Parenchymal Cell Loss Research Articles

Initiation of non-neoplastic late effects: the role of endothelium and connective tissue.

While early radiation lesions might be a direct consequence of parenchymal cell loss, late-radiation injury most probably develops as a consequence of functional perturbations that may involve both parenchymal and nonparenchymal elements. Damage to blood vessels and consequent perturbations in blood flow and endothelial physiology play an important role in the development of late effects. The development of late-radiation damage has been studied in three different tissue systems: the skin, kidney and central nervous system. The results suggested that damage to vascular tissue played a major role in the development of radiation-induced late effects.

Scatter factor/hepatocyte growth factor is essential for liver development.

Polypeptide growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor/hepatocyte growth factor (SF/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood proteinase plasminogen. The cellular responses of SF/HGF are mediated by the c-Met tyrosine kinase receptor. Here we report that mice lacking SF/HGF fail to complete development and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. Thus, SF/HGF is essential for the development of several epithelial organs.

The Response of the Microvascular System to Radiation: A Review

The microvasculature is a ubiquitous organ system having a major role in the pathogenesis of radiation damage to normal tissues. Although the kinetics of radiation damage to endothelial cells is similar to other tissues (as reflected by Do and Dq) the late effect is a manifestation of injury, not only to the endothelial cell population, but also to the basement membrane. Tissue damage is progressive. The initial expression of radiation injury is an increased permeability leading to changes in the extracellular milieu. There is an irregular proliferation of endothelial cells leading to capillaries of irregular diameter and shape. Fibrous proliferation increases the histohematic barrier and is ultimately reflected in a loss of parenchymal cells. Replacement fibrosis progresses until a steady state is reached where the surviving parenchymal cells can be sustained by the microvasculature. The clinical significance depends on the role of the organ system involved. For patients who have medical conditions which adversely effect the stability of the vascular system (hypertension, diabetes, etc.), the expressions of radiation injury may be more severe and increase the morbidity associated with these diseases. Angiogenesis in granulation tissue is less radiosensitive than in steady-state parenchymal tissues. Wound healing is not significantly affected by commonly used therapeutic doses of irradiation, 40-50 Gy delivered 4-6 weeks preoperatively or postoperatively early in the development of the granulation tissue, but may be complicated where a significant degree of fibrosis has developed. The vascular responses leading to telangiectasia were discussed.

The predictive value of skin telangiectasia for late radiation effects in different normal tissues

Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiation of different organs. Whether parenchymal cell loss is a process well dissociated from vasculoconnective damage, or a consequence of this, is much debated. However, comprehensive radiopathological studies have shown that vasculoconnective tissue is an important common target for late effects in various organs. Scoring of skin telangiectasia was used by us as a clinical assay of late tissue effects after different dose schedules. All studies were done prospectively with standardized skin area, field size and radiation quality. The patients were scored regularly up to 10 years. The number of patients at risk for a prescribed score versus time was calculated with the life-table method. The late effects after 5 X 2.0 Gy/wk, in the dose range 40 to 70 Gy and after 2 X 4.0 Gy/wk, in the dose range 40 to 56 Gy have been established. The skin dose is 90% of the referred dose. Dose-response curves, relating the proportion of patients with a certain score at a fixed time and radiation dose and dose-latency curves, relating the latent period for a fixed proportion of patients with a certain score and radiation dose, were constructed. The analysis shows that: (1) ED 10/5 yr and ED 50/5 yr for 5 X 2.0 Gy/wk is 50 Gy and 65 Gy, respectively, for distinct telangiectasia; (2) The latent period, concerning both a certain frequency and degree of reaction, varies exponentially with dose level; (3) The latent period for 50% of the patients, to obtain a certain score, LP 50, is correlated to that for 10%, LP 10, with LP 50/LP 10 = 2.2 ± 0.2 (S.D.). This correlation is independent of score, total dose, and fractionation; (4) Isoeffective doses for 5 X 2.0 Gy/wk and 2 X 4.0 Gy/wk, determined from the dose-response curves, resulted in the repair factors exp N between 0.31 and 0.32 and α β ratio between 2.9 and 3.1 Gy and determined from the dose-latency curves in exp N between 0.30 and 0.32 and α β ratio between 3.4 and 2.9 Gy. In conclusion, frequent and careful follow-up with registration of normal tissue reactions, until at least 10% of the patients have obtained the prescribed effect, is predictive for the further progression of the late effects. The fractionation characteristics for telangiectasia agree well with those for animal experimental morphological and functional endpoints for late effects in different organs and support the relevance of telangiectasia as a model for predicting late effects.

