Pathogenesis of Polyarteritis Nodosa in Hypertensive...

Pathogenesis of Polyarteritis Nodosa inHypertensive Rats

By GEORGE J. RACE, M.D., AND ERNST PESCHEL, M.D.

The pathogenesis of the vascular lesions of polyarteritis nodosa found in young rats with experi-mental renal hypertension is described. The panarteritic lesion was a product of the combinationof renal injury and feeding sodium chloride. It began with a fibrinoid necrosis of the intima andmedia which was followed by an extensive inflammatory reaction with subsequent fibrosis of alllayers of the vessel wall.

DURING the course of investigations ofthe effects of dietary factors uponyoung hypertensive rats, a character-

istic panarteritis rather frequently developed inanimals receiving varying amounts of supple-mentary sodium chloride in the diet. Thislesion is not unlike the lesion of human poly-arteritis nodosa. Similar lesions have beenpreviously reported in aged rats as a spon-taneously occurring vascular disease,1 in youngrats Avith renal damage due to alloxau and useof a 10 per cent sodium chloride diet,2 in ratsgiven desoxycorticosterone and sodium chlo-ride,3 and in rats made hypertensive by varyingexperimental procedures. In addition, an acutenecrotizing arteritis has been produced bypurely mechanical, transient elevation of theblood pressure.4 The etiology of the panarteriticlesion has been considered by the aboveauthors and others.6' 6

Inasmuch as the arterial lesions observed byus have many similarities to, but also notabledifferences from, the lesions described by theprevious authors, a morphologic description ofthe pathogenesis is deemed worthwhile.

EXPERIMENTAL PROCEDURE

Twenty normal and 80 hypertensive female ratsof the Osborn-Mendel strain were used. The latter

From the Departments of Pathology and Medi-cine, Duke University School of Medicine, Durham,N. C.

This investigation was supported (in part) bygrants from the Anna H. Hanes Research Fund andthe National Heart Institute of the National In-stitutes of Health, United States Public HealthService.

Received for publication June 14, 1954.

were made hypertensive by the technic of renalencapsulation and subsequent contralateral ne-phrectomy. Details will be included in a subsequentpaper.7 At the time of nephrectomy,the animals wereapproximately 40 days of age and had a systolicblood pressure of from 100 to 120 mm. Hg. Subse-quently, the blood pressure rose within four to sevendays to 180 to 220 mm. Hg, often followed by risesto 300 mm. Hg or more. The animals were then fedvarying diets containing varying amounts of sodiumchloride, as outlined in table 1. The hypertensiveanimals were allowed to die spontaneously. Noselection for microscopic study was made except forgroup II ; these represent animals with a survivaltime similar to that of the other groups. The normo-tensive controls were killed at varying intervals tomatch the average age at death of the hypertensivelats. Complete autopsies were done and histologicsections prepared from all organs, including theperipheral vessels, and, in addition, from the arteriallesions where they were observed grossly. All arteriallesions were stained with hematoxylin and eosin,and representative examples were stained with theVerhoeff-Van Gieson elastic tissue stain, the periodicacid-Schiff stain, the Masson trichrome stain forconnective tissue, and theMcCallum bacterial stain.

RESULTS

The hypertensive rats died spontaneously atan average age of 127 days. A contributingcause of death in many cases was broncho-pneumonia. The incidence of polyarteritisnodosa in this series of young animals was 31.2per cent (as contrasted with 9.7 per cent occur-ring in the aged rats with an average age of 856days'). No instance of polyarteritis occurred inthe 20 normal control rats. The distribution ofthe lesions, in order of frequency, was: mesen-tery, pancreas, spleen, extremities, ovary, andheart.

Grossly, the lesions were detected in themesenteric and occasionally in pancreatic

483 Circulation Research, Vol. 11, November 1954

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484 PATHOGENESIS OF POLYARTERITIS NODOSA

TABLE 1.—Correlation of Diet, Survival Time, Degree of Hypertension, Heart Weight and Incidence ofPolyarteritis in 80 Rats xoith Experimental Hypertension

Group No. and Diet

I. Normotensive Controls. Dog Chow (20 Gm./Day, Containing 200 mg. NaCl)

II. Rice, Plus 25-50 mg. NaCl Daily throughoutLife

III. Rice 50% with Meat, Plus 25-75 mg. NaClDaily throughout Life

IV. Rico, Plus 75 mg. NaCl Daily (NaCl for 1-3Weeks Only)

V. Different Foods Consisting of Carbohydrateand Small Amounts of Protein, Plus 75 mg.NaCl throughout Life

VI. Rice, Plus 50-250 mg. NaCl Daily throughoutLife

Totals for Hypertensive Animals

No. ofAnimals

20

10

12

IS

IS

22

SO

Avg. age atDeath (Days)

130(31-413)

135(57-454)

114(54-259)

127(58-271)

123(54-204)

133(55-302)

127(54-454)

BloodPressure

Avgs.(systolic;mm. Hg)

112

190

190

195

223

237

211

Heart Wt.>n %

o( Body Wt.

