The nature of postirradiation repair in the livers of rats irradiated during hypokinesia is investigated. Hepatocyte population counts, mitotic activity, binuclear cell content, and karyometric studies were done to ascertain the effects of combined hypokinesia and radiation. Hypokinesia is shown to change the nature and rate of post-irradiation changes in the liver, the effect varying with the timing of irradiation relative to the length of hypokinesia. It is concluded that the changes in the compensatory and restorative processes are caused by stress developed in response to isolation and restricted mobility. By changing neuroendocrine system activity, the stress stimulates cell and tissue repair mechanisms at a certain stage essential to the body's reaction of subsequent irradiation

Chernov, I. P.

Trusova, L. V.

English

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NASA TM-76513NASA TECHNICAL MEMORANDUM
COMPENSATORY AND RESTORATIVE PROCESSES
OF ANIMALS IRRADIATED DURING HYPOKINESIA
F. Chernov and L. V. Trusova
THE NATURE OF COMPEKSATORY	
N 81 -27779
pROCESSES IN THE LIVENS OF
ANIMALS IRRADIATED DURING HYPOKI1,iESZA	 UnclaS
cs and Space	
CSCL 06R G5/51 26875rNation l Aeronaut 
Administration) 11 p
Translation of "Kharakter kompensatorno-vosstanovitel'nykh protsessov
v pecheni zhivotnykh, obl.uchennykh v usloviyakh gipokinezii It
skaya radiologiya, Vol. 24 , No. 4, April 1979, pp. 42-417.
-X
4 .^^FP
THE NATURE Ol
IN WE LIVERS
I.
(NASA-Tti-76513)
AND RESTORATIVE
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
WASHINGTON, D.C. 2Q546	 JULY 1981
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STANDARD TITLE ,PAGE
1C
^i
h:
r
i
I	 '
1. RgMrt No. 2. Government Accession No, ? Recipient's Catalog No.
NASA TM-7 6511
4. Title and 3vbtiHe S
^u^y
 ^ $1THE NATURE OF COMPENSATORY AND RESTORA-
6. poefo aeing orpni wionCedeIVE PROCESSES IN THE LIVERS OF ANIMALS
RRADIATED DUBING HYPOKINESIA
7. Autiwds) i. Performing Organisation Report No.I. P. Chernov and I,. V; . Trusova
Pavlov Medical Institute, Ryazan 10. work Wit No,
1. lrer4rming Orgeni sotaon Nome and Address 11. Contract or Gran o No.
teo•Kanner Associates NASW-1199
19. Typo of Report and PorioA CoveredRedwood City, California 94 , 0 63
Translation
12. $Ponseeing Agent: y Nome enti A"ress'
National Aeronautics and Sp&cc Adminis —
trat on, washington, D. C.
	
