The pathogenesis and conservative management of radiation injuries.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
A Michalowski
Publications and source records attributed to A Michalowski.
Radiation damage to mouse skin and oesophagus.
Explore the source record for details and available documents.
Animals↗
Cisplatin-induced reductions in renal functional reserve uncovered by unilateral nephrectomy: an experimental study in the pig.
Groups of mature Large White female pigs, approximately 10 months of age, received single intravenous infusions of 1.5, 2 or 2.5 mg/kg body weight (equivalent to approximately 90, approximately 120 and approximately 150 mg/m2) cisplatin. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured before and at 4 weeks after cisplatin infusion by renography using [99 mTc]-DTPA (diethylenetriamminepentaacetic acid and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated animal plus that of four age-matched control pigs was then removed surgically, and GFR and ERPF were measured in the remaining kidney at 4 weekly intervals for up to 24 weeks after unilateral nephrectomy (UN). The pigs treated with cisplatin exhibited no consistent change in either GFR or ERPF at 4 weeks after treatment. A histological evaluation of kidneys from animals treated with greater than or equal to 2 mg/kg cisplatin that had been removed at UN revealed both tubular and glomerular lesions. The latter consisted of cell proliferation on the parietal surface of the urinary space; damage to the S1 portion of the proximal convolution was also noted. Following UN there was a pronounced dose-dependent reduction in the functional status of the remaining kidney such that the increase in GFR and ERPF in pigs initially receiving 2.5 mg/kg cisplatin was less than 50% of that seen in age-matched UN controls. Moreover, the glomerular lesions observed at 4 weeks after cisplatin infusion had apparently progressed to glomerular hyalinisation by 24 weeks after UN. Thus, prior treatment with cisplatin may cause a permanent reduction in renal functional reserve that may be clinically "silent" until exposure to an additional nephrotoxic insult.
Animals↗
The relationship between regional variations in blood flow and histology in a transplanted rat fibrosarcoma.
The regional distribution of blood flow to the LBDS1 fibrosarcoma, transplanted into the subcutaneous site in rats, was investigated using the readily diffusible compound 14C-iodo-antipyrine (14C-IAP). Quantitative autoradiography was used to establish absolute values of specific blood flow F for 100 X 100 X 20 microns adjacent tissue volumes of the unperturbed tumour. Mean blood flow to whole tumours was found to decrease with increase in tumour size. This relationship was abolished if blood flow was only measured in sections cut from the periphery of the tumours. Detailed analysis of a sub-group of tumours showed that blood flow to individual tumours was heterogeneous. The range of blood flow was large, indicating that mean blood flow to a whole tumour is a poor reflection of the blood perfusion pattern of that tumour. Necrotic tumour regions were usually very poorly perfused. With the exception of the smallest tumours studied, blood flow was lower in the centre of tumours than in the periphery. Necrosis also tended to develop centrally. However, the peripheral to central gradient of blood flow was apparent even when densely cellular, viable tumour regions and necrotic regions were analysed separately. The decrease in blood flow with tumour size was also apparent in densely cellular, viable tumour regions when analysed separately. Qualitative comparison of tumour histology and regional blood flow showed that there were areas of very low blood flow associated with viable tumour regions. Less common were areas of rather high blood flow associated with necrotic tumour regions. A complicated relationship exists between tumour histology and blood flow. The quantitative autoradiography technique is suitable for investigating the most poorly perfused and the most well perfused viable fractions of animal tumours which may limit the efficacy of different types of therapy.
Animals↗
On radiation damage to normal tissues and its treatment. I. Growth factors.
