Morphologic changes in the thymus and lymphoid nodules of the appendix of the white rat subjected to increasing physical loads

By means of histological and morphometrical methods the thymus and appendage have been studied in male white rats subjected to a dosed physical loading (swimming). The physical loading is accompanied with essential changes in structure and cell composition of the immunogenic organs. The rate and character of the changes depend on the adaptability level of the animal's organism to the physical loading. At adaptation to the loading, the process of age involution of the thymus decelerates, amount of lymphoid nodules in the appendage increases, comparing the control parameters, contents of lymphocytes noticeably increase in all zones of the lymphoid nodules. When adaptation to the physical loading is not sufficient, the rate of the thymus involution sharply increases, while in the appendage the number of the lymphoid nodules decreases. However, in some animals at a sharp involution of the thymus, the changes in the appendage do not differ from the control ones.     

Features of the ultrastructural organization of the muscles of skaters in relation to their sport specialization and muscle fiber composition

An electron microscopical and histochemical investigation of bioptates obtained from the external broad femoral muscle of 74 sportsmen-skaters has been performed. Structural adaptation of the muscles to speed loadings and to endurance loadings has been analysed taking into consideration contents of muscle fibers (MF) of various type. Peculiarities in ultrastructural organization of the skeletal MF in the sprinter- and stayer-skaters, who undergo training according to a special program, are described; the character of the muscle changes is also followed in the sportsmen who undergo training according to the program that does not correspond to the contents of their MF. Lesions in the latter up to the necrotic ones are mostly found in the muscles of the stayer-skaters, as well as in the sprinters trained according to the stayer program. Presence of essential destructive alterations of the muscles in the skaters, especially in those whose contents of slow muscles do not correspond to their specialization, demonstrates, evidently, the fact that the given physical loading is not adequate to the functional or potential possibilities of the organism.     

关于法氏囊自然退化的研究

实验结果进一步表明法氏囊的发育是受性激素控制的。法氏囊的自然退化是机体内性激素浓度达到一定的水平所致。 在法氏襄的退化过程中起关键作用的细胞成分是FAE细胞,当它们完全地受到性激素的影响时,淋巴细胞分化的微环境遭到破坏,法氏襄发生不可逆性的退化。     

Morphological characteristics of the motor neurons of the spinal cord in physical loading up to the limit

The experiments have been performed on 98 white rats adapted and nonadapted to the effect of physical loadings. The loadings up to the limit are reached by swimming of the rats up to fatigue. The swimming lasts for 10-15, 20-35, 40-65, 70-90 h. Under the conditions mentioned, morphological changes of the neurons are of mosaic pattern. Light optic and electron microscopic methods demonstrate swelling of neurons, endocellular and pericellular edema, vacuolization, appearance of gigantic degeneratively altered mitochondria, presence of vesicles in mitochondria, hollow mitochondria, dilated cysterns of the endoplasmic reticulum, degenerated synapses and glial reaction. These changes are considered as adaptive and compensatory reactions in the process of physiological strain of the organism, directed towards increasing stability against the effect of the extermal factor. In the animals nonadapted to any physical loadings, morphological changes in neurons of the ventral horns of the spinal cord are more deeply and widely spread in character.     

Bacteriological investigation of the postpartum uterus: Relationship to involution and histopathological findings

A bacteriological investigation of the postpartum uteri of suckled and nonsuckled Bunaji (White Fulani) cows was undertaken to determine the microflora, the effect of suckling on the flora and the influence of the flora on uterine involution and histopathology. Uterine contamination by bacteria was highest between days 10 and 21 postpartum with Staphylococcus aureus being the commonest organism isolated. There was no consistent isolation of one type of bacterial organism from a cow throughout the sampling period. Suckling did not affect the incidence of uterine contamination by bacteria. Foci of leucocytes (mainly lymphocytes) were found in uterine sections in an increasing frequency with days postpartum. Bacteria were isolated from only 3 of the 12 uteri that had the leucocytic foci. Uterine involution was normal and complete by 25 days after calving irrespective of the presence or absence of bacteria or leucocytic foci. We concluded that postpartum uterine contamination by bacteria was not influenced by suckling and that puerperal uterine contamination by bacteria did not interfere with the normal process and duration of uterine involution.     