20546
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►eneoring Agency Code
13. Supplementary Notes
Translation of "Kharakter kompensatorno-vosstanovitel'nykh
protsessov v pec4eni,zhivotnykh, obluchennykh v usloviyakh
gipok	 )ezii•, 11 Meditsinskaya radiologiya, Vol.	 24, No.	 4,
April 1979, pp,	 42-47.
16,	 Alsrreet
150 nonl'ineal rats were divided into 4 groups and.subjected
to irradiation after varying pdriods of hypokl.nesia.'	 Hepato-
cyte population counts, mitotic activity, binuclear cell Conte
and karyometric studies were done to ascertain the'effects of
combined hypokinesa,and radiation.	 Hy'pokinesia was shown to
change the nature and rate of postirradiaFt".on changes.in the
liver,,the. effect varying with the timing of irradiation
relative , to the longth of . hypokinesia..
'	 r
17. Key words (Selected by Author($)) ism►uti^n Ste m n
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from VAAP.
THE NATURE OF COMPENSATORY AND RESTORATIVE PROCESSES
IN THE LIVERS OF ANIMALS IRPADIATED DURING HYPOKINESIA
1. P. ChernoV and L. V. Trusova
Pavlov Medical Institute, Ryazan
- Available information on the combined effects of hypokinesia and /42#
radiation on the body and certain of its functions is contradictory
(V. M. Seraya and 1. A. Abakumova; N. A. Ilyushko; R. A. Belitskaya and
L. Ye, Yegorov ­ Keizer and Putten). This situation may be explained
by the fact that the irradia^.Ion was done during varying periods of
the hypokinetic state,, which,, according to current ideas (Ye. A. Kova-
lenko), consists of stages.
In view of this fact, we attempted with the aid of several quanti-
tative tests to discover the nature of postirradiation repair in the
livers of rats irradiated during; 	 of hypokinesia showing the
greatent fluctuations in body resistance, as ascertRined by survival
rate studies, b f,,haviorol reactions, and body and organ weight figures.
Materials and Methods
Experiments were done on 150 nonlineal inale rats with initial weights
of 150-170 S. A state of hypokinesia was achieved by keeping tAe animals
in containers restricting movement in all directions. Total y-radiation,
in 800-rad doses with dose strengths of 65 rads per minute, was adminis-
tered on a "Luch" installation. The experiment consisted of 4 series.
Series I was irradiation of intact rats (control). In series 11 the
animals were irradiated on the 3Pd day of hypokinesia, when they had
lost 12% of initial body weight and there was high functional activity
or the hypothalamus-hypophysis-adrenal system (plasma hydroxycortico-
steroid content was 14.83 v,s%, versus 6.3 Vjg% in the intact rats). Series
III of the experiments consisted of rats irradiated on the 20th day of
hypokinesia, when weight figures and hypothalamus-hypophysis-adrenal,
system activity were at near-initial levels, and the survival rate of
*Numbers, in the margin indicate pagination in the foreign text.
these animals by the 45th day significantly exceeded that of the controls
(75 :t 8.18%, versus 30 + 10.1%). Radiation sickness in series 11 and III
rsibs was doncomitant with the hypoklnesia. In series Wthe irradiation
was done on the 3rd day of the recovery period following the 20-day
hypokinesia, when the animals appeared exalted by their release from
the containers and their resistance to radiation remained elevated
(survivability in this group amounted to 58.33 + 10.1% and significantly
exceeded that of the controls; P < 0.02). The animals In all series
were decapitated 1, 3, 10, 30,, and 1 5 days following irradiation. Liver
sections were fixed in Carnoy's fluid and sealed In paraffin, stained
with hematoxylin-eosin ,  and Feulgen stained for DNA. I-Tepatocyte popul-
ation numbers were computed within the standard, visual field (in an
eyepieo ,,
