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British Journal of Radiology (2005) Supplement_27, 95-99
© 2005 British Institute of Radiology
doi: 10.1259/bjr/32774071
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British Journal of Radiology Supplement_27 (2005),95-99 © 2005 The British Institute of Radiology

Full Paper

The role of damage to the cutaneous system in radiation-induced multi-organ failure

V Meineke, MD

Bundeswehr Institute of Radiobiology, 80937 Munich, Germany

Correspondence: Viktor Meineke, Institut für Radiobiologie der Bundeswehr, Neuherbergstr. 11, 80937 München, Germany. E-mail: ViktorMeineke@bundeswehr.org


   Abstract
Top
 Abstract
Introduction
 Clinical aspects of cutaneous...
 Cutaneous radiation reactions at...
 Cutaneous radiation reactions...
 References
 
Recent radiation accidents have dramatically shown that radiation damage to the skin is a key diagnostic and prognostic parameter for patients who have been accidentally exposed to radiation. The precise role of the cutaneous system in radiation-induced multi-organ failure (RIMOF) is not yet completely understood. However, there is evidence suggesting that radiation-induced skin damage may play an important role as a factor triggering the failure of other organ systems. Based on this premise, this paper discusses clinical and molecular biological aspects of cutaneous radiation reactions. It draws attention to particular problems and future challenges regarding the clinical management of this condition and emphasises the need for further studies that will help us to understand better the pathophysiology of RIMOF in association with the skin.


   Introduction
Top
 Abstract
 Introduction
Clinical aspects of cutaneous...
 Cutaneous radiation reactions at...
 Cutaneous radiation reactions...
 References
 
The term cutaneous radiation reaction – also known as cutaneous radiation syndrome [1] – is used to designate the specific reactions of the skin to ionising radiation. Shortly after roentgen rays were discovered by WC Röntgen in December 1895, physicians and physicists noted that these rays induced erythema on the skin [2]. Attempts were then made to use roentgen rays for therapeutic purposes. In the first radiobiological experiments, skin reactions were observed after contact with radionuclides or ionising radiation. Although these more or less "unintentional" experiments can be regarded as accidental exposures, they provided the first important findings regarding the effects of ionising radiation on the basis of the skin reactions observed. It has been reported that in 1901 Pierre Curie repeatedly used a radium source to induce skin reactions and a radiation ulcer on his own forearm [3]. Moreover, prior to the development of more reliable methods of assessing radiation and the introduction of the first radiation dose units such as roentgen (R) in 1931, a descriptive approach had been used for evaluating radiation reactions such as the threshold dose for erythema.

Even today, the radiation reaction of the skin continues to play an important role. Recent radiation accidents [4, 5] have dramatically shown that radiation-induced skin damage can be a factor determining the prognosis and outcome of radiation-induced multi-organ failure (RIMOF).

Skin complications play an important role not only in radiation accidents but also in other situations where a cutaneous radiation reaction can occur. These situations include but are not limited to radiotherapy and radio-oncology, which can give us important insights into what is happening in radiation-induced multi-organ interactions. Radiotherapy affects not only the target site but also the surrounding healthy tissue. In particular, the reactions of the skin to irradiation must be taken into consideration [6–8]. Both an inflammatory response and a proliferation-modulating effect can occur, damaging the skin and affecting its integrity.

The purpose of this paper is to help to better understand the role of the skin organ in RIMOF. This special aspect of disturbances of physiological skin functions has never been addressed before. Neither clinical nor experimental data on multi-organ failure triggered by the skin or involving the skin have thus far been reported. For this reason, a step-by-step approach to this complex subject appears to be reasonable. This paper will first focus on the radiation reaction of the skin and associated problems. Special aspects of cutaneous radiation reactions will then be discussed and evaluated at both the clinical and the molecular level. Finally, cutaneous radiation reactions will be discussed in association with multi-organ involvement. Since this paper provides only a brief overview of the subject, it does not consider a number of interesting publications that are not directly related to RIMOF.


