This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

Escherichia coli entry into the bladder is met with potent innate defenses, including neutrophil influx and epithelial exfoliation. Bacterial subversion of innate responses involves invasion into bladder superficial cells. We discovered that the intracellular bacteria matured into biofilms, creating pod-like bulges on the bladder surface. Pods contained bacteria encased in a polysaccharide-rich matrix surrounded by a protective shell of uroplakin. Within the biofilm, bacterial structures interacted extensively with the surrounding matrix, and biofilm associated factors had regional variation in expression. The discovery of intracellular biofilm-like pods explains how bladder infections can persist in the face of robust host defenses.

http://science.sciencemag.org/content/sci/301/5629/105.full.pdf

Intracellular bacterial biofilm-like pods in urinary tract infections

GUEST EDITORIAL PART I: ICRP STATEMENT ON TISSUE REACTIONS PART II: EARLY AND LATE EFFECTS OF RADIATION IN NORMAL TISSUES AND ORGANS - THRESHOLD DOSES FOR TISSUE REACTIONS IN A RADIATION PROTECTION CONTEXT ABSTRACT PREFACE EXECUTIVE SUMMARY GLOSSARY 1. INTRODUCTION 1.1. Purpose of report 1.2. Definition and nature of tissue reactions to ionising radiation 1.3. General principles of radiation effects in cells and tissues 1.4. References 2. RESPONSE OF TISSUES AND ORGANS TO RADIATION 2.1. Haematopoietic and immune systems 2.2. Digestive system 2.3. Reproductive system 2.4. Skin 2.5. Cardiovascular and cerebrovascular systems 2.6. Eye 2.7. Respiratory system 2.8. Urinary tract 2.9. Musculoskeletal system 2.10. Endocrine system 2.11. Nervous system 2.12. References 3. MODIFIERS OF NORMAL TISSUE RESPONSE 3.1. Terminology 3.2. Mechanisms of action 3.3. Influence of modifiers on radiation response in tissue 3.4. References 4. THRESHOLD DOSES IN RELATION TO RADIOSENSITIVITY OF ORGANS AND TISSUES 4.1. Introduction 4.2. Haematopoietic and immune systems 4.3. Digestive system 4.4. Reproductive system 4.5. Skin 4.6. Cardiovascular and cerebrovascular systems 4.7. Eye 4.8. Respiratory system 4.9. Urinary tract 4.10. Musculoskeletal system 4.11. Endocrine system 4.12. Nervous system 4.13. Conclusions 4.14. References ANNEX A. SUMMARY OF STUDIES OF EXPOSURE AND OPACITIES OR CATARACTS

ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs -- threshold doses for tissue reactions in a radiation protection context

Virtually all uropathogenic strains of Escherichia coli encode filamentous surface adhesive organelles called type 1 pili. High-resolution electron microscopy of infected mouse bladders revealed that type 1 pilus tips interacted directly with the lumenal surface of the bladder, which is embedded with hexagonal arrays of integral membrane glycoproteins known as uroplakins. Attached pili were shortened and facilitated intimate contact of the bacteria with the uroplakin-coated host cells. Bacterial attachment resulted in exfoliation of host bladder epithelial cells as part of an innate host defense system. Exfoliation occurred through a rapid apoptosis-like mechanism involving caspase activation and host DNA fragmentation. Bacteria resisted clearance in the face of host defenses within the bladder by invading into the epithelium.

https://science.sciencemag.org/content/sci/282/5393/1494.full.pdf

Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli.

The vast majority of urinary tract infections are caused by strains of uropathogenic Escherichia coli that encode filamentous adhesive organelles called type 1 pili. These structures mediate both bacterial attachment to and invasion of bladder epithelial cells. However, the mechanism by which type 1 pilus-mediated bacterial invasion contributes to the pathogenesis of a urinary tract infection is unknown. Here we show that type 1-piliated uropathogens can invade the superficial epithelial cells that line the lumenal surface of the bladder and subsequently replicate, forming massive foci of intracellular E. coli termed bacterial factories. In response to infection, superficial bladder cells exfoliate and are removed with the flow of urine. To avoid clearance by exfoliation, intracellular uropathogens can reemerge and eventually establish a persistent, quiescent bacterial reservoir within the bladder mucosa that may serve as a source for recurrent acute infections. These observations suggest that urinary tract infections are more chronic and invasive than generally assumed.

