British Journal of Radiology (2005) Supplement_27, 62-68
© 2005 British Institute of Radiology
doi: 10.1259/bjr/15393845
British Journal of Radiology Supplement_27 (2005),62-68 © 2005 The British Institute of Radiology
Involvement of the central nervous system in radiation-induced multi-organ dysfunction and/or failure
P Gourmelon, MD1,
C Marquette, PhD1,
D Agay, PhD2,
J Mathieu, PhD2 and
D Clarençon, MD2
1 Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses and 2 Centre de Recherches du Service de Santé des Armées, La Tronche, France
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Abstract
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The presence of multiple organ dysfunction syndrome (MODS) in victims of the recent accidents in Nesvizh and Tokai-mura suggests that radiation-induced systemic inflammatory response syndrome (SIRS) occurs in acute radiation sickness (ARS). Multiple organ failure (MOF) refers to the gradual and sequential failure of organs occurring after a wide spectrum of insults. MOF is believed to be the consequence of the host's response to the insult and is strongly linked to SIRS. It is believed that SIRS is mediated by endogenous regulators that are released during the acute phase reaction. The resulting interplay of cytokines may compromise homeostasis of various organ systems, resulting in MODS. In the classical description of ARS, the role of the central nervous system (CNS) has been underestimated. Today, it is recognised that the CNS is a radiosensitive organ whose degree of dysfunction can be quantified by electrophysiological, biochemical and/or behavioural parameters. Abnormalities in CNS function defined by these parameters may occur at a low dose of whole body radiation. The evolving concept of radiation-induced MODS in ARS provides a framework for evaluating injury to the CNS. Ionising radiation also induces an inflammatory response that may be specific to the CNS. This response is observed after either local irradiation of the CNS or whole body irradiation. The relationship between inflammatory responses in the CNS and the peripheral nervous system is undefined. Whether or not the CNS inflammatory response syndrome is a consequence of SIRS or is an independent syndrome remains an open question. The answer to this question may have implications regarding therapy and medical management of irradiated victims.
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Introduction
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Historical theories of the pathogenic processes of acute radiation sickness (ARS) are based on the concept of radiological damage to a single organ (such as the bone marrow or gut) that is critical for survival. The radiosensitivity of the critical organ and the kinetics of proliferation and differentiation of its stem cells may explain the characteristics of survival relative to radiation dose and time of exposure. This concept is now considered to be reductionist and is currently being challenged. In the revised concept, survivability is determined by progression to multiple organ dysfunction syndrome (MODS), resulting in multiple organ failure (MOF). Thus, the ARS involves complex modifications of several physiological functions rather than individual syndromes that occur according to the radiation dose and the time after irradiation.
In the classical radiopathological concept of ARS, the role of the central nervous system (CNS) has been underestimated. Indeed, it was generally assumed that adult nervous tissue is highly radioresistant and is only affected at doses of 20–30 Gy, above which transient or permanent incapacitation of the CNS occurs, leading to coma and death [1, 2]. This concept of radioresistance of the CNS derives from morphological and structural criteria that have been applied in animal studies addressing radiation-induced damage to the nervous tissue, and from the theoretical concept that the CNS is constituted to a great extent by non-proliferating cells. In reality, the CNS is radiosensitive in terms of functional criteria (i.e. brain electrical activity and neurochemical metabolism) for doses as low as a few Grays [3, 4]. Moreover, the emerging concept of radiation-induced MODS in ARS raises the possibility that the CNS participates in the development of multi-organ dysfunction through the production of biochemical mediators that escape physiological control mechanisms.
MOF is characterised by a gradual and sequential failure of organs occurring after a wide spectrum of insults. MOF is not a direct consequence of the noxious stimuli but rather results from the host's response to the insult. MOF is strongly linked to the process of inflammation and more particularly, to the development of systemic inflammatory response syndrome (SIRS).