   Clinical aspects of cutaneous radiation reactions
Top
 Abstract
 Introduction
 Clinical aspects of cutaneous...
Cutaneous radiation reactions at...
 Cutaneous radiation reactions...
 References
 
Holzknecht [9] and Miescher [10] were the first to describe the various phases of cutaneous radiation reactions. In simple terms, they distinguished between a prodromal stage, a manifest illness stage and a chronic stage. However, these phases can be further differentiated [11, 12]. A quasi-threshold dose (Dq) of approximately 3.5 Gy [13], which defines the level below which no effect is expected, is a post-irradiation skin reaction parameter of particular radiobiological importance. Compared with highly radiosensitive systems such as the haematopoietic system, the skin shows the first responses to radiation at a relatively high dose. Data on cutaneous radiation reactions have been obtained from animal experiments [14–17]. However, since different species may show different types of erythema following radiation exposure, the findings obtained in animal studies have only limited value for assessing human responses to irradiation. For purely didactic purposes, however, it is useful to distinguish different forms of erythema indicative of the clinical reaction phases of the skin to irradiation. Simply put, we can distinguish between early erythema, main erythema and late erythema following radiation exposure. This distinction does not follow strict rules and there may be considerable intraindividual differences in the clinical radiation response of the skin and thus in the presence of cardinal symptoms depending on the dose and quality of radiation.

The radiation dose determines the onset and severity of early erythema, making it an important cardinal symptom. A distinction between the various phases of cutaneous radiation reactions on the basis of the forms of erythema therefore has a number of advantages. It is, for example, possible to classify radiation reactions on the basis of phases. As a result, it is possible to evaluate the acuteness of a radiation reaction on the basis of the history of exposure and clinical findings and thus to make a rough dose assessment using the clinical signs and symptoms present. This distinction is no longer relevant in modern clinical radio-oncology, where radiation is, of course, used in such a way that damage is minimised and this "clinical parameter" does not occur at all. However, Porock et al [18] report that up to 95% of all patients who receive radiation therapy show early or late skin reactions of varying severity.

Sometimes it can still be useful to conduct a dose assessment on the basis of clinical manifestations, for example in the case of radiation accidents where radiation exposure is known to have occurred but the radiation dose is unknown. More than 800 radiation accidents have been reported worldwide [19]. Among the radiation accidents in which skin damage has played a major role are the Chernobyl accident in 1986 and the Goiania accidents in 1997 and 2001 [20, 21]. Recent findings suggest that early treatment of radiation damage can significantly improve prognosis. For this reason, a dosimetry system based on clinical signs and symptoms has proved to be effective [22, 23].

Unlike the response of other organs, the clinical reaction of the skin to radiation is directly visible to the examiner. Especially in mass casualty situations, the different phases of cutaneous radiation reactions provide an important basis for instituting timely and targeted medical treatment [24, 25]. This clinical dosimetry is easy to perform and provides results more rapidly than the classical methods of biological dosimetry [26]. It can, however, offer only supplementary and provisional information until concrete biological dosimetry results are available.

The most severe complication associated with radiation exposure is haematopoietic radiation syndrome [27, 28]. When radiation victims such as those of the Tokai-mura accident received medical treatment for this syndrome, excellent results were reported with stem cell transplantation [29]. Now that it is possible to treat successfully patients with radiation damage to the most radiosensitive system, namely the haematopoietic system, these patients may present with other organ complications caused by considerably higher radiation doses. This applies, in particular, to cutaneous radiation syndrome, which can occur with an unprecedented severity and for which there is currently no causal and specific therapy. In the criticality accident that occurred at the nuclear fuel reprocessing plant in Tokai-mura in 1999, three workers were exposed to an extremely high whole body neutron and {gamma}-radiation dose of up to 20 Gy [4, 30]. An absorbed skin dose of up to 61.8 Gy was noted [29]. Two patients who presented with particularly severe cutaneous radiation syndrome eventually died from multi-organ failure. Owing to the severity of the skin injuries that these radiation victims had sustained, the clinical management of cutaneous damage was one of the major medical problems. For this reason, extensive foreign skin transplantations were performed. One of the lessons learned from this radiation accident is that the development of artificial skin material must be given high priority in order to ensure that the consequences of radiation accidents can be successfully managed.