The first part of the review outlines the classical interpretation of radiation damage to normal organs based on dose-response relationships for clonogenic cell survival and tissue kinetics. Proliferative organization of critical cell lineages (three-compartmental or H-type and one-compartmental or F-type) is considered as an additional determinant in the development of overt radiation injury. This leads to testable predictions concerned with divergent outcomes of stimulation of cell proliferation after radiation exposure using polypeptide growth factors. The prediction of favourable effects of such stimulation in H-type lineages is borne out by recent experiments on treatment with cytokines of radiation-induced haemopoietic insufficiency. The second prediction of deleterious effects of proliferative stimulation in recently, heavily irradiated F-type cell lineages remains to be verified or refuted.
Animals↗
Histamine, histamine formation capacity and gastrin in cysteamine-induced peptic ulcer.
We attempted to induce chronic peptic ulcer in the rat by injection of consecutive doses of cysteamine. We investigated the incidence of peptic ulceration and measured gastric mucosal histamine, histamine formation capacity (HFC), plasma gastrin and tissue (oesophagus, duodenum, liver and lung) histamine in rats 1, 7, 14, 21, and 28 days after injection of cysteamine-HCl (300 mg/kg s.c. and 100 mg/kg 8 h later). Saline injections were used in control rats. After 24 h all rats given cysteamine had duodenal ulcers and the ulcer incidences after 7 and 14 days were 60 and 40%, respectively. After Day 21 no ulcers were found. Microscopy revealed ulcer healing seen as epithelialized scars from Day 14 onwards. A rising incidence of gastric metaplasia of the duodenal mucosa was noted from Day 7 after cysteamine treatment, which may have pathophysiological significance. Gastric mucosal histamine was higher and plasma gastrin was lower after 24 h compared with controls and values obtained later in the study. Rats with duodenal ulceration had significantly higher gastric mucosal histamine than those without lesions and control rats. A direct relationship was found between plasma gastrin and HFC in rats given cysteamine. A small but significant increase in histamine content of the liver was also observed after 24 h. No significant changes were found in other tissue specimens. Thus, a rise in gastric histamine is associated with duodenal ulcers in this model.
Animals↗
Effect of gastric irradiation on gastric secretion and histamine in mice.
Gastric irradiation selectively inhibits acid secretion. Histamine may have a role in the inhibitory process. Seven days after gastric irradiation with 9 Gy X-rays, mice underwent a stomach perfusion and secretion test. Under pentagastrin stimulation (62.5 micrograms/kg), acid and histamine secretion was significantly lower than that of the unirradiated controls, while pepsin and potassium outputs were unchanged. Histamine concentration in the oxyntic region of the stomach assayed after the perfusion test was significantly lower than that of controls. It is postulated that the fall in the endogenous histamine store may contribute to the reduction in acid production.
Animals↗
Development of villous damage in mouse small intestine after local hyperthermia or irradiation.
Damage to mouse small intestine has been assessed in the period up to twenty-four hours after heating a portion of the gut for 20 min at 43 degrees C and also in the period up to nine days after 10 Gy/whole body X-irradiation. The surface changes and the light microscopic appearances after the two types of treatment were described. The damage was evaluated using scores produced by assessing villous collapse as seen with a scanning electron microscope (SEM). Maximum damage was seen two hours after hyperthermia and was more pronounced in antimesenteric portions of the same specimen. Maximum damage was observed three days after X-irradiation. Despite the difference in the time scale and severity of development of surface changes after the two types of treatment, the structure of the damaged and recovering villi looked similar, except for the apical extrusion of the enterocytes immediately following the heat treatment.
Animals↗
Gastrointestinal histamine after gastric irradiation in the mouse.
A single dose of 9 or 15 Gy of X-rays was given to the stomach of mice. Gastric histamine formation capacity (HFC) rose in a dose-related fashion during days 4 to 11 after irradiation. This rise coincided with a dose-dependent fall in gastric mural histamine concentration. 15 Gy X-rays also resulted in a transient loss of body weight (days 4-8 after irradiation). These results suggest that irradiation of the stomach mobilizes gastric histamine and that gastric histamine stores may be radiosensitive.
Animals↗
The pathogenesis of the late side-effects of radiotherapy.