SIRS is a clinical syndrome characterised by fever, tachycardia, hyperventilation and/or hypocarbia. It is triggered by infection, pancreatitis, trauma and other clinical insults. When severe, hypotension and shock develop, which are unresponsive to fluid resuscitation. SIRS is associated with organ system dysfunction, including abnormalities of the respiratory, cardiovascular, renal, hepatic, haematological and central nervous systems. Evidence has accumulated suggesting that SIRS is the clinical expression of the action of intrinsic endogenous mediators of the acute phase reaction [5]. In SIRS, the function of various organ systems is compromised, resulting in MODS, a disorder that disrupts tissue homeostasis. Accordingly, systemic inflammation and organ failure are on the same continuum.
An open question is whether radiation induces SIRS and if so, whether SIRS is a component of ARS. It is possible that the magnitude of the effect of the collapse of the bone marrow or the gut may have masked the clinical sequelae associated with SIRS. According to the traditional concept, SIRS could not be a major phenomenon, since radiation-induced mitotic death alone could explain the collapse of an organ that is essential for life. However, description of patients in the Nesvizh and Tokai-mura accidents, who showed a mixed pathology involving organs (including the liver and kidney) other than the classical target organs [6, 7], suggests that radiation-induced SIRS is a component of ARS.
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Radiation-induced systemic inflammatory response syndrome in the primate model
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Experimental data in a primate model support the existence of radiation-induced SIRS. Figure 1
illustrates the temporal kinetics of the pro-inflammatory cytokine interleukin-8 (IL-8) in baboons after whole body irradiation ranging from 2 Gy to 8 Gy in a mixed neutron-gamma field. Pro-inflammatory cytokines such as IL-8 peaked in the blood during the initial 24 h of the prodromal phase of ARS, and returned to a normal level during the clinical remission phase. For animals irradiated to sublethal doses, the level of pro-inflammatory cytokines increased again during several days of the manifest illness. The time profile of this second elevation in cytokines depends on the outcome of ARS. In the animal with a lethal dose (8 Gy), the level of cytokine increased dramatically at several days before death, whilst in the surviving animal the level of cytokine slowly returned to normal [8]. The temporal profile of systemic pro-inflammatory cytokines is characterised by an acute phase response and a late phase response, which is a prognostic indicator of the ARS. The systemic time profile of the pro-inflammatory IL-6 follows the same general pattern as that for IL-8, with both early and late phases (data not shown). This overwhelming production of systemic cytokines is in the same vein as the overproduction of peripheral potential sources of cytokines observed in response to radiation at the level of lung, gut, epithelial and endothelial cells, and which could contribute to the inflammatory response [9–12].
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Figure 1. Kinetics of interleukin-8 (IL-8) production in serum during early and late phases following 4 Gy, 6 Gy and 8 Gy mixed neutron– whole body irradiation in a non-human primate model.
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The systemic production of cytokines in the baboon model is associated with secretion of acute phase proteins (plasma glycoproteins) by the liver, leading to the generation of inflammatory reactants, including C-reactive protein (CRP), orosomucoid and fibrinogen. The time profile for appearance of CRP is characterised by a two-phase pattern: an initial phase occurring after the initial syndrome of the ARS, lasting several days, with a peak independent of the magnitude of the dose; and a second phase characterised by a dose–effect relationship [13]. As illustrated in Figure 2, the blood values of CRP in the baboons surviving 6 Gy reached a peak at day 12, and decreased progressively with recovery. In contrast, the level of CRP sharply increased several days before death in animals receiving a lethal dose of 8 Gy.
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Figure 2. Kinetics of C-reactive protein release in serum during early and late phases following 2 Gy, 4 Gy, 6 Gy and 8 Gy mixed neutron– whole body irradiation in a non-human primate model.
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These data in the baboon model support the hypothesis that the critical determinant for mortality is the presence of a late overwhelming inflammatory response. The extent of this late response varies according to the magnitude of the dose of radiation and is dependent on the prognosis of ARS. Figure 3 illustrates this concept of radiation-induced SIRS that shares common responses with other initial insults, including infection, burn and trauma.