Liver Tumor Induction.

The significance of the development of nodular liver lesions in rodents following the administration of test agents raises several questions which could be placed in one of two general categories: diagnostic and interpretational. From a diagnostic point of view, the proper classification of liver tumors into a benign and malignant category has to be based on the direct correlation between the morphology and the biologic behavior of the lesions. Therefore, extreme care should be taken to separate the malignant tumors from the benign and the benign neoplasia from the hyperplasia. The substitution of the term "neoplastic nodule" for hyperplastic nodule in rats is misleading. Most of these nodules, when induced under special experimental conditions, may regress or remodel and thus they are not neoplastic in nature. Chronic carcinogenicity bioassays should include "stop" type of treatment leaving enough of the observational time to establish the fate of induced nodular lesions. The induction of histochemically changed foci can serve only as an indication of potential hepatocarcinogenicity and should not be equated with the induction of bona fide cancer. The biologic interpretation of nodular liver lesions, especially in mice, needs further scrutiny because these lesions have a tendency to develop spontaneously with high incidence in some strains. This characteristic then raises the question as to the mechanism by which various agents augment and/or accelerate the development of such tumors. Is this action primarily promoting or initiating in nature or does it represent the induction of tumors de novo? The answer to this dilemma may have a decisive bearing on carcinogenic risk assessment and the type of regulatory action, since the promoting agents possess a threshold effect and the promoted changes may regress following withdrawal of treatment. The interpretation of hepatocarcinogenesis is further complicated by the fact that several factors, such as sex hormonal environment, increased mitotic activity following an excessive loss of parenchymal cells, degree of caloric intake, enzymatic complement, and animals' age at the time of the exposure to a test agent, may influence the outcome of liver tumor development by modulating "initiation" and/or "promotion" of carcinogenesis. Broad fluctuation in the historic incidence of liver tumors further compounds the complexity of the proper bioassay interpretation. The specifically designed experiments may have the objective to explore predominantly the initiating or promoting effects of the agent. Such protocols should be used whenever necessary to differentiate between these two mechanisms of action. In the Caucasians, the "spontaneous" development of the primary hepatocellular tumors is rare. The majority of these tumors are malignant and rapidly fatal. According to some human pathologists, the benign variety of liver tumors is rare and it does not represent necessarily a premalignant stage in tumor development. Carcinoma of the liver may occur in infancy, especially in males before the age of 2 years. This suggests a genetic causation or carcinogenic exposure in utero. One of the geographic factors which significantly enhances the incidence of hepatocellular carcinoma in humans is exposure to aflatoxin B1 which is apparently potentiated by concurrent liver cirrhosis. Because many more agents have been found to be hepatocarcinogenic in mice and rats than in men, a question arises as to the direct relevance of rodent studies to humans. A balanced assessment of the carcinogenicity of the agent could only be reached in considering both the pharmacokinetics and the development of malignant neoplasia in other organs. In the case of positive carcinogenicity assessment, the outcome of the mutagenicity bioassays can suggest genic (genotoxic) or paragenic (epigenetic) mode of action in mammalian systems.

Effect of ACTH on the proliferative and secretory activities of the adrenal glomerulosa.