Although late damage usually plays only a minor role in RIMOF as a result of the fulminant clinical course, it should not be neglected in the case of a prolonged disease course. Some of the characteristic late sequelae of radiation exposure are vascular lesions or telangiectasia, fibrotic changes [31–33] and carcinogenesis. Basal cell and squamous cell carcinomas are the tumours most commonly induced by radiation [34]. Among the survivors of the Hiroshima and Nagasaki atomic bombings, an increased occurrence of skin tumours was observed. It should be noted that damage was aggravated by additional exposure to ultraviolet radiation in many cases [35]. Many patients receiving radiation therapy develop secondary skin tumours as well [36]. The extent to which irradiation can induce secondary malignant melanoma is still unclear [37]. It is, however, an important and undisputed fact that lifelong control both of clinical and of selected molecular parameters associated with cutaneous radiation reactions is of the essence [38].


   Cutaneous radiation reactions at the molecular level
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 Abstract
 Introduction
 Clinical aspects of cutaneous...
 Cutaneous radiation reactions at...
Cutaneous radiation reactions...
 References
 
Both the degree of skin damage and the ability of skin cells to recover from radiation damage depend on the radiation quality, the radiation dose and the depth of radiation penetration. In the epidermis, clonogenic cells in the hair follicular epithelium play a key role in regeneration processes [39].

Ionising radiation acts on the cellular organisation at different levels. Recent studies have shown that DNA damage is not the only important factor at the cellular level or the only factor that determines the radiation reaction. Cell surface structures such as adhesion molecules [40] as well as cellular signalling processes [41] are receiving more and more attention. An important inflammatory adhesion molecule is the intercellular adhesion molecule-1 (ICAM-1) [42, 43]. Upregulation of ICAM-1 in association with release of ICAM-1 from the cell surface [25] may be an interesting target for the development of a therapy that influences the radiation reaction. Moreover, {beta}1-integrins in the skin are of crucial importance since they ensure tissue integrity and regulate keratinocyte adhesion and differentiation [44, 45]. Integrin expression is normally confined to the basal layer of the epidermis. During wound healing and in certain pathological conditions, however, integrins are also expressed by suprabasal keratinocytes, and several integrin receptors are expressed by the epidermal keratinocytes, including {alpha}2{beta}1 and {alpha}3{beta}1. Recently, it has been shown that the proliferation of skin cells after irradiation can also be mediated by altered {beta}1-integrin expression. These data showed that in vitro not only the expression of integrins but also cell–matrix interactions play an important role in cell-adhesion-mediated radioresistance [46]. If this finding was confirmed in vivo, we would probably better understand both the radiation response at different levels of biological organisation and the special case of RIMOF.

As a mediator of cellular DNA damage, the transforming growth factor-{beta} (TGF-{beta}) pathway should also be taken into consideration in an evaluation of skin reactions at the molecular level [47]. Recently, interferences with Smad3 signalling and TGF-{beta} have been shown to play an important role in the healing of irradiated skin wounds [48]. Identification of selected molecular targets may therefore help to find prognostic indicators for the radiation reaction of the skin and to guide the way to specific therapeutic options.

The molecular biological mechanisms involved in the development of radiation-induced late effects on the skin are not yet completely understood. In particular, skin fibrosis and epidermal hyperplasia caused by altered differentiation of skin fibroblasts should be taken into consideration [49]. The influence of ionising radiation on pre-existing malignancies and relevant pathways is a further important aspect that should not be ignored. An example is Ku70/80 DNA binding activity, which appears to be an important parameter for the aggressiveness of basal cell carcinomas after exposure to ionising radiation [50].

