulin were done immunochemicaily.


lized per day is dependent upon the total

body pool of that protein; e.g., at a plasma

concentration of 1000 mg/100 ml, the rate of

catabolism would be 10 times that when the

concentration is 100 mg/100 ml, provided,

of course, that the body distribution of that

protein in both instances is identical. These

facts are not always cleanly seen in clinical

investigation, however, since alteration of

the body pool or plasma concentration of

a protein is frequently either the result of

a primary change on is accompanied by a

compensatory change in the catabolic half-

life of the protein.5

The same metabolic and mathematical

considerations discussed for albumin apply

equally well to the metabolism of �-giobu-

un, fibninogen, iron-binding globulin andother plasma proteins. But the inadequacy

of a given tracer on label for the plasma

proteins may make certain quantitative data

subject to considerable doubt although

qualitatively, the labeled protein may be-

have like its unlabeled analogue. This seems

to be the case for ?-globulin.

Unlabeled -.‘-globulin, in the form of

whole plasma, injected intravenously into

children with congenital agammagiobu-

linemia has a similar rapid initial fall in con-

centration followed by a phase of slower

exponential decline.’3 No exogenous label is

used and determinations are made by im-

munochemicai methods. The initial part of

the curve, as with albumin, is associated

with the appearance of ‘1’-globuiin in the

interstitial fluid of the connective tissues

throughout the body. The half-life of the

unaltered -�‘-giobulin in these patients, how-

ever, is 30 to 60 days (Fig. 5). Radio-

iodinated -�‘-globulin prepared from concen-

trated purified -�‘-giobulin has a half-life of

about 20 days in the same patients (Fig. 6).

The difference in half-lives would give pro-

portionate differences in the calculated rates

of catabolism. The same preparation of con-

centrated �-globulin used for the iodina-

tion procedure when given intramuscularly

and unlabeled has a half-life of 30 to 60

days after the steady state has been

reached. The differences in half-lives are

attributable either to the iodination pro-

cedure or to the atoms of iodine on the ‘i-

globulin molecule.

In addition, there is no method presently

available which will accurately estimate the

concentration of -1’-globulin in plasma on

other body fluids.’4 These difficulties leave

the quantitative aspects of -�‘-globulin

metabolism with much to be desired. How-

ever, for practical purposes, even calcula-


L�AVi


Fi;. 6. The half-lives, t3�, of unlabeled and radio-iodinated, pooled ?-globulin in

a child with congenital agan#{238}maglobulinemia after the “steady state” had been

attained. #{149}Immunochemical estimations. 0 Radioactivity estimations.

tions from available data can be very useful

5

Consider the simple problem of deciding

how mitch -‘-globiilin would be necessary to

raise the plasma concentration in a child by

100 mg/100 ml. As the plasma volume is

roughly 5% of the body weight, there would

be 50 ml of plasma per kilogram of body

weight. Fifty milliliters of plasma per kilo-

gram multiplied by 100 mg of -1-globulin per

100 ml of plasma, the increment desired, is

50 mg of �-globulin/kg; this is the amount

needed for the plasma component. But only

half of the T-globulin given will remain in

the vascular system and hence twice this

amount or 100 mg of ‘1-globulin/kg would

raise the concentration in the vicinity of

100 mg/100 ml. With a half-life of roughly

30 days, the increment in concentration

wotild fall to 50 mg/100 ml at the end of

this time; an additional injection of 100 mg

of v-globulin/kg of body weight would then

raise the increment to a total of 150 mg/

100 ml. At the end of 30 days the concentra-

tion would be about 75 mg/100 ml. ‘�-

Globulin administered intramuscularly (Fig.

7) readily reaches the vascular system; in

fact, after the stea(ly state has been reached,

the concentration achieved in the plasma

via the intramuscular route is essentially the

same as that attained via the intravenous

route.