Explore the source record for details and available documents.
Adrenal Glands↗
Assays of damage to the alimentary canal.
Explore the source record for details and available documents.
Animals↗
Gastrointestinal histamine after thoracic irradiation in the mouse.
Thoracic irradiation induced duodenal lesions in mice as an indirect effect. We studied the influence of partial thoracic irradiation on endogenous histamine stores in the alimentary canal. Mice subjected to lower mediastinal irradiation had significantly higher (+19%) median gastric histamine, but lower (-44%) distal duodenal histamine than controls. They also had significantly lower proximal (-39%) and distal (-44%) duodenal histamine than mice who received upper mediastinal irradiation. Twenty-three percent of mice after lower mediastinal irradiation had duodenal lesions; these had significantly lower proximal (-30%) and distal (-44%) duodenal histamine than controls. Thus, irradiation to the lower mediastinum induced both duodenal lesions and significant changes in gastric and duodenal histamine stores. Histamine may be involved in the pathogenesis of these lesions.
Animals↗
Surface studies of duodenal lesions induced by thoracic irradiation.
Acute duodenal ulcers are produced in mice as a remote ("abscopal") effect of irradiation to the lower mediastinum. Such lesions have been examined with scanning electron microscopy at 5, 8 and 28 days after irradiation with 18 Gy of X-rays. All the ulcers occur within the first 1 cm long segment of the duodenum which is endowed with Brunner's glands. The single lesions vary in size, shape and position. The damaged area often includes much of the duodenal circumference and is distinguished by conical or rudimentary villi, or even by the complete absence of villi. In contrast, around the periphery of the ulcer the villi are mostly vertical. Although the floor of these lesions appears to be covered with a continuous epithelial layer, during the first 4 weeks after irradiation the severity of the focal duodenal damage seems to increase gradually with time. The lesions have been compared with specimens from unirradiated mice and also with samples taken 3 days after partial thoracic irradiation when little damage is seen. The pattern of fully developed duodenal lesions differs greatly from that seen after direct irradiation where damage has not included localised ulceration in the samples of jejunum so far examined. The lesions induced by partial thoracic irradiation may be related to radiation injury to vascular or autonomic nerve targets in the lower mediastinum. Such injury could result in malfunction of the pyloric sphincter or could alter the secretion by Brunner's glands and thus lead to duodenal ulceration.
Animals↗
A critical appraisal of clonogenic survival assays in the evaluation of radiation damage to normal tissues.
Assessment of radiation damage to normal tissues in terms of dose-response curves for infinite proliferative potential ("survival curves") does not take into account the decrease with increasing dose of the multiplication rate of the clonogenic and non-clonogenic (radiation-sterilized) cells which may be implicated in the expression of the damage to tissue function or gross appearance. While radiation selectively lowers the chance of successful mitotic divisions, other anticancer agents may in addition interfere with different cellular processes. Comparisons of effectiveness of radiation with that of other modalities should not therefore be limited to analysis of survival curves. Assays of cell "survival" in self-renewing normal tissues in situ often define properties of a non-random sample of the clonogens. The nature of repair associated with the post-irradiation delay in performance of transplantation assays for normal clonogenic cells remains unclear. Dose-response relationships for functional impairment or gross damage to tissue, especially those obtained by irradiation with many fractions, do not necessarily yield to interpretation in terms of clonogenic cell "survival".
Animals↗
Can cell survival parameters be deduced from non clonogenic assays of radiation damage to normal tissues?