/pdf/establishment-of-a-persistent-escherichia-coli-reservoir-35vdojrt7o.pdf

Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection.

Summary

1. Urinary bladders are found in the amphibia, chelonian reptiles and mammals. In these orders liquid urine is stored in the bladder and eliminated at intervals from the body by micturation.



2. In the amphibia and chelonian reptiles, the urinary bladder is a functional extension of the renal tubules. The composition of the urine in the bladder is modified by the active movement of water and ions across the bladder wall, and these transporting processes are under hormonal control. The bladder acts as a water reservoir which can be drawn upon in times of water shortage.



3. The mammalian bladder separates two widely differing water phases, namely the urine which is frequently hypertonic to the blood and the tissue fluids which are isotonic. Its function is uniquely one of storage, and no adjustment to the composition of the urine is made by active transport of either water or ions across the bladder wall.



4. The epithelium lining the mammalian bladder is the site of the osmotic barrier between urine and tissue fluids. This functional barrier is dependent on the structure of the epithelium and is maintained despite large alterations in the surface area of the epithelium as the bladder rapidly contracts, or slowly dilates.



5. The epithelium is of mixed mesodermal and endodermal origin, is transitional in type and is usually 3 or 4 cell-layers thick. If this urothelium is damaged, it has a high capacity for regeneration and rapidly re-establishes an intact barrier over the luminal surface.



6. The superficial cell layer of this epithelium is composed of large, polyploid, highly differentiated squamous cells which have a long life span. These cells are limited on their free surface by an unusual, angular, semi-rigid luminal membrane. This membrane is assembled in the Golgi complex.



7. The luminal membrane is composed of thickened, discoidal plaques, separated by narrow bands of thinner membrane. When the bladder contracts, the membrane folds along the thinner ‘hinge’ regions, and the rigid discoidal plates invaginate to form fusiform, cytoplasmic vacuoles. The thickened plaques contain a hexagonal lattice of sub-units, spaced at 14 nm centre-to-centre. Each sub-unit in the lattice is itself composed of 12 smaller particles. These particles may be envisaged as small rods 3 nm in diameter and 12 nm long, and are inserted into matrix from which they project on the luminal face by about 3 nm. Each rod has a central hydrophobic portion separating distal hydrophilic ends.



8. The chemical composition of this luminal membrane is unusual. Cerebroside is a major component of the polar lipid fraction and there is an unusually high proline content in the protein fraction. When the mucoproteins are adequately dispersed, and the proteins separated by electrophoresis, a few major proteins are revealed in 33000–80000 dalton range of molecular weight.



9. If the normal structure of the luminal membrane is altered, either by physical damage or by failure of the cells to produce it, the barrier function of the epithelium is lost.



10. The structure and function of this membrane depend ultimately on its chemical composition. Cerebroside is known to decrease the permeability of lipid bi-layers to water, but for maximum impermeability a lipid bi-layer must be maintained in a condensed configuration. The stresses of bladder distension and contraction might be expected to disrupt the bi-layer, and it is suggested that the function of the rigid plaque regions is to reduce mechanical stresses in the membrane to a minimum. The plaque areas occupy between 73 and 90 % of the membrane surface, and only the remaining 10–27% of the membrane is thus subject to bending and distortion when the bladder contracts or expands. The structure of the plaque areas is probably determined by the nature of the complex proteins which form the sub-units. Proline is known to confer rigidity on polypeptide chains, and may play an important role in ordering the structure of the plaques.



11. The bladder epithelium, though normally differentiated as a transitional epithelium, has other biologicai potentialities. It can undergo squamous metaplasia to form a stratified cornified epithelium in response to mechanical irritation and/or vitamin A deficiency. If transplanted from its normal location, it can induce other supporting mesenchyme tissues to lay down bone. When regenerating in response to damage, the newly formed transitional cells can act as phagocytes and engulf and digest damaged or dying cells. In the normal animal the epithelium is largely protected from tumour formation by cell-mediated immunological surveillance. The defensive mechanisms are triggered by tissue-type specific antigens which develop in neoplastic bladder epithelial cells.

R. Marian Hicks

Papers

The mammalian urinary bladderan accommodating organ