The total amount of a specific plasma pro-

tein in the body is dependent upon its rate

of synthesis and its rate of catabolism. It is

not reasonable, then, to attempt to predict

the metabolic mechanisms involved in any

given protein or group of proteins, and it

is the mechanisms involved that dictate the

type of replacement therapy. For example,

patients with agammaglobulinemia and pa-

tients with the nephrotic syndrome manifest

very low concentrations of ‘1’-giobuiin in the

body; yet, in each instance, the mechanism

is quite different and replacement therapy

is effective in one, but impractical and in-effective in the other.

In agammaglobulinemia the defect is one

in synthesis.h316 A patient with either the

congenital on acquired form of this disease

has few, if any, plasma 718 these cells

are the sites of synthesis of antibodies or

-�‘-globuiin (Fig. 8)18 19 in addition, perhaps,

to several other plasma proteins.20 This state

of affairs is reflected in the normal or less

than normal fractional rate of catabolism of

administered ‘�‘-globulin in these patients.

To obtain insignificant concentrations of ‘�-

globulin in the face of no increase in the

fractional nate of catabolism, synthesis

would have to be insignificant; we have al-

ready discussed how the actual rate of syn-

thesis may be calculated from such data.

In children with the fully developed

nephnotic syndrome, on the other hand,

tracer studies reveal that the low concen-


oj-

“i:N

0’/I I I I I I I I I I

‘7 4 d c� /0/? /4/c� /O2O

L:L4vJ


/0

o,�,

ooof0�4 -

Co�w�’ivr.e’u7a’�’ a� G�wAix 62ao��/L,wIN 7//f PIdJM’A APTER

INr2441uJc�/L�4P IM%fCT/ON

1’IG. 7. The 1)115mn1 curve of nornial unlabeled y-glohulin in a child with con-genital againmaglobulincinia after intramuscular injection. The half-life of the

descendmg slope, after the steady state was reached, was 30 clays in this instance.

trations of albumin, “-globulin, and iron-

binding globulin found in this disease are

(Itle to a greatly increased fractional rate

of catabolism in coml)ination with severe

urinary losses (Table I). The over-all loss

of albumin, for example, is so great that

these children lose at least half of the total

body p1�ssnia albumin every 12 hours. The

rate of synthesis of these proteins in this

disease is not greatly increased. It is in-

teresting that in a child with a mild ne-

phrotic syndrome, i.e., with minimal or no

ascites and minimal edema, the low plasma

protein concentrations may be due either

to severe urinary losses or to an increased

fractional rate of catabolism, but not both,

Fie. 8. Sections of human lymph nodes after stimulation with diphtheria toxoid; stained by

the fluorescent-antibody method. The white areas indicate diphtheria antitoxin in the cytoplasm,

and occasionally the nuclei, of plasma cells. (x 1200.)


Patient Stage of Di.!ea.ie

Per Cent of Body Pool Turned Over Per Day

CaIaboli.�m Urinary Lo88 Total

Album inIt.S.B. Latent 4.0 0.7 4.7

A.B.� . . .

E.Tj Mild (mimmnimal edema)

25.�

7.99.3

23.734.5

31.6

KS.S.L. Severe (anasarca and ascites)D.W.

43.433 . 1

16.�

�O.451 .8

�

63.884.9

83.8

Nornial (average) 5.0

LJVNTMES/JI

I OW DfNJ/TV- 4-LIPOPROTEIN

(�xL/P/Ds)M6�X

NfPN�a’T/c

[JYNrMEJ/JJ

4Lo141/iv3,

A�’�AM(41 QC7�fF,4TTk’,4C/DJ fkUtl

PLAJUA

AL 8�/A1/N

�QE4IO�’AL � ,c�QFEFAT�fr- .4C/DS P’�l

P�ASA1A


NaQ1WAL

4 L/P�VTJ,

Fic. 9. A simplified diagram of the metabolism of f11-lipoprotein in normal mdi-

viduals and in children with the nephrotic syndrome.