 grid square with a total. 	 of 1350X), and the
percentage of cells in the Irradiated animals was calculated relative
to that in the initial period prior to irradiation. The number of
mitoses and binuclear cells per 1.000 hepal;ootytes was counted in the
liver preparations. The karyometry was done using an eyepiece micrometer.
Large (L) and small (S) diamctQrt5 were measured and the volumes were
ascertained using the formula V = IT - L D 2. Ploidy was determined from
nuclear volume, since it has been demonsi"rnted (Mortreuil-Langlois;
Z. A. Ryabinina and V. A. Benyush) that ploidy in the liver, as calculated
from nuclear volumes, correlates with data obtained from DNA content
measurements. Nuclei with volume logarithms of 2.05 (112 pm3 ) were
categorized as diploid and those Wt;h volumes of 224 jim 3 and above were
categorized as polyploid. In all series the counts and measurements were
performed on 5 rats for each period, the results were subjected to
variation statistics methods (I. A. Oyvin; Ya. Ye. Khesin), and the
statistical significance was determined using Student's criteria.
Results and Discussion
Irradiation of intact rats led to reduced numbers of hepatocytes
by the end of the Ist day (table 1). As the variability in cell dimen-
sions increased during the later stages of raddation sickness, population
numb-Ors differed insignificantly from initial data. Large hepatocyte8
Initially predominated in the livers of rats irradiated on the 3rd and
20th days of bypokinesia and during the readaptation period. Subsequent
2
':19±2,6
I Irradiation with-
out additional
" influences 1no±2,,;
II Irradiation on the
3rd day o.f hypokin.110*2,4:
III Irradiation on P
°0,ir.►
the 20th da y of
hypokine sia
	P u;4xl1
IV Irradiation on
the 3rd day of
reada,ptation after.
hypokinesia	 P +0,0:
8 4±;1,4 1 01±2,0 105:t3,2
134±4A
• (1,4K)1
130±3,9
.0,+101
14i;i+li3O
r ;0;4►QI
1311+4 ,'?
x„0,001
171±1,2
<0,IH11
111<J ±1,7
a,0
franc
to L
signi
Lative
Note: Here and in tables 2-
discrepancies in series II, III
107±3,8
121±5,6
; 0,05
162±6.6
,;0,001
120-x-:1,+3
-'0,05
of
fries I.
106.t1,8 137±0,9
,,nM 4-'0'001
143±S, 2 1 .14 -1-:► ,1i
,;0,01!1 ,.; 0,001
I IS±;1,9 1;111±1,5
4, P is the
, and IV re
TABLE 1. HEPATOCYTE POPULATION NUMBERS FOR RATS IRRADIATED WITH 800 HAD
DOSES UNDER VARIOUS EXPERIMENTAL CONDITIONS AND CALCULATED IN PERCENTS
OF INITIAL VALUES SET AT - 100 (M ± jr.).
Series # Experimental
Conditions
Back-`Observation period following
groundirradiation, in days
lst 3rd 10th 30th 45th,
irradiation led to a steady increase in the population numbers because
of increasing numbers of small hepatocytes. This process was more
significantly shown in series III of the experiments.
The liver is known (D. S. Sarkisov) to be representative of a;
group of organs whose reparative regeneration under various pathogenetic
influences is accomplished through a combination of intracellular hyper-
plastic processes in retained cells and intensified cellineoplasia 	 /45
consequent to increased mitotic activity. Varying levels of mitotic
activity appeared in the initial (background) period when analyzing
fnitotic^ ndices in the livers of the rats of series being compared
(table 2). Irradiation on the 3rd day of hypokinesia was done upon a
background of statistically significant increases in mitotic indices.
Background mitotic activity figures in series III and IV did not differ
from those in the controls. We should also note the similar trends of
hepatocyte mitotic activities in series I and II (initial inhibition,
then progressive increase) and contrasting shifts of mitotic activity
in the group of rats irradiated on the 20th day of the experiment. Liver
mitotic activity vacillated widely during the observation period when
I
ORIGINAL PAGE IS
OF POOR QUALITY
3i
 
