STUDIES ON THE CHANGES PRODUCED BY ROENTGEN RAYS IN INFLAMED CONNECTIVE TISSUE.
The action of x-rays upon inflamed tissue manifests itself in the first place by a considerable depression of the usual reaction on the part of the fibroblasts. Under normal circumstances these elements begin to divide mitotically during the first 24 hours and soon form a layer of new connective tissue, surrounding the foreign body. After treatment with x-rays they remain idle, do not multiply at all, or start very late and often the division is abnormal. They undergo a high degree of pathological hypertrophy of protoplasm and nucleus. Instead of mitosis often amitotic constrictions appear in the nucleus. The capacity for collagen formation seems also to be lost. Simultaneously with these changes of the fibroblasts an intensive edema of the connective tissue surrounding the foreign body is to be noted and in the immediate neighborhood of the latter a thick layer of net-like clotted fibrinous exudate is formed. No distinctive qualitative changes could be found in the leucocytes and polyblasts. Degeneration was present here only to the same extent as in common aseptic inflammation. But first the rate and the duration of the emigration of all the cells coming from the blood were increased, and secondly there was always a distinct delay in the process of the common transformations usually undergone by the polyblasts on the field of inflammation. The transformation of the polyblasts into fixed resting forms seems above all to be delayed. Therefore, even in late stages, the tissue is overcrowded with granular special leucocytes and with mostly young, lymphocyte-like polyblasts, whereas in the early stages the local resting wandering cells only slowly undergo mobilization. Furthermore, in the blood vessels swelling of the endothelial cells with fragmentation of the nuclei and, in the striated muscles, degeneration of the fibers can be detected. In the latter there occur partly typical coagulation necrosis, partly atrophy, accompanied by loss of striation, separation of fibrillae from one another, relative increase of sarcoplasm, and amitotic division of nuclei. What the ultimate result of all these changes would be, is as yet not clear. In the case of longest duration, in which 60 days had elapsed since the last exposure, no distinct difference could be found between the exposed and control preparations. Thus one might believe that the cell injuries caused by the x-rays, and above all the inability of the fibroblasts to multiply and to elaborate collagen, are again repaired in due time. However, my material is decidedly inadequate in this respect and several cases of long duration should be examined. It is surprising that the results obtained seem not to agree with the predominating views on the action of x-rays on cells. Apart from the endothelium of the blood vessels, of all the cells present in the field of inflammation the fibroblasts undoubtedly are to be considered as the elements most highly differentiated in a specific sense. I have shown that, as a rule, they do not round up in inflammation and do not produce ameboid cells, but remain unchanged in morphology and, through mitotic division, give rise to the new connective tissue. On the other hand, there can be no doubt that the lymphocytes and the polyblasts are to be looked upon as relatively indifferent cells, endowed with great prospective potencies of development. Thus it might be expected that just the lymphocytes of the inflamed area would be affected in the first place by the rays, as they are in the blood-forming organs, and that the fibroblasts, on the contrary, would be refractory. But the facts have proved that the most conspicuous and constant changes concern the fibroblasts. They are paralyzed for a long time and made unable to build up new tissue. The fibrinous exudate and the edema might perhaps also depend partly on a direct injury of the colloidal intercellular substance, partly on changes of the endothelium of the blood vessels, cells which are again to be considered as highly differentiated. Noteworthy signs of degeneration could not be found in the lymphocytes and polyblasts. But here again the necessary early stages 1 to 3 days after the last exposure were not available; it is possible that the emigrated lymphocytes are destroyed by the x-rays rapidly, in an explosive manner, in 24 to 48 hours, as in the lymph nodes or the thymus, or as described by Pautrier in the chronically inflamed tissue of the skin in mycosis fungoides. Their remains might be quickly resorbed and after the last exposure new lymphocytes would have time to emigrate out of the blood vessels and to pass to the tissue. However, if we take this for granted, there remains another inexplicable fact, concerning the local resting wandering cells-their close genetic relationship with the lymphocytes is beyond doubt and yet exposure to x-rays does not seem to affect them. In this connection it may be stated that Soper found that the reticulo-endothelial apparatus, whose cells correspond to the resting wandering cells, is stimulated by small doses of x-rays and paralyzed by large doses. For deciding these problems further investigations are necessary. The classical researches of O. Hertwig and his school have proved beyond doubt that of all the parts of the cell, the nucleus with its chromatin is affected most by the rays. It is believed that the nuclei in mitotic division are especially sensitive (Holthusen) and that the nuclei of exposed cells lose, in the first place, their capacity for normal mitosis; they either do not undergo division at all or they show pathological mitoses (Grasnick, Gaskell, and others). The observations described above fully coincide with these statements. The nuclei of the hypertrophied fibroblasts attain an enormous size, contain an abnormal amount of chromatin, are sometimes vacuolated, and appear paralyzed and incapable of mitosis or divide abnormally. Perhaps the reason that the fibroblasts in the present experiments are so strongly affected by the x-rays is that they are the only cells which are preparing for mitotic division directly after the introduction of the foreign body, whereas the lymphocytes and polyblasts only rarely divide in the field of inflammation. The fibroblasts thus are becoming especially sensitive towards the rays, whereas for example in the scar tissue, where they remain quiescent, they are not affected. As the inflammatory changes in the normal skin after exposure to x-rays are not known sufficiently from the histological standpoint it would be promising to study the action of x-rays on the normal loose connective tissue. It is evident that the changes in the cells of the inflamed area, chiefly in the fibroblasts, but also in the muscle fibers, under the influence of Roentgen rays, are the result of complicated interrelations between two different agents, first, the inflammation stimulus, and, second, the radiant energy. Neither agent alone in the doses used is able to produce the changes observed. Only the combination of both gives the results described above. It seems to be immaterial, to a certain degree, which of the two stimuli is applied first-whether the foreign body be introduced in previously exposed tissue, or the latter be exposed after the introduction of the body-in both cases practically the same results have been obtained. The strong inhibitory and deleterious influence of x-rays on inflamed connective tissue ought to be always kept in mind in the therapeutical use of this kind of energy, especially in cases of malignant tumors, in which the local connective tissue in most cases is found in a state of inflammatory irritation.
Maximow
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Hull Laboratory of Anatomy of the University of Chicago, Chicago.