Though dose-response curves for large scale radiation injury to tissues are undoubtedly related to survival curves for clonogenic cells, the relationship between the two sets of curves is not necessarily simple. Sterilization of clonogenic cells occurs near-instantaneously by comparison with the protracted lag period for gross injury to tissues. Moreover, with some types of macroscopic damage, the shapes of the dose-response curves may depend on time of assay. Changes in the area or volume of irradiated tissue may also influence the shapes of these curves. The temporal pattern of expression of large scale injury also varies between tissues, and two distinct groups can be recognized. In rapidly proliferating tissues, the lag period is almost independent of dose, whilst in slowly proliferating tissues, it is inversely proportional to dose. This might be explained by invoking differences in corresponding proliferative structures of the tissues (Three compartmental Type H versus One compartmental Type F proliferative organization). For the second group of tissues, in particular, mathematical modelling suggests a systematic dissociation of the dose-response curves for clonogenic cell survival and for large scale injury. This dissociation, which arises even in the case of single doses, may be even more important when radiation is fractionated. In particular, it may be difficult to disentangle the contributions made to inter-fraction sparing by cellular repair processes and by proliferation-related factors.
Animals↗
The effect of local hyperthermia on nonproliferative, compared with proliferative, epithelial cells of the mouse intestinal mucosa.
The effects of local hyperthermia on different components of mouse intestinal mucosa were investigated. The intestine was heated by immersion in Krebs-Ringer solution at various times after intraperitoneal injection of [3H]thymidine, and thermal injury was assessed by measuring loss of label. The interval between labeling and heating was either 14 hr, when the majority of labeled epithelial cells were still in the crypts, or 65-72 hr, when the majority of the label had moved onto the villi. Heating at 42 degrees C for up to 1 hr had no observable effect. When intestine was heated at 43 degrees C 14 hr after labeling, the characteristics of the loss of label were very similar to loss of crypts with regard to both the fraction lost and the time over which the response occurred. The threshold heating time to cause an effect was between 20 and 30 min and the response was complete by 6 hr after treatment. If, however, intestine was heated at 43 degrees C either 65 or 72 hr after injection of [3H]thymidine, the threshold heating time required to cause an effect was reduced to between 10 and 20 min and loss of label was not necessarily accompanied by crypt loss. For example, 40% of radioactivity could be lost from the villi without any corresponding loss of crypts. Both the labeling experiments and histological examination indicated that the nonproliferative cells of the intestinal mucosa that line the lumen are more susceptible to thermal injury than the crypt cells. Thus, although crypt loss may remain a useful endpoint in the assessment of thermal damage, the data would underestimate early mucosal injury and the impairment of functional integrity of small intestine.
Animals↗
Alternative types of duodenal ulcer induced in mice by partial X irradiation of the thorax.
The present study extends our earlier observations [A. Michalowski, Br. J. Radiol. 54, 713 (1981); A. Michalowski and J. Burgin, in Progress in Radio-Oncology II, pp. 105-110] on gastrointestinal pathology in thorax-irradiated female CFLP mice. It shows that exposure of the lower mediastinum to single doses of 14-30 Gy X rays results in the formation of the proximal duodenal ulcer accompanied frequently by erosion of the antral gastric mucosa. X irradiation of the lateral thoracic fields is responsible for single ulcers in the proximity of duodenal papilla, often associated with a circumscribed area of degeneration of the fundic mucosa of the stomach. In view of the small amount of radiation received by the subdiaphragmatic parts of the alimentary tract, these gastro-duodenal lesions represent abscopal effects of thoracic irradiation.
Animals↗
Scanning and transmission electron microscopy of the damage to small intestinal mucosa following X irradiation or hyperthermia.
Scanning and transmission electron microscopy (S.E.M. and T.E.M.) and resin histology have been used to investigate the effects on mouse small intestinal villi of heating at 43 degrees C for 20 minutes and of irradiation with 10 Gy X-rays. Damage after irradiation included conical villi and giant cells. Damage after heating included the production of conical and rudimentary villi and the stacking of enterocytes. Individual cells showed signs of abnormalities in their cell membranes, nuclei and cytoplasmic components. The differences in the response after irradiation and hyperthermia are linked to the fact that heating has a primary effect on villous structure, whereas irradiation mainly affects the proliferative pool of crypt cells.
Animals↗