 
 
 
 
 
"Page missing from available version"
irradiation was performed during the readaptation period. 1. B. Tokin
considers that mitotic activity inhibition occurs during -arty stages
following irradiation because most cells are repairing vadiatio n damage.
Blocking is reduced following the completion of repairs and the cells,
under the influence of mitotic activity stimulators, rapidly return to
the mitotic cycle. The lack of a mitotic inhibition phase in the livers
of series 1x1 rats indicates either that the intracj p llular repair phase
period is curtailed, o" that the amount of damage to cell structures is
reduced, or both.
The number of btnucl,ear cells in the livers of rats irradiated
without additional influences exceeded initial levels during the entire
period of the experiments (table 3). Peak increase occurred on the
30th day of the experiment:. By changing the binuclear cell content
extant prior to irradiation, hypokinesia also affected the nature of
postirradiation changes in this factor. Thus when irradiation was
performed after 3 days of hypokinesia and during the readaptation period,
the initial reaction consisted not of an increase, but of a reduction
in the total number of binuclear cells. In the rats irradiated on the
20th day of hypokinesia, however, the number of binuclear cells rose
more dramatically, after 3 days, than in the animals in the other series.
The increase in the number of binuclear cells in our experiments basically
either was consequent to or accompanied the elevation of mitotic activity.
Other investigators have also found this regularity during acute radiation
sickness (V. I. Bulgak). In the opinion of V. Ya. Brodskiy, only 	 /46
20-25% of all binuclear cells in the liver may be formed as a result
of mitosis. It is possible that the fraction of cells with incomplete
mitosis rises following irradiation ., when the frequency of chromosomal
aberrations increases. The increased frequency of binuclear cells is
viewed as a manifestation of adaptation to the effects of radiation
(I. B. Tokin). Multinuclear cells are complete units with high mitotic
activities and are considered a possible functional reserve for such
organs as the livers of mammals (Z. A. Ryabina and V. A. Benyush).
Nuclear volume measurements indicated that there was a significant
increase of this factor in the livers of series I irradiated rats can the
1st, 10th, and 30th days of the experiment (table 4). Here the number
^,	
5
M
of polyploid .cells rose up to 85, 65, and 42%, respectively, versus
37% in the initial period. Average hepatocyte nuclear volumes in the
rats irradiated on the 3rd day of hypokinesia :exceeded those in the
intact rats during the initial period, and the number of polyploid cells
in them was 52% of the intact animals'. Enlarged nuclei were recorded
only on the first day of radiation sickness in this series. In other
periods of observation, a distinct tendency was noted for nuclear size
and plbidy to diminish. Polyploid cells constituted 24% on the 10th
day of the experiment and 20% on the 45th. Nuclear volumes increased
before irradiation even more significantly in series III than in series
II, while following irradiation the average value never once exceeded
initial. The number of polyploid cells was also reduced in these rats,
amounting to 51, 57, 52, 34, and 30%, respectively to the periods of
of the experiment, versus 75% in the initial period. A similar regularity
was seen in series IV as well, where discrepancies in nuclear volume
and number of polyploid cells from initial values were least.
Thus the results of our study indicate that hypokinesia alters the
nature of postirradiation compensatory and restorative processes in
the liver. With irradiation of intact rats, restoration of liver
structures was provided at early stages of radiation sickness by cell
hypertrophy consequent to delay of mitoses and increased hepatocyte
ploidy; another form of reparative regeneration -- cell neoplasia --
gradually increased at later stages, and the fractional content of
binuclear cells also rose. This conc?.;Asion agrees with the data of
L. F. Romanova and V. N. Strel'tsova which showed the role of hepato-
cyte endomitosis and polyploidization to be a prominent type of post
irradiation restoration. A second type of restoration dominates during
the entire observation period when irradiation occurre with hypokinesia;,
It is provided by the enlarged pool of dividing cells gust before
irradiation (series II)-and by the lack of a mitotic division delay
phase in the initial period of radiation sickness (series III and IV).
We should note that the rate of cell proliferation in the initial phase
of radiation sickness is higher in series II.I animals, but in groups
I and II rats at later stages.
Lew, the changes in the nature of compensatory and restor-
as in the livers of rats irradiated during hypokinesia
are caused by stress developing in the animals in response to isolation
and restricted mobility. By changing neuroendocrIne system activity,
the latter .timulates aell and tissue repair mechanisms at a certain
stage, wh1ch is essential. In the body's reaction to subsequent irradiation.
The intimate relationship of body radiosensit.ivity to cell and tissue
repair system activity has been emphasized repeatedly (Kbossler; I. 0.
Akoyev). It has been shown that forming products of lymphoid cell decom-
position may serve as the signal for restorative process activation daring
stress (I. G. Akoyev).
OP F'^ , . ^Z?.t l n CS
7
TABLE 2,	 MITUM INDEX (111000) IN TIM LIVERS OF RATS IRRADIATED IN 000 RADDO3113 UNDER DIFFERING
EXPERIMENTAL CONDITIONS IN + ,1).
Buries Lxprrimpotal Conditions
	 Background Periods of Observation Following irradiation, Days'
1 3 10 30 45
T Irradiation along 	(
TI Irradintir^n on 3rd Ray Ilypknsa. 1,3:!±3'00,0 0.000 00±0,0310 1,33±0,0323 2.76*0,0750 3.510.1410
P
S,CA±0,1010
0,041
I,Sd±0, 19,10
-MM
1,66±0,00!20
<00l
2 166x .0510
-C IM,001
1 .00. 05100 15,00±11.2w
III Irmiiation an 20th day Itypkn * ) 04^ 021311 2,70±0 .2774 1,0R+0 . 1410 2.(K.	 0,13#0 1 t)
	