Abstract. The mitotic, trophic and secretory responses of the adrenal cortex to various preparations and doses of ACTH were investigated in the rat. 1-24-ACTH depot (Synacthen) elicited the highest mitotic and trophic stimulation. The mitotic stimulation occurred exclusively in the glomerulosa, the trophic stimulation occurred mainly in the fasciculata-reticularis and the functional stimulation was found in both, as indicated by the plasma aldosterone and corticosterone levels. The functional changes occurred first, the trophic changes later. Large doses of ACTH inhibited cell proliferation in the fasciculata. The trophic action consisted in an enlargement of the adrenal, to a great extent in the fasciculata-reticularis, and to a lesser extent in the glomerulosa. This enlargement was due partly to parenchymal cell hypertrophy, but also and mostly to stromal hypertrophy, especially hyperaemia. The largest dose of ACTH caused a considerable widening of the sinusoids of the fasciculata-reticularis and medulla, and possibly caused a loss of parenchymal cells in the reticularis. These effects are reminiscent of the well documented haemorrhagic conditions of the adrenals in humans.

The Chronological Development of Late Radiation Injury in the Liver of the Rat

Surgically exteriorized left anterior liver lobes of rats were X-irradiated with 8 kR, and changes in liver weight and histology were evaluated for 40 weeks after irradiation. Irradiation prevented growth in the irradiated lobe. A decrease in irradiated lobe weight occurred approximately 14 weeks after irradiation and was associated with parenchymal cell loss. Inflammatory cell infiltration into the irradiated lobe occurred immediately after irradiation and remained constant for 12 weeks after which there was a further increase in numbers of inflammatory cells. Fibrosis was apparent by 2 weeks and exhibited a second increase in severity after 12 weeks. Nuclear injury in some parenchymal cells was apparent in the irradiated lobe, especially after 24 weeks. Concentric lamellations in the veins with compromise of their lumen became evident after the 10th week. The temporal response of these alterations and consideration of other reports on late radiation effects suggest that early liver injury (0 to 12 weeks) is associated with an autoimmune reaction while the more extensive liver injury which occurs later (16 to 40 weeks) is the result of more direct radiation damage to the vasculature.

Effects of Phomopsis rossiana toxin on the cell cycle and on the pathogenesis of lupinosis in mice

Crude extract of the toxin produced by the fungus Phomopsis rossiana growing on lupin seed was administered by intra-peritoneal injection to adult male C3H mice. Effects on several aspects of the cell cycle were investigated over periods of up to 10 days in the liver and in less detail in kidney, duodenum, lung and spleen. An increase in the number of mitotic parenehymal cells in the liver commenced about 26 h, after injection of the toxin, reached a maximum between the second and third day and then declined. A high proportion of the mitotic cells were abnormal, arrested metaphases. Morphological abnormalities were frequent in the nuclei of interphase cells, which also showed a progressive increase in mean cell and nuclear diameters. There is considerable daily loss of parenchymal cells, including those arrested in metaphase. It is concluded that the pathology seen after the administration of a single dose of toxin results from the interaction of several factors, including mitosis-arresting and cytotoxic effects, and secondary regenerative responses. Effects in the kidney were similar to those in the liver but were mainly restricted to the proximal convoluted tubules. The wave of mitotic arrest commenced several hours later than that in the liver and was of much shorter duration. No evidence of mitotic arrest or other effect was observed in the duodenum, lung or spleen.

X-Radiation-Sensitivity of Rat Liver to Interphase Death

JACKSON, K. L., CHRISTENSEN, G. M., HEBARD, D. W., AND PARKER, R. G. X-Radiation-Sensitivity of Rat Liver to Interphase Death. Radiat. Res. 59, 585-596 (1974). This report describes the response of the liver to local irradiation of the surgically exteriorized left anterior lobe during a period of 9 wk following exposures of 5-40 kR. Decrease in irradiated left lobe weight relative to shielded right lobe weight was dosedependent and exhibited a maximum response by 20 days. Histological examination and DNA analysis indicate there was a radiation-dose-related loss of parenchymal cells. Incorporation of 3H-labeled leucine relative to weight change indicated that metabolically dead cells were rapidly removed from the irradiated lobe. The findings do not clarify whether interphase death of parenchymal cells was a direct response to irradiation or resulted indirectly from radiation-induced vascular damage. The estimated curve for survival of hepatocytes from interphase death in vivo as a function of dose has an extrapolation number of 2.7 and a Do of 9.1 kR.