Ziegler first advocated the view, in the first edition of his Lehrbuch, that hypertrophy is due to a lessening of the resistance to growth. He thinks that while hyperæmia and transudation may support the new growth, they are never the only cause of the formation of new tissue. While Virchow’s view that any injury to the body or to an organ excites proliferation finds support in the work of Stricker and Grawitz, yet the view has been combated by Cohnheim and by Weigert, and is no longer held by many pathologists. Ziegler points out that as a result of his own work, and that of his students, traumatic and chemical lesions are not followed at once by new growth of the tissue, but by degeneration of the tissue, and by changes in the circulation that lead to exudations. The new growth begins, at the earliest, eight hours after the operation, and generally only after twenty-four hours. Also after mechanical, chemical, or thermal injuries, a long interval elapses before phenomena of growth begin. The injury itself does not appear to produce the growth, but brings about those conditions that lead to cell-multiplication. Ziegler discusses what is meant by the idea of a lessening of the resistance to growth. He himself does not mean by this that hypertrophy depends on changes in the physical conditions, because it is known that living phenomena are the outcome of chemical processes and it is, therefore, à priori probable that the effect is brought about by chemical substances in the fluids of the tissues. These substances affect functional actions, and may even bring about regenerative changes. This action of chemical substances on the formative activity of the cell is theoretically possible in either of two ways; first, chemical substances of definite concentration are set free, or, second, chemical substances are present in the normal condition that prevent proliferation, but if their influence should be counteracted by other substances the conditions become favorable to growth. It is known in the case of certain unicellular organisms, that derive their nourishment from the surrounding medium, that their increase in number may be retarded by the presence of certain chemical substances. It is also known that certain organisms may themselves produce chemical substances that prevent their own multiplication. It is, therefore, at least conceivable that after a part has been injured a new substance may be produced that acts upon and destroys in the organ itself the substances there present that have prevented its further growth. The other interpretation is that in the breaking down of the tissue of the organ a substance is produced that excites the cells to proliferation.
Klebs suggested that the accumulation of the leucocytes at the wounded surface may act as a stimulus to growth, and that the chromatin of their nuclei might be absorbed by the cells of the tissue, and combining with the nuclei of these cells bring about the new growth. But Ziegler points out that we now know that although the leucocytes are dissolved and absorbed over the wounded surface, no process of absorption, of the sort postulated by Klebs, takes place. Ziegler thinks that Nothnagel is wrong in supposing that an increase in the blood supply, bringing with it an increase in the nourishment, can account for the hypertrophy of the kidney. On the contrary he believes that the growth is the result of an increase in the function of the organ due to the increase of the chemical substance, urea, that is brought to the secreting cells. The muscles of the body also hypertrophy as a result of their activity and not as a result of the additional blood supply.
In connection with these problems of hypertrophy it may be pointed out that, under certain conditions, blood vessels may enlarge and their walls become thickened. To cite a single example, Nothnagel found that if the femoral artery of the rabbit is tied, the blood vessels, that come off immediately above the ligature, and which have already, through their subdivisions, connections in the muscles with other branches of the same femoral artery (that come off below the ligature), grow larger after a time. This he believes to be due, in the first instance, to the increased speed of the blood in the vessels, and thereby the bringing to these arteries of an increased food supply. Other writers have given different interpretations. Ziegler himself believes that several factors may be capable of bringing about the result. He thinks it improbable that the increase in the food supply can alone be the cause, and thinks it much more probable that the increased work that the vessels must perform while carrying more blood will account for the enlargement.
In connection with this discussion it may not be unprofitable to recall that in the regeneration of the lower animals we find simpler conditions in which proliferation of the cells takes place under circumstances where many of the factors suggested in the above discussion are absent. In the first place we find that new growth may occur without any increase in the nourishment that is brought to the organ. Regeneration takes place in the entire absence of food, except so far as it may be stored up in the tissues. Even in a planarian that is starving and decreasing in size, proliferation of new cells will take place if a part is removed. In many of the lower forms there may be proportionately even a much greater proliferation than in the regeneration and hypertrophy in the mammalian organs. It is true that proliferation may be more active if the tissues are well fed, but this does not show that the presence of food is a factor in the proliferation except so far as it keeps the proliferating cells in their best condition for growth. It is possible in many animals, more especially in some of the lower forms, to force them to grow rapidly by supplying them with a large amount of food, and conversely by decreasing the food to delay the growth. While this shows that the rate of growth is, within certain limits, a function of the amount of food, there may be also other factors that enter into the result, and in all cases there is an upper limit beyond which it is not possible to make the animal grow any larger.