0.40

0.62

0.59

0.71

0.71

0.74

0.69

Incidence ofPolyarteritis

No. ofAnimals

0

i

I

7

S

s

25

% withinGroup

0

10%

S.3%

3S.9%

44.4%

36.4%

31.2%

arteries. They usually formed tortuous, ad-herent, nodular masses. The degree of involve-ment was extremely variable and ranged froma single 3 mm. nodule to extensive accumulationof nodules which included the entire mesentericarterial system. The diameter of the nodulesranged from 1 to 10 mm. The affected vesselswere of medium to small size. Gross examina-tion alone failed to reveal the lesions in periph-eral vessels or parenchymatous organs.

Microscopically, the arterial changes wereinvariably those of a panarteritis. Three stagesof development, based on necrosis, presenceand type of inflammatory exudate, and degreeof healing, were observed: an acute, a subacute,and a healing stage.

The acute lesions were seen in the heart andmesenteric arteries. The most acute changeobserved was a complete recent fibrinoidnecrosis of the entire vessel wall without evi-dence of inflammatory reaction. This occurredin smaller blood vessels and might be inter-preted from morphologic appearance alone assimilar to the process which occurs in humanmalignant hypertension. Other acute, butslightly older and less severe lesions werecharacterized by fibrinoid necrosis of the intimaand inner layers of the media with accumula-tion of fibrin in subendothelial spaces. Also

there was edema of the outer media and ad-ventitia, and infiltration by many polymorpho-nuclear leukocytes, and a few lymphocytes andmacrophages. Elastic tissue stains showedfragmentation of the elastica interna andexterna. The fibrinoid material was demon-strated to be positvely stained by the periodicacid-Schiff stain. The Masson trichrome stainshowed the presence of connective tissue onlyin the adventitia. McCallum bacterial stainsfailed to demonstrate bacteria within thearterial walls.

The subacute lesions were characterized by amixed inflammatory infiltrate and early evi-dence of healing. This stage of panarteritis wasobserved in pancreas, intestine, and ovarianarteries. Here the entire wall of the vessel wasdisorganized so that it was impossible to definethe limits of the intima, media and adventitia.The elastica interna and externa were frag-mented and often laminated. The vessel wallwas infiltrated throughout with polymorpho-nuclear leukocytes, macrophages, lymphocytes,and a few plasmocytes. Also, some proliferationof endothelial cells was observed. The peculiarfibrinoid material beneath the intima seen in theearly lesion was no longer present, and therewas marked fibroblastic proliferation and or-ganization of the entire wall. Masson trichrome

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GEORGE J. RACE AND ERNST PESCHUL 4S5

FIG. 1. Fibiinoid necrosis and edema of small artery in heart. (Hematoxylin and eosin. X 25-1.)FIG. 2. Fibiinoid necrosis of intima and inner media with edema and cellular infiltration of media

andadventitia of mesenteric artery. (Hematoxylin and eosin. X 36.)FIG. 3. Same as figure 2. Note the apparent thickening of the endothelium due to accumulation

of fibiinoid material. (Hematoxylin and eosin. X 128.)FIG. 4. Same as figure 2. Note fibiinoid necrosis, cellular exudatc and edema. (Periodic acid-

SchifT's reaction. X 764.)

stains demonstrated the marked degree offibroblastic proliferation and the virtualabsence of the musculature of the media.Thromboses were observed, both recent andorganizing.