Fic. 10. Sections of biopsies from a child with afibrinogenemia stained for fibrmnogenby the fluorescent-antibody method. A + B : Absence of fibrinogen from the connective

tissue (arrows) of skin (A) and muscle (B). C + I): Presence of fibrinogen in the

connective tissue of skin (C) and muscle (D) biopsies taken 24 hours after the intra-venous infusion of fibninogen. (All x210.)



genital, but not the acquired, form of the

latter disease, where concentrations of �

globulin between 50 and 100 mg/1(X) ml

Lr(’ iiot iincon�inon.� ‘ That nephrosis and

aganiii�aglobulinein ia are distinguishable

clinically, cannot l)C argued, but there are

iIl(liVi(1llalS �vitIi an isolated finding of

severe hypogamniaglobulineniia on the

basis of increased catabolism, just as in

nephrosis. These are taken simply as cx-

aI’IlI)les. AIlother example of similar nature

is hY1)oall)u11�ineflhia as a result of failure in

� in contrast to idiopathic hypo-

albuminemia on the basis of an increased

fractional rate of catabolism.�� There are

many other examples.

Similarly, in cases where a high plasma

concentration of a specific protein may exist,

it is not possible to predict in advance

whether there is an increased rate of syn-

thesis or a decreased fractional rate of ca-

tabolisni or loss. In the nephrotic syndrome,

for example, all of these factors play a pant

in the production of the hvpercholes-

terolemia and hyperlipoproteinemia found

in this disease. In the iiormal individual, low-

density �i-lipoproteins, containing relatively

large amount of lipid, are synthesized an(l

released into the I)la5I�k1; these are in part

catabolized directly, but for the most part

are conyerted into high-density �-iipopro-

teins, or �-liI)Opr0teins �vith less lipid, al-

l)urnin I)elng necessary in the mechanism

for the removal of released fatty acids (Fig.

9). The low-density �-lipoproteins are ca-

tabolized at a definite rate. In the nephrotic

Fir.. 11. Sections of lungs from children succumbing to “hyalinemembrane disease,” stained for fibrin by the fluorescent-antibody

method. The white areas, indicating fibrin, clearly delineate themembranes in the alveolar ducts. (x210.)


ANIERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 669

Fic. 12. Sections of tissue frons patients with “collagen diseases”

stained for fil)rin (white areas) by the fluorescent-antibody niethod.A. Fibrin in a rheuiiiatoid nodule. ( X 100.) B. Fibrin in the pro-

liferating intiiiia of a renal blood vessel in a patient with polyarteritis.

(x210.) C. Fibrin in the glomerulus of a child with lupus erythe-iii�ttostis disseniinatns. (x210.) I). Fil)rin in niyocardial connectivetissue and around necrotic muscle fibers in a child with hipus

erythematosus disseminatus. (x 210.)

syndrome, there is a greatly increased syn-

thesis of low-density or lipid-rich �-lipopro-

teins as �vell as a decreased rate of conver-

sion to the high-density �-lipoproteins.54

The poor rate of conversion is apparently

due in part to the very low concentration

of all)umin in the plasma encountered in

this disease.�� Consequently, as the result

of these factors, there is an accumulation

of the low-density �l-iipoproteins in the

plasma with the accompanying lipids.

This study of the metabolism of the

Plu5�11 1)rOteins has sometimes led us intostrange Paths. In a study of the distribution

of fibroiiiogen, it was found that this pro-

tein also diffuses from the vascular system.26

It, too, is normally present in the intersti-

tial fluids.’ In a Patient with afibrino-

genemia, fibninogen given intravenoushr can

l)e detected in the contiective tissues within

24 hours (Fig. 10). A study of the nature of

the hyaline membrane found in certain

newborn infants succumbing to asphyxia27

revealed that this membrane is made up

principally of fibnin, as demonstrated by the

fluorescent antibody method (Fig. 11). As

there is little or no fibnin demonstrable in

human amniotic fluid, the fibrin in the hya-

line membrane must have come from the

infant. Fibnin cannot traverse the capillary

walls, but fibrinogen can. It would appear

from the evidence obtained that the hyaline

membrane is formed as the result of an

effusion from the pulmonary capillaries, the

fibrinogen in the effusion being then con-

verted to fibrin. Because amniotic fluid con-



tains thromboplastic materials, its presence

in the lung at the time of the effusion would

enhance the conversion of fibrinogen to

fibnin. The cause of the effusion, however,

has not yet been � Amniotic

fluid in the lung apparently does not induce

such effusions. We are inclined to the opin-

ion that this effusion may be accounted for

on the basis of left ventricular failure, pos-

sibiy due to sudden increase in peripheral

resistance encountered when the umbilical

cord is tied off.

