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7 August 1960

CHARACTERISTICS OF THE REACTION OF THE GASTROINTESTINAL

TRACT TO CHEMICAL STIMULATION UNDER CONDTITIONS OF INJURY

OF THE ORGANISM DTTJ- TO RiDIOACTIVE STRONTIUM

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by G. A. Lebedeva

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CHARACTERISTICS OF THE REACTION OF THE GASTROINTESTINALTRACT TO CHEMICAL STIMULATION UNDER CONDITIONS OF INJURY

OF THE ORGANISM DUE TO RADIOACTIVE STRONTIUM

/Following is a translation of an article byG. A. Lebedeva in Arkhiv Patologii (Archivesof Pathology), Vol. 22, No. 4, 1960, pages21-28.j

It is well known from the literature that the react-ivity of the organism is changed when ionizing radiationacts on it. The majority of works which have been conductedin this direction have been devoted to the study of react-ivity in the presence of X-ray irradiation. In the earlierinvestigations, where on the whole small dosages were used,a stimulating action of radiation was recorded (Freund,1929; Fukase, 1930; Buhtz, 1932; B. N. Mogil'nitskiy andL. A. Gol'st, 1935); communications later appeared concern-ing a lowering of the ractivity of the organism in the pre-sence of irradiation (V. V. Brunst, 1936, 1937; V. G. Garshinand co-workers, 1938; S. I. Matuskov, 1947; V. V. Shikhody-rov, 1957; A. Ye. Ivanov and V. F. Sosova, 1956).

There are only isolated communications in the liter-ature pertaining to the question of the reactivity of theorganism in the presence of injury due to radioactive sub-stances. Thus, a lowering of the inmunobiological propert-ies of the organism in the presence of the administration ofpolonium is reported (B. B. Moroz and V. V. Vasil t yevskaya,1957); a change in the reactivity of the intestine in thepresence of injury due to this isotope is described (Z. I.Poluboyarinova, 1957). The present investigation was con-ducted with the purpose of studying the tissue reaction ofthe gastric and intestinal wall in animals, injured by stron-tium (Sr90 ).

The isotope in question (a B-radiator with a particleenergy of 0.6 mev and a half-life period of 28 years) is oneof the most widely distributed products of uranium fissionand possesses considerable toxicity. When it gets into theorganism, the strontium is deposited in the bony tissue. Itsexcretion proceeds chiefly via the gastrointestinal tract.

The experiments were conducted on 120 male white rats,which were administered Sr90 intraperitoneally in a quantity

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of 0.4 uc/g of weight. The activity utilized appears to becarcinogenic and evokes insignificant morphological changesin the gastrointestinal tracts. A 10 percent solution ofacetic acid served as chemical stimulant and was administer-ed to the rats on an empty stomach through a catheter intothe stomach (1 ml)j the small intestine (0.5 ml) and thepreliminarily c.Leaned large intestine (0.5 ml) one monthafter the SrJ0 lesion. The indicated concentration of theacid was selected experimentally in order not to cause thedeath of the animals. Rats not injured by Sr90 , in whicha burn of the mucous membrane of the stomach and intestinewas evoked by an analogous method, served as control. Thecontrol and the experimental animals were killed simultan-eously at various periods (from the first to the 110th day)after the administration of the acid solution. The materialwas fixed in a 10 percent solution of neutral formalin andsealed in celloidin. The ordinary methods of staininghistological sections were used.

In the stomach of the control rats, an inflammatoryprocess developed in the mucous and submucous membraneswhen the solution was administered. It was accompanied bya change in the character of the secretion in the principalglands of the body of the stomach and by the appearance inthem of granules of a mucoidal secretion. The acute in-flammation subsided toward the seventh to tenth day. Re-sidual phenomena in the form of infiltration with roundcells and the appearance of groups of macrophages, contain-ing hemosiderin, were observed up to 20-25 days. Restorat-ion of the structure of the gastric wall was subsequentlynoted. In only one rat (on the fifth day) was erosion ofthe mucous membrane detected, and in two rats, "traces" offormer erosions were detected in the form of sclerosis ofthe submucosa and accumulations of macrophages, containinghemosiderin.