In the healing phase, fibrosis of the entirevessel wall was the predominant feature. Theintima was greatly thickened by fibrosis, and

the lumen of the vessel was reduced to aboutone-fifth of its previous diameter, or it wascompletely occluded by organizing thrombus.The muscle of the media was replaced by fibroustissue which blended imperceptibly with thescarred adventitia. A few chronic inflammatorycells were present in the fibrous vessel wall.Some thrombi were recanalized. Calcification

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4S6 PATHOGENESIS OF P0LYARTER1TIS NODOSA

FIG. 5. Healing lesion in mesenteric artery, with organizing old thrombi in two stages, and recent,

unorganized thrombus. (Hematoxylin and eosin. X 31.)FIG. 6. Healing artery in pancreas, showing fragmentation of elastica. intcrna. Xote adjacent

small vein which is uninvolved. (Verhoeff's elastic tissue and Van Gieson's connective tissue stain.X 54.)

FIG. 7. Healed mesenteric artery. Xote calcification and degeneration of scarred wall. (Henia-toxylin and cosin. X 36.)

FIG. S. Characteristic reaction in kidney following latex encapsulation and contralateral ne-phrectomy to produce hypertension. (Hematoxylin and eosin. X 36.)

of the intima was common in occurrence. Inone mesenteric artery, there was a healing lesionadjacent to a late acute lesion. Generally, how-ever, the age of the lesions as confined to oneanimal was about the same in all locations.

DISCUSSION

The panarteritis herein described was pro-duced by a combination of renal injury andfeeding sodium chloride. The initial injury tothe vessel produces a fibriiioid necrosis of the

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GEORGE J. RACE AND ERNST PESCHEL 487

intima and sometimes the entire vessel wall. Weconsider this to be the initial lesion because it isimmediately followed by a polymorphonuclearleukocytic exudate. Furthermore, the earlyfibrin accumulation on the surface of, andbeneath the endothelium, is evidence of endo-thelial damage. This concept in pathogenesis isin opposition to the concept of Zeek andassociates8, who state that the initial stage isone of fragmentation, degeneration and edemaof the adventitial collagen, which in turn isfollowed by fibrosis of the adventitia and subse-quent necrosis and degeneration of the innermedia and intima. Such a sequence of events isdifficult to explain if this arterial disease is con-sidered to be a reaction to injury. Our observa-tions coincide with those of Selye3 and of Chuteand associates,2 who describe a change in alllayers of the vessel wall. However, it is thoughtthat the intimal necrosis observed in ouranimals is of an acute fibrinoid type ratherthan a hyalinizing degeneration of the collagenover a long period of time. In agreement withthe observations of the previously quotedauthors, the repair following the injury, whichwe noted in our animals, was characterized byfibroblastic proliferation throughout all layersof the wall, eventually leading to extensivescarring.

SUMMARY

Polyarteritis nodosa can readily be producedin hypertensive young rats by feeding diets

containing sodium chloride. The incidence inthis series was 31.2 per cent.

The arterial injury was characterized bysevere panarteritis. Pathogenetically, it beganwith a fibrinoid necrosis of the intima andmedia, which was followed by an extensiveinflammatory reaction with subsequent fibrosisof all layers of the vessel wall.

REFERENCES1 WILENS, S. L., AND SPBOUL, E. E.: Spontaneous

cardiovascular disease in the rat. II. Lesionsof the vascular system. Am. J. Path. 14: 201,1938.

2 CHUTE, A. L., ORR, J. L., O'BRIEN, M. J., ANDJONES, E. E.: Vascular lesions in alloxan diabeticrats. Arch. Path. 52: 105, 1951.

3 SELYE, H.: Production of hypertension and hyalino-

sis by desoxocortisone. Brit. Med. J. 1: 203,1950.

4 BYROM, F. B., AND DODSON, L. F.: The causation

of acute arterial necrosis in hypertensive disease.J. Path. & Bact. 60: 357, 1949.

5 RICH, A. R., AND GREGORY, J. E.: The experi-

mental demonstration that periarteritis nodosais a manifestation of hypersensitivity. Bull.Johns Hopkins Hosp. 72: 65, 1943.

GZEEK, P. M., SMITH, C. C, AND WEETER, J. C:Studies on periarteritis nodosa. III. The dif-ferentiation between the vascular lesions ofperiarteritis nodosa and of hypersensitivity. Am.J. Path. 24: SS9, 194S.

7 KEMPNER, AV., PESCHEL, E., AND BLACK-SCHAF-FER, B.: Effect of diet on experimental hyper-tension and on the development of polyarteritisin rats. Circulation Research. In press.

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GEORGE J. RACE and ERNST PESCHELPathogenesis of Polyarteritis Nodosa in Hypertensive Rats

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1954 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

doi: 10.1161/01.RES.2.6.4831954;2:483-487Circ Res. 

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