Wound Hormones

WOUND HORMONES, poorly understood substances of protein nature, representing products of the breakdown of dying tissues in the area of wounds, which stimulate cell proliferation. The foundation for concepts of W. h. was laid by numerous works of the German botanist Haberlandt, devoted to the problem of cultivating cells and tissues of plants outside the organism. The starting point for Haberlandt was the observation of the growth in culture of various mechanically isolated cells, which, remaining alive and capable of growth, never divided. Believing that in this case there was a deficiency of special "enzymes of multiplication," Haberlandt approached the experimental resolution of the question. When studying thin plates from the cortical and medullary layers of the potato tubule, it was found that cell divisions appear only in plates supplied with at least fragments of the vascular-fibrous system (leptomes). In the vessel-free potato plate, mitoses are absent, but they can be caused, however, in the case of contact of such a plate with a vessel-containing plate, separated from the first by a thin layer of agar-agar. From this, Haberlandt drew the main conclusion that special hormones of "cell division" move and diffuse into the tissue along the vascular-fibrous bundles. These initial data were subsequently confirmed on a whole series of objects—pieces of stems and leaves of Sedum, Brassica, Bryophyllum, etc. Proceeding further to the experimental verification of the repeatedly expressed position (Wiesner, Ktister, Bier) that products of breakdown in wounds stimulate cell divisions, Haberlandt, by intensive washing of the wound surface in plates of kohlrabi, achieved almost complete absence of regenerative mitoses; they could be caused anew in the case of applying to the plate a tissue mash from crushed and dying cells. Fundamentally coinciding results were obtained by Haberlandt with various methods of damaging the leaves of certain Crassulaceae—Semper-vivum, Crassula, etc. Cell divisions were almost completely absent in the case of tearing off a cell strip without damaging the cells, but were very numerous in the case of cutting the leaf with damage to its cells. Special studies showed that the wound hormone of plants is not specific within a genus and species, while hormones of different families are no longer active. Continuing the same series of research, Haberlandt clarified the effect of mechanical damage (wounds) on cells of hairs, cells of the plant epidermis, etc. In this case, it was established that a single plant cell, through local mechanical damage (partial crushing), receives an impulse to divide; this latter must be regarded as the result of the action of W. h. formed intracellularly. In the case of death of damaged cells of such formations (e.g., hair), cell divisions arise in neighboring healthy cells. Generalizing his theory of W. h., Haberlandt asserts that in cases of traumatic parthenogenesis there is an effect of W. h. According to Haberlandt, mechanical damage to the cells surrounding the egg cell of the seed rudiment or fruiting body should also lead to parthenogenetic development. Experiments on the plant Oenothera lamarkiana showed the correctness of this assumption—with mechanical damage to the cells of the fruiting body (formation of W. h.), it was possible to note both cases of beginning parthenogenesis and the formation of a secondary embryo sac. Such a wound effect also leads to the formation of additional embryos in the fruiting body. Along with the concept of W. h. arising as a result of external damage, Haberlandt introduces the concept of necrohormones, products of cellular breakdown arising as a result of internal, sometimes unknown to us, causes. In all cases of apogamy (see), development of additional embryos, as well as in natural parthenogenesis in plants, Haberlandt indicates the sources of necrohormones appearing as a result of the breakdown of various cells of the fruiting body (e.g., in the composite Taraxacum officinale, etc.). In all these cases, the presence of necrotizing areas in the immediate vicinity of the developing rudiment was noted. Of particular interest are the results of the study made by Haberlandt of an old preparation by Strasburger on parthenogenesis in the pteridophyte Marsilia Drummondi; in this case, it was possible to establish a direct connection between the dying surrounding cells (cells of the embryo canal) and the egg cell, thanks to which the transition of necrohormones into the latter is possible. Generalizing his theory, Haberlandt proceeds to the factors affecting the normal division of the fertilized egg cell. This impulse to division, Haberlandt considers to be the wound hormones arising from the penetration of the spermatozoon into the egg (damage), as well as as a result of the breakdown within the egg cell of the constituent parts of the spermatozoon (or the pollen tube in plants), and perhaps also as a result of the partial breakdown of the egg protoplasm under the influence of special digestive substances produced by the spermatozoon. The structure of the latter (for example, in the guinea pig) gives reason for the concept of damage to the egg at the moment of fertilization. In plants, injury to the egg cell is produced by a large spermatozoon (cycads) or by a pollen tube that completely penetrates into the egg (e.g., in conifers). As for the chemistry of W. h., at the present time exact data are lacking. Haberlandt's concepts, created on botanical material, have been accepted by a number of scientists who attribute to them broad general biological significance. Freund (N. Freund) published a work on the influence of "hormones of cellular breakdown" (Zellzerfallhormone) on the course of various processes in the organism. Freund sees the source of this breakdown in the normal death of some cellular elements of the organism (white blood cells, blood plates). The introduction into the organism of products of breakdown of these cells is a nonspecific irritant. In 1926, similar views were expressed by Gutherz, who devoted a special book to the problem of "partial death" (Partialtod) of certain tissues of the organism. According to Gutherz, as a result of this partial death, protein breakdown products (necrotin, metabolin) arise, which stimulate the normal life activity of the organism. Mention should be made of the data of Akamatsu, who showed by the method of tissue culture an increase in the amount of growth-stimulating substances in the plasma of wounded animals. The fullest development in the field of general pathology of Haberlandt's views was obtained in the numerous works and generalizations of Caspari, who put forward the theory of necrohormones, by which he understands all substances arising in the organism (regardless of the causes causing their appearance) as a result of the breakdown of large protein molecules. The first object on which Caspari tried to apply the positions put forward by Haberlandt was the mechanism of the biological action of radiant energy. Caspari puts at the foundation of his views the Punktwarmetheorie ("theory of the thermal action of points") of Dessauer, the essence of which is that significant amounts of radiant energy, acting on certain limited areas (molecules) of living substance, develop at the same time an extremely large amount of heat and thereby bring about thermal coagulation. As a result of the latter, there occurs a partial breakdown of living substance (cells or individual areas of tissue), leading to the appearance of necrohormones, the exact chemical nature of which at the present time cannot be established. Caspari assumes that in this case the greatest activity is possessed by various amino acids (choline), amides, some lipoids. Depending on the amount of necrohormones formed, different, sometimes diametrically opposite effects on the organism are obtained, as is known, repeatedly described specifically for the biological effect of radiant energy. Small doses of necrohormones lead to stimulation of metabolic processes, more significant doses cause some slowing of these processes, and finally excessively large doses give severe intoxication of the organism by products of protein breakdown. The amount of necrohormones formed is determined both by the dose of the radiant energy that acted and by the individual characteristics of the object acted upon, its greater or lesser sensitivity to the action of rays. Thus, according to Caspari, for necrohormones, the "Arndt-Schulz law" (see) retains its significance to a certain extent. In necrohormones, Caspari sees the carrier of nonspecific irritation, the concept of which penetrates very deeply into modern medicine (introduction of serum, proteinotherapy, Weichert's nonspecific therapy). Caspari reduces the mechanism of action of necrohormones to the exit of the aforementioned products of protein breakdown into the blood, the consequence of which is the experimentally established change in a number of its properties—acidity, osmotic pressure, serum content.