Elective detection of thymus epithelium and assessment of the degree of functional and pathological involution of the organ in mice

With the help of antibodies-containing serum reacting with the thymus reticulum epithelial cells components by immunofluorescence method the thymus parenchimal tissue in mice with functional and pathological involution has been detected electively. In spite of large thymus changes in hairless mice with the mutation of gene hrrhy in 14-th chromosome of B10.R109/Y animals the basal cells antigen in epithelial reticulum has been preserved. It permits to estimate thymus involution level of this organ. Low lymphocyte content in the thymus of C57BL/6 mice is accompanied by total decamouflage of the epithelium. The functional thymus involution of pregnant mice is characterized by the luminescence of large number of epithelial cells, the restoration of organ after the delivery--by their few number. The elective detection of thymus epithelium many serve as additional test for the estimation of functional and pathological involution level.     

Status of the rat thymus after antenatal antigenic stimulation

Morphological reactions of the thymus to penetration of foreign antigens into the organism should be further investigated. In the work presented, morphometric, histological and histochemical methods have been applied to study specific thymic reactions of the rat fetuses to antenatal antigenic stimulation. The antigenic stimulation of the fetuses results in an increased thymic function. The changes observed in it resemble, in general, an accidental involution. A specific feature of the fetal thymic reaction is an essential enlargement of the medullary substance volume and appearance of the thymic bodies (Hassall's bodies) that demonstrates an accelerated maturation of the thymus.     

How and why the mechanisms of ageing and carcinogenesis originated: a hypothesis

A hypothesis explaning the nature of ageing and carcinogenesis is proposed. The hypothesis is based on the notion of a unitary organism as a module of a colony that has lost the ability to reproduce asexually. The evolutionary forerunner of the old age involution was the asexual iteroparity of colony modules, and the evolutionary forerunner of carcinogenesis was the semelparity of such colonies; the evolutionary forerunner or tumour regression was the switch of the colony module from semelparity to iteroparity. The donor-acceptor relations of a colony module emerge in unitary organisms in the course of ageing and carcinogenesis. The mechanisms of ageing and carcinogenesis originated at the stages of Metazoa evolution when the organisms had not yet acquired the nervous and the endocrine systems.     

Natural and abrupt involution of the mammary gland affects differently the metabolic and health consequences of weaning

In most mammals under natural conditions weaning is gradual. Weaning occurs after the mammary gland naturally produces much less milk than it did at peak and established lactation. Involution occurs following the cessation of milk evacuation from the mammary glands. The abrupt termination of the evacuation of milk from the mammary gland at peak and established lactation induces abrupt involution. Evidence on mice has shown that during abrupt involution, mammary gland utilizes some of the same tissue remodeling programs that are activated during wound healing. These results led to the proposition of the “involution hypothesis”. According to the involution hypothesis, involution is associated with increased risk for developing breast cancer. However, the involution hypothesis is challenged by the metabolic and immunological events that characterize the involution process that follows gradual weaning. It has been shown that gradual weaning is associated with pre-adaption to the forthcoming break between dam and offspring and is followed by an orderly reprogramming of the mammary gland tissue. As discussed herein, such response may actually protect the mammary glands against the development of breast cancer and thus, may explain the protective effect of extended breastfeeding. On the other hand, the termination of breastfeeding during the first 6 months of lactation is likely associated with an abrupt involution and thus with an increased risk for developing breast cancer. Review of the literature on the epidemiology of breast cancer principally supports those conclusions.     

Knocking Off SOCS Genes in the Mammary Gland

Suppressors of cytokine signaling (SOCS) proteins are critical regulators of cytokinemediatedresponses in diverse tissues. In the mammary gland, signal transductionpathways elicited by cytokines and hormones have been shown to control distinct stagesof development. In vivo evidence points to essential roles for Socs1 and Socs2 as keyphysiological attenuators of prolactin receptor (PRLR) signaling during pregnancy andlactogenesis. Recently, Socs3 has been shown to be a critical regulator of involution, thecoordinated process of programmed cell death and tissue remodelling that is initiatedafter the cessation of lactation. This review will predominantly focus on the antiapoptoticfunction of Socs3 during mammary gland involution in which it acts as a keyattenuator of Stat3-mediated signal transduction. Perturbation of this pathway leads to anincrease in the levels of c-myc and its likely target genes, p53, bax and E2F-1, providingevidence that c-myc is a central effector of apoptosis during involution.     