This brief and non-exhaustive discussion of molecular interactions in the skin shows that almost everything we know about molecular events within and between skin cells in association with ionising radiation must be considered in an evaluation of RIMOF. In addition, a better understanding of the pathogenesis of RIMOF at the molecular level requires new approaches that avoid focusing on a single organ or a single type of cell. For this reason, the final part of this paper will draw attention to the role of radiation-induced skin reactions in association with multi-organ involvement.


   Cutaneous radiation reactions and multi-organ involvement
Top
 Abstract
 Introduction
 Clinical aspects of cutaneous...
 Cutaneous radiation reactions at...
 Cutaneous radiation reactions...
References
 
The skin is involved in RIMOF in several respects (Table 1Go). The important role of the skin as a diagnostic parameter of the extent of radiation damage to tissues and the whole organism has already been described. Early diagnosis of radiation-induced disturbances within the cutaneous system can be extremely helpful both for the "triage" of radiation victims and in an initial assessment of the potential course of disease and the required diagnostic and therapeutic measures to be taken.


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  		Table 1. The role of the skin in radiation-induced multi-organ failure

 
A further important aspect to be considered is the role that the skin may play as one of the most critical organs in RIMOF. A look at the size and composition of the skin can make this clear (Table 2Go). Disturbances of the whole system such as those seen in accidental whole body radiation exposure or local radiation exposure in large radiation fields can have a considerable effect on the homeostasis of tissue and on the entire organism simply because of the enormous number of cells and organelles affected. The skin may play a critical role for other reasons as well. One of the most important aspects to be considered in this context is the lack of specific and tested treatment protocols for the medical management of radiation-induced skin damage.


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  		Table 2. The size and composition of the skin

 
As mentioned above, the severity and prognosis that have thus far been associated with the failure of different organs are being re-assessed. Organs with tissues and cells that have a far higher Dq than haematopoietic cells cause severe and critical clinical complications following radiation exposure. This has been emphasised by recent radiation accidents such as that in Tokai-mura in 1999 [4]. The skin is now considered to be a critical organ in RIMOF. This finding should redirect scientific research and efforts in this field. A certain amount of radiation-induced skin damage, which remains to be defined, will constitute a fatal "point of no return" in RIMOF. The successful treatment of skin complications after exposure to ionising radiation may help prevent multi-organ failure. From a clinical point of view, the development of stage-dependent treatment protocols for radiation-induced skin damage is most important. The identification of common denominators for the skin and other organs may be helpful in this context.

The vascular system is a common feature shared by all organs, including the skin. As a result of its size in the skin (Table 2Go) and its involvement in the radiation reaction of all other organs, the vascular system may be the most interesting starting point for a targeted multi-organ approach to understanding pathophysiological mechanisms and to developing therapeutic options [51, 52]. Radiation-induced disturbances within the endothelium of blood vessels are typical of barrier dysfunctions and morphological changes within the endothelium of all organs and in some respects also within the epithelium of irradiated skin [53]. Likewise, the immune system may be a promising starting point for future approaches to RIMOF. Disturbances within the imunnocompetent skin organ may reflect immunological reactions in other organs. Since the skin is the outer covering of the body, it has a sentinel function in protection against infections. The management of infections in irradiated skin [54] continues to be a matter of great importance. A radiation-induced disturbance of the barrier function of intact epithelium in combination with a radiation-induced depression of immunocompetent cells may have considerable effects on the course of RIMOF. These are only a few aspects of the role that the cutaneous system may play in RIMOF.

From a radiobiological point of view, the skin is an excellent model for studying radiation reactions. Further studies are required on this subject. The skin is an organ that is easily accessible and therefore particularly suited for introduction into a multi-organ concept. Proceeding from the cellular level to complex biological models [55] and to the clinical situation in vivo is a great challenge. Further research into the pathophysiology of RIMOF will help us to understand better the organ interactions mediated by ionising radiation at doses that do not cause RIMOF.


   References
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 Abstract
 Introduction
 Clinical aspects of cutaneous...
 Cutaneous radiation reactions at...
 Cutaneous radiation reactions...
 References
 

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