In the animals injured by strontium, the inflammatoryprocess was accompanied by the formation on the anteriorand posterior walls of the body of the stomach of broad nec-roses and hemorrhages, embracing the entire mucous membrane.On the boundary with the zone of necrosis there appeared aleucocytic projection, in which on the third to fifth daya considerable breakdown of leucocytes and a further diminu-tion of their number toward the 7-10th day was observed.Tearing off of the necrotic masses was retarded up to the15-20th, and sometimes even the 90th day. At the site oftearing off there were left ulcers, the bottom of which wasfilled with granulation tissue. The latter was rich incellular elements, the quantity of which, however, subseq-uently gradually diminished. On the lOth day collagenous

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fibers appeared in the granulation tissue, and a considerableamount of sclerosis was noted later. Eosinophil and roundcell infiltration was observed in the muscular and serousmembranes for a long time (40-110 days). Epithelization ofthe ulcer ended in some animals toward the 25-30th day; inothers it was not detected before the end of observations.Neoplastic glands, paved with mucoidal cells, often had anunusual form and were located in the submucosa. In certaincases a considerable racemose proliferation of the glandswas observed (Fig. 1). In the areas of the mucous membraneadjacent to the ulcers, dedifferentiation of the glandularcells and the appearance in them of granules of a mucoidalsecretion occurred. Goblet.shaped cells were encounteredamong the cells of the neoplastic epithelium (Fig. 2).Edema and cellular infiltration were observed in the sub-mucosal layer (the latter was observed for the course ofthe entire period of epithelization).

Thus, the most pronounced ch~nges in both groups ofanimals were observed in the region of the body of thestomach. However, this fact still fails to be a demonstrat-ion of the maximal sensitivity of the given section to theaction of chemical factors. It is well known that whensmall quantities of cauterizing substances get into thestomach, the maximal changes arise in the region of thesmall curvature (Lewy, 1886; Haberda, 1895; Strohmeyer,1912), since the liquid can not smooth out the creases ofthe mucous membrane and mechanically flows along the smallcurvature of the stomach (Ernst). When large quantities ofchemical substances are taken, the maximal changes, as theinvestigations of N. A. Krayevskiy and V. S. Mayata (1938)show, are localized in the region of the pyloric section,and here it is not the increased sensitivity of the pyloricsection which plays the basic role, but spasm of the muscul-ature of the pylorus, holding back the gastric contents inits territory. The localization of the changes in the stom-ach of the animals which we investigated was determined, ap-parently, by the location of the catheter and by the direct-ion of the stream of acid solution, being introduced underpressure and getting directly into the region of the body ofthe stomach.

After a burn of the mucous membrane granules of mu-coidal secretion appeared in the principal glands of the bodyof the stomach in rats of both groups. A similar reactioncan arise in the presence of various pathological states(Yu. M. Lazovskiy with coworkers, 1948). Among the controlanimals the mucoidal secretion was noted in the period fromthe third to the 15th day; in the experimental animals itwas sometimes observed before the end of the investigation.

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"Fig.". Stomach of a rat, injured with Sr 9 0 .RintIeth day after the administration of theacid. Defect of thev mucous membrane, filledwith necrotic masses. Racemose proliferationof the glands. Sclerosis of the submucosallayer (hematoxylin-eosin stain. X 60).

Such a prolonged change of the character of the secret-ion is associated, probably, with suppression of thedifferentiation of the neoplastic mucoidal cells.

The racemose proliferation of the 0 astric glands,noted by us in the animals injured by Sr., is closelyassociated, apparently, with an inflammnatory reaction.N. I. Churbanov (1940) considers that the nature of theheterotopic proliferations is always inflammatory. Thegrowth of the epitbelium deep down proceeds only whenthe underlying tissue is granulation tissue (V. G.Garshin, 1927). The changes noted attest concerninga certain defectiveness and distortion of the regener-ation process.

By comparing the results obtained in the experi-mental and control groups, one can establish a raisedvulnerability of the tissues in the animals injured bySr90 and the appearance of broad foci of necrosis asa result of this.

R!~ 2. Stoma-h of' rat s., injured AYithS!-,.Seventh day after the admini-

stratiors of acid. Goblet -l-ike cells.IP tWha epithelium of t~he neoplasticmuou membrane (Stained with -muci-carmine by the. Meier meth~od. X 60).