A study of the nature of fibninoid in col-

lagen diseases�#{176} has led us to the conclusion

that the bulk of the fibninoid material

found in these lesions is also fibnin (Fig. 12).

The lesions in these diseases would appear

to be inflammatory in nature rather than de-

generative.

ACKNOWLEDGMENTS

These studies were made possible by the

generous support of the following organiza-

tions: the National Institute of Arthritis and

Metabolic Diseases of the United States

Public Health Service, the Playtex Park Re-

search Institute, the Children’s Cancer Re-

search Foundation, and the Muscular Dys-

trophy Associations of America. We are in-

deed grateful to Mead Johnson & Company

and the American Academy of Pediatrics for

the recognition accorded our studies, there-

1)y supplying us with an added incentive

to continue.

REFERENCES

1. Sterling, K. : The turnover rate of serum al-

bumin in man as measured by I��’tagged albumin. J. Clin. Investigation,32:746, 1953.

2. Citlin, D., Latta, H., Batchelor, W. H., and

Janeway, C. A. : Experimental hypersen-sitivity in the rabbit; disappearance rates

of native and labeled heterologous pro-

teins from the serum after intravenous

injection. J. Immunol., 66:451, 1951.3. Dixon, F. J., Talmage, D. W., Mauren,

P. H., and Deichmiller, M. : The half-life of homologous gamma globulin (an-tibody) in several species. J. Expen.Med., 96:313, 1952.

4. Berson, S. A., Yaiow, R. S., Schreiber,

S. S., and Post, J.:Tracer experimentswith J131 labeled human serum albumin:

distribution and degradation studies. J.Clin. Investigation, 32:746, 1953.

5. Gitlin, D., Janeway, C. A., and Fanr, L. E.:Studies on the metabolism of plasmaproteins in the nephrotic syndrome. I.Albumin, �-globulin and iron-bindingglobulin. J. Clin. Investigation, 35:44,1956.

6. Robertson, J. S. : Discussion. Fourth An-nual Conference on the Nephrotic Syn-drome, Metcoff, J., Ed. New York,National Nephnosis Foundation, 1952.

7. Coons, A. H., and Kaplan, M. H. : Locali-zation of antigen in tissue cells. II. Im-pnovement in a method for the detectionof antigen by means of fluorescent anti-body. J. Expen. Med., 91:1, 1950.

8. Coons, A. H., Leduc, E. H., and Connoily,

J. M. : Studies on antibody production. I.A method for the histochemical demon-stration of specific antibody and its ap-plication to a study of the hyperimmunerabbit. J. Exper. Med., 102:49, 1955.

9. Gitlin, D., Landing, B. H., and Whip-pie, A. : The localization of homologousplasma proteins in the tissues of younghuman beings as demonstrated withfluorescent antibodies. J. Exper. Med.,97:163, 1953.

10. Citlin, D., and Janeway, C. A. : Studieson the plasma proteins in the interstitialfluid of muscle. Science, 120:461, 1954.

11. Rothschild, M. A., Bauman, A., Yaiow,R. S., and Berson, S. A. : Tissue distni-bution of 1131 labeled human serum al-bumin following intravenous administna-tion. J. Clin. Investigation, 34:1354,1955.

12. Citlin, D., and Janeway, C. A. : The dy-namic equilibrium between circulatingand extravascular plasma proteins. Sci-ence, 118:301, 1953.

13. Bruton, 0. C., Apt, L., Gitlin, D., andJaneway, C. A. : Absence of serumgamma globulins (abstract). Am. J. Dis.Child., 84:632, 1952.

14. Janeway, C. A., and Gitlin, D. : The gammaglobulins, in Advances in Pediatrics,Levine, S. Z., Ed. Chicago, Yr. Bk. Pub.,in press.