p,9050 093¢0,(>Ii1pP •41,2 <(Imoi K iT ooi x;	 01 ' 0;1 •1;0,001
IV irradiation on 3rd Day of 1166+012$10 O.f4,^, 0.1010 1 ,(A±0,0176 2,33±0,2#34 0({±0,0724 2,6610,4740Readnptatinn Period <0.001 ti0,01 X0,001 (..I
P
TABLE 3.	 NUMBmR3 OF BIRUCLEAR CELTS ( 111000) III THE LIVERS OF RATS IRRADIATED IN 800 RAD DOSES
UNDER DIFFERING BXPERIMMAL CONDITIONS (M + m).
Series Experimental Conditions 	 Background Periods of Observation Following Irradiation, Days
1 3 10 30 45
T
II
Irradint.ion alone
irraciintian on 3rd pay Hypknsa 277	 2,9633 ,,0	 I 'm 33,0.01,29 .0	 1,53 10,0±2,0240,3±0.62 31,.11	 1,2239 .0±2,28 02,0	
na
69,66±2,/5
,
630±2,^H
III
P
Irradiation on 20th Day I#ypknsa
*0,1 0,001 0.'*
47,66.11.67 9(150,33±1,99 •0,170,1;13,2.1 x:0.05A0,01±291
P X0.01 !u,(01 * ; u,05 *; 1,	 1 t ,01 *	 (1,01
IV Irradiat ion on 3rd Day of 10,9±t,1 12,4tI,H 11,01±l.tl7 57,9:0^2,97 3 ,33±2,33 4266tv0
Rendaptation Period * ,u,02 « 0.001 u,G < 0,(01 *':(1.001 ; u,t
P
TABLE 4.	 POS"]RRnDIATION FLUCTUATIONS IN NUCLEAR VOLUME (mcm3 ) OF REPATOCYTES OF RATS IRRADIATED IN 800 ICAO
DOSM UNDER DIPPLA , EXPl.IWTNTAL CONDITIONS (M + m) .
Series Experimental, Conditions 	 Background Periods of observation Following irradiation, Days
1 3 10 30 45
I
II
Ir)°ndintian alone
Irradiation an 3rd Day Hypknsa 137,1±1 ,040 205 ,64:1,031 135,8± 1,035 173 ,4±I,O,N1 1139± I,0*1 031 ,3±1,014Ifi,6±1.035 175,4±1.033 145,5	 1,0(2 125,1±1,010 134.0±1.0.16 110,1{1,0:±5P * A.W I x,0 .001 .;,0,1101 c 0,001 " 0,(M11 ' 0.001
III Irradiation on 20th Day Nypknea 10401;1,035 151,9±1,032 (62,0±1,012 163,7±1.010 133 ,0±1,017 12!1±1,012P '0,001 X0,001 <0'oll a,0,(1)1 ';'0AV1 °,0,001
IV Xrradiation on 3rd Day of 141.3±1,012 119,9±1.035 147.9±1.012 13",7±1.010 I.W1S±i.034 110.1±1.035
Roadartation Period y0,001 CO3()ll X0,001	 i a O,U01 ,0401 •;,0,001
P
8
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1. Akoyev ,  1. G., in: Radiatsionnoye porazheniye or^L,^n^i.Da [Radiation
Injury to the Body],'Mos ow, 1976, pp. 190-2116.
2. Belltskaya, R. A., and L. Ye, Yegorov, in: Aktual l nyye voprosv
kosmiche 
8 
koy biogiloi i ineditellny [Current Top7- c* IF"tp=^e
Biology and Medic i tMFicow, 1-975, Pp. 27-28.
3. Brodskiy, V. Ya.,, Trofika kletki [Cell Trophies'), Moscow, 1960.
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mediko-biol.2ZMSSicheskikh problem	 , 3-ya. Materialy r-mi^E76rYals
Prom the
-Trd 'UW Ministry or HeRah Institute 6r W-Ulcal and
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Moscow, 1969, pp. 141-1112.
6. Keizer, 11, J., and. L. M. von Putteen, Radiat. Res. 66 ., 326-336 (1976).
7. Kbesin, Ya. Ye. 
'
Razmlory yader i funktsional l noye sostoyan ye kletok
	
[Nuclear Dimen s ionsand Cell FuF-a-t-f`o=a7o	 H-T, Moscow,
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13. Ryabinina, Z. A., and V. A. Benyush, Po1ij2zloidiya i r,Ipertrofiyakletok v protsessalch rosta i vosstanovleniva Lcell Polyploidy
and Hypertrophy in Growth and Restoration Processes], Moscow, 1973•
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1969^ 1 44 -1'W-5.
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Radiation Cytology j, Leningrad, 1974.
9


The nature of compensatory and restorative processes in the livers of animals irradiated during hypokinesia

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