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Stress: From Concept to ModernImmunologya

GEORGE LÁZÁRb

Albert Szent-Györgyi Medical University, Institute of Pathophysiology,P.O. Box 531, Szeged, H-6701, Hungary

One of my early dreams as a young scientist engaged in biomedical research wasto visit the famous Institute of Professor Hans Selye in Montreal and even to workwith him. Although I did not know him personally, for me he was the scientistwho incarnated creativity and originality. I knew his basic discoveries and hisconcept of stress, the exhaustion of the organism, pluricausal diseases, and theadaptation syndrome. I was particularly excited because the focus of my interestwas very close to that of the research topics in the Selye Institute.

Hans Selye demonstrated that stress from a variety of sources causes adrenalenlargement and thymus atrophy. The idea that stress alters the immune functiongained notable interest among clinicians and scientists and has led to the devel-opment of the modern concept of psychoneuroimmunology.

When I received an invitation from Professor Hans Selye in 1967, we haddescribed that a rare earth metal complex, phlogodym (neodymium pyrocatechindisulfonate), with anticoagulant and antiphlogistic properties,1 aggravatesintravascular coagulation during different forms of shock (traumatic, endotoxin,and tourniquet), and we had observed that in the hind limbs of animals treatedwith phlogodym and submitted to a tourniquet, a thrombo-hemorrhagic phe-nomenon developed that macroscopically and microscopically resembled theShwartzman reaction.2,3 At that time, it was demonstrated in the Selye Institutethat the rare earth metals, which exhibit an anticoagulant property, sensitize theorganism to the development of a thrombo-hemorrhagic phenomenon induced bycatecholamine administration.4,5

The thrombo-hemorrhagic phenomenon was therefore the bridge that led meto Montreal. Even the four-year delay before I received my exit permit is vivid inmy memory. I was always afraid that Professor Selye would become weary ofwaiting for me and that his invitation would not be valid forever. Nevertheless,finally I was there. I shall never forget my first steps in the corridor of the insti-tute. The whole staff of the institute wanted to follow Selye during his visits to thelaboratories to watch the animals in experiments or to hold personal discussionsduring the weekends. He spent all his weekends and holidays in the institute,including Christmas and New Year’s Day.

Because my plan was to study the effects of rare earth metals on reticuloen-dothelial activity, I was delighted to find almost all the rare earth metals on theshelf of the pharmacy of the Selye Institute. At this time in Hungary, the rare earthmetals were extremely rare.

One of my first papers published from the Selye Institute was a report thatthe rare earth metal salts, among them gadolinium chloride (GdCl3), depress

aThis work was supported by the Hungarian National Science Foundation (OKTA, GrantNo. TO12963, 23638) and the Council of Medical Science of the Hungarian Ministry ofWelfare (ETT, No. 640/1996 02).

bAdditional correspondence information: Telephone: 36 (62) 310 651; Fax: 36 (62) 455 695.

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reticuloendothelial activity.6 This work became determinant in my further scien-tific work.

Much later, in Hungary, we demonstrated that the reticuloendothelial blockadeinduced by GdCl3 is due to the depressed phagocytic activity of the Kupffer cells.Our electron-microscopic investigations showed that the Kupffer cell blockade isa primary one, due to defects in the surface attachment and in the engulfmentphases of phagocytosis.7

How is our research work related to the stress concept? Macrophages are thebody’s “alarm” cells that synthesize and excrete highly reactive materials, such asthe superoxide anion, hydrogen peroxide, nitric oxide, eicosanoids, peptide medi-ators, and proteolytic enzymes. These biologically active materials are very impor-tant in killing bacteria and tumor cells. However, macrophages not only act as afirst line of defence and have pivotal roles in regulating the immune response, butalso the “over”-activation of macrophages and the excessive release ofmacrophage-derived destructive and immunosuppressive products may con-tribute to organ damage and the development of “multiple organ failure” insevere stress and injuries such as shock states.

In the Selye Institute, we demonstrated that macrophage activity greatly influ-ences splenic calcification and fatty liver degeneration induced by rare earth met-als8 and liver injury induced by cadmium chloride.9

Recent studies from many laboratories, including our own, have shown thatthe Kupffer cell blockade induced by GdCl3 modifies immune response,10 exertsprotective effects on anaphylactic,11 and endotoxic/septic shock,12 and decreasesthe liver-damaging effects of several hepatotoxins13 and ischemic-reperfusion.14

In the old Selye Institute, in the mornings, after Dr. Selye had been writingfor about two hours in his office, he very frequently visited us in our offices, andsaid “only the Hungarians know the hard-working Hungarian farmers, whostart their work early in the morning when the day is just breaking.” ProfessorSelye started to work early in the morning every day and stopped at exactly sixo’clock in the evening. Once I asked him, whether he occupied himself withreading special literature, scientific articles, or something else connected withhis scientific work. He answered that he never did because he needed the freetime to regenerate his energy. Professor Selye guarded his youthfulness, ambi-tion, energy, and high spirit until almost the very end of his life. He truly livedaccording to his teaching.