In te sallintetin ofthe cont-rol rats,

a~ter th adnninist-ation of' the acid solut-ion th-rearose an acute inflmmmation vrithn the fonrmatnion of'

supefical ecrsesand hemorrhages, destruction.of he pitheommof hecryjpts, adleucocyticIn

Ji.tration of the ,xacous membranne and the stibmucosa"Ilayer were observed., Tearing off' of the necroticmas~ses began from the first day; epithelizatior, ofthe eros-Iorns whhich had formed began from the secondday, and ended on the fourth day. Residual phenomenain the form of~ round cell infiltration of' the sub-MIUcosa,-layer were noted on the fifth day. 'No changesrin the intesti1ne, were observed subs'-quen~.y,

Amon- the an.-imals injlured wdith Sr 'J, as wellas among Ithe control animals, the development of an±nfla-minatory process, the appearance of' superficialnecroses, hemorrhages, the destruction of the epthL-

ium of the crypts* was determined. The epithelizationof the erosions, Which had formed after tearing off thenecrotic masses, began from the third and ended towardthe seventh day. Irregularly located deformed villiwere encountered in the neoplastic macous membrane.Residual phenomena in the form of small acctumulationsof round cell elements in the suobmucosal layer werenoted on the 10-15th day. No changes were subsequent-•ly determined.It is evident from the data presented thatchanges in the small intestine are expressed consider-

Pig. 3. Large intestine of a controlR. e First day after the administra-

tion of acid. Acute inflammation. Ne-crosis and hemorrhages in the mucous mem-brane.. Leucocytic infiltration of thesubmucosal layer (hematoxylin-eosin stain.X 100).

ably more weakly than in the stomach and the large in-testine (see below). The epithelization of ulcers andthe restoration of the structure of the mucous mem-brane set in here rather rapidly. The lesser suscepti-bility to injury, possibly, is explained by the factthat the aeid administered is partially neutralized. bythe alkaline contents of this section. It is also well

known that the small intestine possessed a larger regenerat-ive capacity in comparison with the other sections of thegastrointestinal tract (Friedman, Warren, 1942).

Th6 comparison of the changes in the experimental andthe conti01 groups shows a later epithelization of the eros-ions in the experimental animals (those injured by strontium)and the appearance among them of atypically located villi inthe neoplastic mucous membrane.

Ln the large intestine of the control rats after theadministration of acid there developed an acute inflammationwith the formation of superficial necroses and hemorrhages,and destruction of the epithelium of the crypts was observed(Fig. 3). On the third day necrotic masses were torn offinto the lumen, on the fifibh day -- epithelization of theerosions which had formed began. The destruction of theepithelium of the crypts was determined in the course of thefirst three days; however, in certain cases it was retardedto the 15th day. In the neoplastic mucous membrane an in-crease in the number of goblet-like cells and their over-crowding with mucus was noted. Residual phenomena in theform of round cell infiltration of the submucosa were de-tected on the 20th day,. No changes in the intestine weresubsequently determined.

Among the experimental animals after the administrat-ion of the acid, necrosis of the entire mucous membrane, andsometimes also of the submucosa, was observed, and also theformation of a leucocytic projection (Fig. 4). In the courseof the first 2 weeks new foci offnecrosis appeared as a con-sequence of the perishing of the old leucocytic projectionand the areas of underlying granulation tissue (Fig. 5). Atthe site of tearing off of the necrotic masses (30th dayafter the administration of acid) ulcers were left with theformation of granulation tissue at the bottom. The cellu-lar composition of the inflammation infiltrate was gradu-ally changed. In the first day, neutrophil leucocytes pre-dominated, which subsequently underwent breakdown; on thethird day macrophages appeared, on the seventh day -- eosin-ophils, fibroblasts, and then lymphoidal and plasmatic cellsappeared. The beginning phenomena of organization of granu-lation tissue in the form of coarsening of the collagenousfibers, a diminished number of cellular elements, were notedon the 15-25th day; however, in individual animals the pro-cess was drawn out until the 50th day. Epithelization ofthe ulcers began from the third day and ended in general onthe 60-80th day, The neoplastic mucous membrane was of ir-regular thickness; the widened intestinal crypts, containingmany goblet-like cells, had an atypical form and were oftenlocated in groups in the submucosal layer. Residual phenomena

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Fig. 4. Large intestine of a rat injuredy r. First day after administration of

acid. Acute inflammation. Necrosis of themucous and submucosal membranes. Leucocyticinfiltration of the muscular layer (stainingwith hematoxylin.-eosin. X 100).

in the form of round cell infiltration of the submucosa,thickening of the muscularis mucosae, and accumulationsof macrophages, containing hemosiderin, were observedup to the last period of the investigation. In theareas of the mucous membrane adjacent to the ulcers,destruction of the epithelium, broadening of the lumensof the crypts, and accumulation in them of products ofcellular breakdown, were noted. 'ese phenomena sub-sequently disappeared; however, in the crypts a con-siderable quantity of goblet-like cells were detected.An inflammatory reaction was also noted in the serousmembrane, where sclerotic changes appeared in laterperiods.