According to Caspari, the site of action of necrohormones is the autonomic nervous system and the reticulo-endothelium, whose reactions in turn determine a particular state of the entire organism. Caspari applies the theory of necrohormones to explain the non-specific immunity in transplants of malignant tumors. Necrohormones, which arise in small quantities during the breakdown of the transplanted tissue, primarily stimulate the cells of the reticulo-endothelium and promote the development of protective reactions in the body. However, an excessive amount of these necrohormones leads to the opposite effect—blockade by protein substances of the reticulo-endothelium and a decrease in the body's resistance, resulting in its exhaustion (cachexia). Justifying the theory of necrohormones as a theory of non-specific effects on the body, Caspari points to the existence of a specific component of this factor, expressed in the fact that for one or another effect, the nature and origin of the disintegrating cells are important. The theory of necrohormones by Caspari cannot be considered generally accepted and applicable in the broad limits that the author assigns to it at the present time.

The question of the relationship between the R. g. (Haberlandt), which stimulate cell division, and mitogenetic rays (Gurvich) deserves special attention. The connection between mitogenetic rays and wound tissues (and consequently with the R. g. they produce) is indicated in the works of Blyakher and Bromley, who clarified the significance of necrotizing tissues of the wound as a source of mitogenetic radiation. The totality of the available facts, clarified in recent times by the special research of Haberlandt and the response work of Gurvich, forces one to accept that: 1) R. g. are indeed related to the formation of mitogenetic rays, 2) the action of R. g. on non-dividing cells (potato tuber tissue, spongy and palisade parenchyma of the leaf, etc.) consists not only in the production of rays but also in a purely chemical effect, creating in these cells a readiness for division (see Mitogenetic rays) and leading to the fact that these cells become accessible to the action of mitogenetic rays produced by R. g. The source of mitogenetic rays in R. g. is apparently the proteolytic processes.