Professor Selye’s philosophy is reflected in his writing. For example, he wrotein his book The Story of the Adaptation Syndrome,15 “Adaptability is probably themost distinctive characteristic of life;”and much later, in Stress without Distress,16

“How to achieve a rewarding lifestyle in harmony with the laws of nature, byusing stress as a positive force for personal achievement and happiness.” Evennowadays the main question of stress remains how to find one’s own appropriatestress level.

Professor Selye formulated his personal philosophy of conduct in the term ofthis simple maxim: “Fight for your highest attainable aim,/But do not put upresistance in vain.”16 It served his main aim to reserve his energy and ambition:“I find it wise to set aside an hour a day for moderate rhythmic endurance exer-cise . . . I get it bicycling around the university campus in the quiet of the earlymorning.”16

When I try to recall our life in the company of Hans Selye, my feeling is alwaysthat time has stopped, and we are young again, full of energy and ambition, as wewere so many years ago in the old Selye Institute.

LÁZÁR: FROM STRESS CONCEPT TO MODERN IMMUNOLOGY 17

REFERENCES

1. JANCSÓ, N. 1961. Inflammation and the inflammatory mechanism. J. Pharm. Pharmacol.13: 577–594.

2. LÁZÁR, G. & S. KARÁDY. 1965. Traumatic and endotoxin shock in rats. J. Pharm.Pharmacol. 17: 517–518.

3. LÁZÁR, G., S. KARÁDY & E. HUSZTIK. 1969. Effect of phlogodym on the tourniquet shock.Thrombos. Diathes. Hemorrh. 21: 159–165.

4. GABBIANI, G., M. L. JACQMIN & H. SELYE. 1966. Thrombohemorrhagic lesions induced bycombined treatment with rare earth metals and epinephrine. J. Pharmacol. Exp. Ther.152: 275–281.

5. SOLYMOSS, B., H. SELYE & G. GABBIANI. 1966. Predisposition to thrombosis not reflectedby the blood coagulogram. J. Clin. Pathol. 19: 331–333.

6. LÁZÁR, G. 1993. The reticuloendothelial-blocking effect of rare earth metals in rats. J.Reticuloendoth. Soc. 13: 231–237.

7. HUSZTIK, E., G. LÁZÁR & Á. PÁRDUCZ. 1980. Electron microscopic study of Kupffer cellphagocytosis blockade induced by gadolinium chloride. Br. J. Pathol. 61: 624–630.

8. LÁZÁR, G. 1973. Effect of reticuloendothelial stimulation and depression on rare earthmetal chloride-induced splenic calcification and fatty degeneration of the liver.Experientia 29: 818–819.

9. LÁZÁR, G., D. SERRA & B. TUCHWEBER. 1974. Effect on cadmium toxicity of substancesinfluencing reticuloendothelial activity. Toxicol. Appl. Pharmacol. 29: 367–376.

10. LÁZÁR, G. JR., GY. FARKAS, J. CSANÁDI & G. LÁZÁR. 1997. Gadolinium chloride (GdCl3)-induced macrophage blockade prevents rejection of human insulinoma cell xenograftin rats. Transplantation 63: 729–731.

11. LÁZÁR, G., G. LÁZÁR, JR., J. KASZAKI, J. OLÁH, I. KISS & E. HUSZTIK. 1995. Protectionagainst anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade. J.Alloys Comp. 225: 619–622.

12. VOLLMAR, B., D. RÜTTINGER, G. A.WANNER, R. LEIDER & M. D. MENGER. 1996. Modulationof Kupffer cell activity by gadolinium chloride in endotoxemic rats. Shock 6: 434–441.

13. BARRIAULT, C., M. AUDET, I. M. YOUSEF & B. TUCHWEBER. 1995. Effect of agents whichmodify reticuloendothelial system function on acute phalloidin-induced lethality andhepatotoxicity in mice. Toxicol. Appl. Pharmacol. 131: 206–215.

14. IMAMURA, H., F. SUTTO, A. BRAULT & P. M. HUET. 1995. Role of Kupffer cells in coldischemia-reperfusion injury of rat liver. Gastroenterology 109:189–197.

15. SELYE, HANS. 1950. The Story of the Adaptation Syndrome. Acta Inc. Medical Publishers.Montreal, Canada.

16. SELYE, H. & S. SZABO. 1974. Stress without Distress. McClelland and Stewart, Ltd.Toronto.

18 ANNALS NEW YORK ACADEMY OF SCIENCES