The localization of injuries in the large in-testine (the middle or the lower third) correspondedto the location of the catheter, through which the ad-ministration of the acid was performed.

A comparison of the changes in the experimentaland the control'animals showedoa different degree of

2Fi 5. Large Intestine of a rat injuredwith S;0. 15th day after the administra-tion of acid. Perishing of an old leucocy-tic projection and an area of underlyinggranulation tissue. Formation of a newprojection (hematoxylin-eosin stain. X 80).

injury of the large intestine. In the control animalsthe superficial areas of the mucous membrane were sub-jected to necrosis; in the animals injured with stron-tium -- the entire mucous membrane and the submucosallayer were ,subjected to necrosis. In addition, in thesubsequent 15 days in the experimental animals thezone of necrosis was enlarged as a consequence of theperishing of the leucocytic projection and of thesection of underlying granulation tissue. The processof tearing off of necrotic masses was retarded up to30 days. The epithelization lasted until the 60-80thday. In the control rats the restoration of the epi-thelial cover ended on the fifth day. In both groupsof animals the destruction of tte epithelium of thecrypts in the areas of the mucous membrane adjacentto the zone of necrosis was observed, In tne controlgroup it was noted in the course of 15 days, in theexperimental animals it was retarded until the. end ofepithelization of the ulcers. The neoplastic mucousmembrane had an irregular thickness; atypical forms

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of cryptp were encountered in it, which were located in thesubmucosa layer and were rich in goblet-like cells,

It should also be noted that the changes in the nervecells of'the Auerbach plexus of the stomach and intestine inthe control and experimental animals were not identical.Thus, inthe rats not injured with strontium, the number ofchanged heurons was very small and injury of the-mucous mem-brane was only observed in spots; in the experimental animalsthese disturbances were of a more pronounced character.

In summarizing the results of all three series of exper-iments, it should be underlined that under conditions of in-jury of the organism with radiostrontium, the administrationinto the gastrointestinal tract of a solution of aceticacid evoked in them the development of an-acute inflammatoryprocess, which, in spite of certain peculiarities of thecourse in each section (the'stomach, the small and large in-testine), was characterized by a number of common factors.All the phases of the inflammatory process in the injuredanimals were considerably drawn out in time, which led tothe prolonged existence and slow healing of the ulcers whichformed. A raited vulnerability of the tissues and the forma-tion as a consequence of this of broad foci of necrosis wasobserved. The fusion end tearing off of necrotic masses wassignificantly retarded. A slowing and sometimes a distortionof the process of regeneration occurred, as a consequence ofwhich structures atypical for the given organ arose (race-mosely proliferating glands and goblet-like cells -- in themucous membrane of the stomach). In certain animals completeepithelization of the ulcers was not observed in the courseof the entire period of the investigation.

The results obtained attest to the lowering of thereactivity of the gastrointestinal tract under conditions ofinjury of the organism by radioactive strontium. The changesin the neural cells of the Auerbach plexus of the stomachand intestine, detected by us, apparently play a definiterole in the development of the described disturbances.

In conclusion it should be noted that, in spite ofthe scantiness of morphological changes, arising in thegastrointestinaltract in the presence of the administrationof such a quantity of radioactive strontium, injury of theorganism by the indicated isotope leads to the appearance ofa certain defectiveness of the course of the inflammatoryand reparative processes, which is rather clearly manifestedwith the aid of the methods which we used.

Conclusions

1. The reaction of the mucous membrane of the gastro-

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intestinal tract to chemical stimulation in the presence ofthe intraperitoneal administration of St90 is characterizedby a number of peculiarities: a) in the presence of the actionof a chemical stimulant a raised vulnerability of the tissuesis Oberved; b) all phases of the course of the inflammatoryprocess are considerably dran out in time; c) a retardation,and iometimes also a distortion of the regenerative process,is noted.

2. The changes detected attest to a lowering of thereactivity of the gastrointestinal t3act under conditionsof injury of the organism due to Sr90

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Submitted 10 May 1958

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