15. Gitlin, D., and Janeway, C. A. : Agamma-globulinemia. Congenital, acquired andtransient forms, in Progress in Hema-tology, Tocantins, L., Ed. New York,

Crune & Stratton, 1956.16. Janeway, C. A., Apt, L., and Gitlin, D.:

Agammaglobulinemia. Tr. A. Am. Physi-cians, 66:200, 1953.

17. Good, R. A., and Zak, S. J. : Disturbancesin gamma globulin synthesis as “expeni-



ments of nature.” PEDIAmIc5, 18:109,1056.

18. Craig, J. M., Gitlin, D., and Jewett, T. C.:Response of lymph nodes of normal chil-

dren and congenitally agammagiobulin-ernie children to antigenic stimulation

(abstract). Am. J. Dis. Child., 88:626,1954.

19. Leduc, E. H., Coons, A. H., and Connollv,

1. XI. : Studies on antibody production.II. The primary and secondary responsesin the popliteal lymph node of the

rabbit. J.Exper. Med., 102:61, 1955.20. Gitlin, D., Hitzig, W. H., and Janewav,

C. A. : Multiple serum protein deficien-cies in congenital and acquired agamma-globulinemia . J. Cliii . Investigation, inpress.

21. Citlin, D. : Low resistance to infections:

Relationship to abnormalities in ��-glubu-liii. Bull. N.Y. Acad. Med., 31:359,

1955.22. Bennhold, H., Peters, H., and Roth, E.:

Uber einen Fail von kompletter Anal-

buminaemie ohne wesentliche klinischeKrankheitszeichen. Verhandl. Deutsch.

Gesellsch. inn. Med., 60:630, 1954.

2:3. Citlin, D., Janeway, C. A., and Kaitz, A.:Unpublished data.

24. Gitlin, D., and Cornweii, D. : Plasma lipo-

protein metal)oliSm in normal individuals

and in children with the nephrotic syn-drome (abstract). J. Clin. Investigation,35:706, 1956.

25. Rosenman, R. H., Friedman, M., and

Bvers, S. 0. : The causal role of plasma

albumin deficiency in experimentalnephrotic h�sperlipemia and hypercho-

lesterolemia. J. Cliii. Investigation, 35:522, 1956.

26. Gitlin, D., and Borges, W. H. : Studies on

the metabolism of fibrinogen in two pa-

tients with congenital afibrinogenemia.

Blood, 8:679, 1953.27. Citlin, D., and Craig, J. M. : The nature of

the hyaline membrane in asphyxia of the

newborn. PEDIATRICS, 17:64, 1956.28. Farber, S., and Wilson, J. L. : Atelectasis

of the newborn; a study and critical re-

view. Am. J. Dis. Child., 46:572, 1933.29. Miller, H. C., and Hamilton, T. H. : The

pathogenesis of the “vernix membrane.”

Relation to aspiration pneumonia in still-born and newborn infants. PEDIATRICS,3:735, 1949.

30. Citlin, D., and Craig, J. M. : Studies onthe nature of fibrinoid in the collagendiseases. Am. J. Path., in press.


1957;19;657Pediatrics David Gitlin

Johnson Award AddressSOME CONCEPTS OF PLASMA PROTEIN METABOLISM, A.D. 1956: E. Mead

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/19/4/657including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlentirety can be found online at: Information about reproducing this article in parts (figures, tables) or in its

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:


http://http://pediatrics.aappublications.org/content/19/4/657http://www.aappublications.org/site/misc/Permissions.xhtmlhttp://www.aappublications.org/site/misc/reprints.xhtml

1957;19;657Pediatrics David Gitlin

Johnson Award AddressSOME CONCEPTS OF PLASMA PROTEIN METABOLISM, A.D. 1956: E. Mead

http://pediatrics.aappublications.org/content/19/4/657the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1957 by thebeen published continuously since 1948. Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has


http://pediatrics.aappublications.org/content/19/4/657

Date post:	23-Oct-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

SOME CONCEPTS OF PLASMA PROTEIN METABOLISM, A.D. …660 CITLIN-PLASMA PROTEIN METABOLISM analogous...

Documents