Mathematical model of the effect of glucocorticoids on the movement and proliferation kinetics of mammalian lymphocytes

Effect of glucocorticoids on proliferation, death and migration of T-lymphocytes was studied by mathematical methods. A model of the interaction between hormone and thymus T1-lymphocytes is proposed which imitates involution of lymphoid tissue under stress. There were constructed models of migrations of free and radioactive chromium labeled lymphocytes in lymphoid and non-lymphoid organs, blood and lymph at arbitrary concentration of glucocorticoids in the blood. Possible mechanisms of immunodepression due to increased hormone concentrations in the organism are discussed.     

Study of the accidental thymus involution during the formation of hierarchic communities by a novel physical method for recording the social stress

A novel method for recording the aggressive behavior in newly formed hierarchic communities has been developed. A temporal and age-related dynamics of the accidental thymus involution in mammals has been studied.     

Histological changes of the mouse thymus during involution and regeneration following administration of hydrocortisone

Summary A histological study has been made of the thymus in mice during acute involution and regeneration following administration of hydrocortisone. The cortex undergoes remarkable changes in the microscopic structure during involution and regeneration. During involution the lymphocytes in the cortex rapidly decrease and are removed. Then a rapid replacement of lymphocytes occurs during regeneration. On the basis of formation and repopulation of lymphocytes the regenerative process of the cortex is divided into seven phases. The reconstitution of the cortex proceeds more rapidly in females than in males. Newly formed lymphocytes take origin from the mesenchymal cells in the cortex. Such mesenchymal cells become distinguishable from epithelial reticular cells during involution. They appear to engulf destroyed lymphocytes and debris during involution and then transform into immature lymphoid cells during early regeneration. The findings may support the recent reutilization concept that destroyed lymphocytes are phagocytized and reutilized by reticular cells in heteroplastic differentiation into immature lymphoid cells. In the cortex PAS-positive sudanophilic cells which are derived from the perivascular and subcapsular connective tissue appear with involutionary changes. They become gradually reduced again with progress of the regeneration of the cortex. During involution the medulla are temporarily filled with lymphocytes migrated from the cortex. The epithelial reticular cells in the medulla are found grouped in cords or clumps in the severely involuted thymus. In the medulla there are two types of PAS-positive epithelial reticular cells; one contains a large, colloid-like, PAS-positive inclusion within the cytoplasm and the other has cytoplasm diffusely filled with PAS-positive substance. During involution and early regeneration, the former type increases while the other shows almost no significant changes. Hassall's corpuscles somewhat increase in frequency during involution and early regeneration.     

Dynamics of acid phosphatase activity in the liver in the process of involution of cirrhosis

Changes in the total activity of acid phosphatase in the liver as well as changes in the enzyme activity in hepatocytes and connective tissue cells of fibrosis layers were investigated, using quantitative histochemical method, in the process of mouse cirrhosis involution. After discontinuation of CCl4 injection, the animals with cirrhosis were divided into two groups. In the first group the resection of the left lobe of the liver was performed. The animals of the second group were not subject to operation. The results demonstrate that there is a close correlation between lysosomal hydrolase activity of hepatocytes and connective tissue cells of the liver and collagen resorption during cirrhosis involution. The most intensive lysis of collagen takes place within the first three weeks of cirrhosis involution in both experimental groups. Partial resection in cirrhosis has no significant effect on the changes and level of total activity of lysosomal hydrolase enzymes in the liver during cirrhosis involution.     

Apoptosis does not affect the vasculature of the corpus luteum of pregnancy in the rat

There has been much research into the mechanics of angiogenesis and many studies have demonstrated that newly formed vessels regress during angiogenesis. This vascular involution has been shown to involve basement membrane dissolution and endothelial cell apoptosis. The corpus luteum provides an ideal in vivo model to study physiologic angiogenesis and studies have shown that involution of newly formed vessels occurs during corpus luteum regression. However, few studies to date have investigated the role of apoptosis on the vasculature which develops during pregnancy. By the use of the TUNEL technique to detect apoptotic cells and immunohistochemistry to distinguish between endothelial cells and pericytes, this present study demonstrated that the vasculature of the corpus luteum of pregnancy in the rat does not undergo apoptosis.     

Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice

During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4⁺CD8⁺ immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.     

Involution of the female Mullerian duct of the fetal rat in the organ-culture assay for the detection of Mullerian Inhibiting Substance

The study of Mullerian Inhibiting Substance (MIS) has been made possible because of the organ-culture bioassay devised by Picon ('69) for detecting MIS in vitro. We have studied the degeneration of the female Mullerian duct of the rat fetus, the target tissue of the assay, with electron microscopy. We have observed that the involution of the female Mullerian duct in the organ-culture assay follows a pattern of degeneration similar to the normal involution of the male Mullerian duct under the influence of MIS from the fetal testis (Price et al., '77). This involution involves alterations in the duct epithelium subsequent to a response of the mesenchyme surrounding the duct. The degeneration of a specific organ system under the direct influence of a specific factor, Mullerian Inhibiting Substance, represents an example of "programmed cell death."     

Immunoendocrine modulation and stimulation of hematopoiesis with the ionophore copolymer T150R1

T150R1, an 8000-dalton copolymer with sodium ionophore activity, has been shown to modulate cellular responses in multiple systems. In this article, we studied its effects on lymphoid and hematopoietic organs in the context of the adrenal-pituitary axis. When injected in mice as an oil in water emulsion, T150R1 caused a rapid, profound, and dose-dependent thymic involution accompanied by splenic hyperplasia. Time course experiments with a 2.5-mg dose revealed that the thymus size was minimal at Day 2, rose to normal by Day 14, then enlarged and gradually returned to normal by Week 6 postinjection. Thymic involution was due to cellular depletion of the cortical area, whereas thymic enlargement was due to cortical hyperplasia. Splenomegaly was seen as early as Day 4, peaked by Day 14, and gradually returned to normal by Week 6. The splenic enlargement was due to hyperplasia of the red pulp, with evidence of proliferating erythropoietic, myelopoietic, and megakaryopoietic precursors. In addition, the bone marrow was stimulated and extramedullary hematopoiesis was present in the liver. The effects of T150R1 on the thymus appeared to be mediated by corticosteroids while the effects on hematopoiesis were not. Corticosterone and ACTH levels were increased in treated animals. Adrenalectomy diminished the T150R1-induced thymic involution but enhanced the splenic hyperplasia. Hypophysectomy did not prevent thymic involution, suggesting that T150R1 has endocrine stimulatory effects. These data suggest that T150R1 represents a new class of ionophores which may act on excitable cells within the endocrine, immune, and hematopoietic systems.     

Cleavage of Histone 3 by Cathepsin D in the Involuting Mammary Gland

The post-lactational regression of mammary gland is a complex multi-step process designed to conserve the biological function of the gland for next pregnancy. This developmental stage is a biological intrigue with great relevance to breast cancer research, and thus has been the subject of intensive scrutiny. Multipronged studies (microarray, proteomics profiling, animal knock-out models) have provided a repertoire of genes critical to involution. However, the caveat of these approaches remains in their failure to reveal post-translational modification(s), an emerging and critical aspect of gene regulation in developmental processes and mammary gland remodeling. The massive surge in the lysosomal enzymes concurrent with the onset of involution has been known for decades, and considered essential for “clearance” purposes. However, functional significance of these enzymes in diverse biological processes distinct from their proteolytic activity is just emerging. Studies from our laboratory had indicated specific post-translational modifications of the aspartyl endopeptidase Cathepsin D (CatD) at distinct stages mammary gland development. This study addresses the biological significance of these modifications in the involution process, and reveals that post-translational modifications drive CatD into the nucleus to cleave Histone 3. The cleavage of Histone 3 has been associated with cellular differentiation and could be critical instigator of involution process. From functional perspective, deregulated expression and increased secretion of CatD are associated with aggressive and metastatic phenotype of breast cancer. Thus unraveling CatD’s physiological functions in mammary gland development will bridge the present gap in understanding its pro-tumorigenic/metastatic functions, and assist in the generation of tailored therapeutic approaches.