That the presence of certain substances may bring about the enlargement of a part must be admitted as probable. It has been shown, for instance, that after the removal of certain lymphatic glands other glands may become larger. This appears to be due to the greater activity of the gland, brought about probably by the presence of an increased amount of some specific substance. In this instance the result can scarcely be due to a decrease in the physical resistance to growth or to an increase in the blood flow, except so far as this is brought about by the increased activity. It is, of course, possible, even if it cannot be positively shown in the case of the lymphatic glands, that a substance in the blood causes the hypertrophy in certain organs, while in others, as in the kidney, an increase in the blood flow may be also a factor in its hypertrophy.
The view held by several pathologists, that hypertrophy and regeneration may be caused by the removal of a physical resistance to growth, cannot be looked upon as a very probable hypothesis. The experiments in grafting of hydra and lumbriculus show that regeneration may still take place when the physical resistance has been reëstablished by grafting two pieces together. These results, which are more fully described in a later chapter, demonstrate that the growth is due to other influences.
A comparison with the lower animals shows that proliferation takes place when all but three of the factors considered in connection with hypertrophy and regeneration in the higher forms have been eliminated. These are, first, the action of substances that act either directly or as counteracting some substance already present, as Ziegler suggests; second, an innate tendency in the organism to complete itself; and, third, the use of the organ. It is impossible that the second factor enters into the problem of hypertrophy. In those cases in which regeneration takes place when a part of an organ is removed, as in the case of the liver, for example, the result may possibly also involve the second of the two factors, for the process is much like that of morphallaxis in the lower animals.
If it be granted that the growth in a hypertrophied organ is brought about by some substance that increases the function of that organ, can we suppose the phenomenon of regeneration to be due to similar factors? In other words, can we reduce both phenomena to the same principle? The case is complicated by two facts that may be illustrated by concrete examples. If a piece is cut from the middle of the body of lumbriculus new cells are produced at both ends of the piece. If we suppose the proliferation is brought about by the accumulation of certain substances in the piece, we must still invoke other factors to account for the differentiation of the proliferated material, since a head forms at one end and a tail at the other. All the hypothesis can do in itself is to account for a proliferation, not for the differentiation, and, both in the case of hypertrophy and in that of regeneration, it is the formation of new structures that we are chiefly concerned with, rather than the simple act of growth or of proliferation. If a piece of a hydra is cut off, the whole piece changes into the typical hydra form. Here there is no extensive process of proliferation, and the change is in the old part. It seems highly improbable that the production of substances in the piece could account for its change of form. These examples will suffice to show that in the process of regeneration it is very improbable that the change is brought about by special substances that may develop or be present in the part. We must suppose that during regeneration the formation of the typical form is not the result of a stimulus originating in a chemical substance acting upon the living material, but due to changes brought about directly in the living part itself. We must conclude, therefore, that despite the apparently close connection between the phenomena of hypertrophy of uninjured organs and of regeneration, they may often involve different factors.
If specific substances can bring about the hypertrophy of an organ, it is still not clear at present whether they do so by directly causing new growth, or whether their presence only stimulates the organ to greater activity and the activity of the organ is the cause of its growth. Since it must be supposed that in each organ a different specific substance brings about its activity and the consequent hypertrophy, it seems more probable that the result is due to the activity itself rather than to a stimulus from the substance. This view is further supported by the fact that in the case of the muscles and of the blood vessels the hypertrophy is directly connected with their use. The greater use brings about a larger supply of blood, but the blood is only different in amount and not in its quality. It must be confessed that it is difficult to see how the use of a part could make its growth increase, for by use the tissues break down; and we are not familiar with any other processes within the body that make for the building up of an organ in more than an inverse ratio to its breaking down. We are, however, familiar with phenomena of building up due to an increase in the food supply. It might appear from this to be more in accordance with what we find, to assume that the hypertrophy is solely due to an increase in the food supply; yet there are other facts known that show that an organ does not increase in size simply because it gets more blood, and that this occurs only when the organs have a greater functional activity. It is a safer conclusion, I think, at present to assume that both the activity of the organ and the increase in its supply of food acting together are factors in the result. On the other hand we are so much in the dark concerning the functioning and growth of organs that we can do little more, as the preceding pages show only too clearly, than speculate in the vaguest sort of way as to what changes take place; but since the processes seem to be within reach of experimental methods we can hope in the near future to learn more of how the processes of hypertrophy are brought about.