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Figure 3. The classical concept of the systemic inflammatory response syndrome (SIRS) as a common response to many stressors, including irradiation. Modified from P-O Nyström [5].
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The CNS inflammatory response syndrome
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The critical question that remains unanswered is whether the CNS participates in this severe inflammatory response and whether this organ is a major contributor to this response. A radiation-induced inflammatory response syndrome at the level of the brain could explain the neurovascular clinical manifestations observed during the prodromal phase of ARS. The early physiological and behavioural effects that occur in the first hours and days of the acute neurovascular response, such as fatigue, weakness, disorientation, and changes in mental status or level of consciousness, cannot be explained by cellular injuries or vascular disruption, which occur only weeks or months after radiation exposure. Moreover, headache, which is the most frequent symptom related by patients after fractionated radiotherapy of the brain and which is mainly treated with corticoids, is more likely related to an inflammatory response of the brain with cerebral oedema.
On the other hand, recent experimental data suggest that radiation could activate reactive processes that generate inflammatory reactions in the CNS. The initial response of the brain to irradiation involves an early acute overexpression of mRNA coding for IL-1
, IL-1
and tumour necrosis factor- (TNF-) 4–8 h following mid-brain X-ray irradiation in mice with a radiation dose-dependent response between 7 Gy and 25 Gy [14]. Transient increases in pro-inflammatory cytokine levels (IL-1, IL-1) following 5 Gy whole body irradiation was also observed in mice at the cortex level 10 h after irradiation (see Figure 4) [15]. Various non-specific symptoms (i.e. fever, asthenia, anorexia and somnolence) observed during infection are related to the production of pro-inflammatory cytokines in the brain [16]. These same symptoms are observed during the acute clinical prodromal phase of ARS and may represent clinical manifestations of local radiation-induced cytokine production in the brain. These data support the hypotheses that: (i) CNS tissue is highly responsive to ionising radiation; (ii) the induction of cytokines is prominent in radiation-induced cellular responses; and (iii) radiation induces local neuroimmune and inflammatory reactions. This pro-inflammatory cytokine response occurs not only during the prodromal phase of ARS but also for several months thereafter, as illustrated by the induction of TNF- gene expression, which persists for 2–3 months following mouse brain irradiation (25 Gy) and is followed by persistent gene overexpression for 6 months [17].
Radiation-induced local neuroimmune and inflammatory reactions of the CNS are dynamic. Chronic overwhelming production of pro-inflammatory cytokines in the brain may have deleterious effects by inducing molecular cascades that disrupt the biochemical intercellular network required for maintenance of homeostasis in the CNS microenvironment. Accordingly, radiation-induced SIRS may occur not only at the peripheral level but also with the CNS. In the latter case, SIRS may be triggered by direct irradiation of the head using 12–36 Gy or by a whole body irradiation with <10 Gy.
Is the CNS inflammatory response syndrome the consequence of SIRS or is it an independent syndrome occurring in parallel with the development of SIRS? Several hypotheses can be developed to explain the induction of pro-inflammatory cytokines in the brain by radiation. Owing to the presence of the blood–brain barrier, the brain has been considered to be a sequestered organ. However, today it is viewed as an immunologically active organ that communicates with the immune and endocrine systems [18].
It is now agreed that functional bilateral pathways exist between the innate immune system and the neuroendocrine system of the CNS [19]. This system allows the brain to co-ordinate, according the severity of the insult, the appropriate endocrine and metabolite changes for control of homeostasis. Several pathways and sites of entry permit the immune system to communicate with the brain [20]. Secretion of pro-inflammatory cytokines into the bloodstream during the acute phase response is the first step in activation of neuroendocrine function and neurophysiological response. Peripheral pro-inflammatory cytokines can enter into the brain or promote signalling at the blood–brain interface. Thus, it appears that brain structures devoid of blood–brain barrier, such as the area postrema, the median eminence, the organum vasculosum of the lamina terminalis and the subfornical organ, are critical targets for systemic cytokines [21].
In addition, neuroimmune communication may occur via activation of peripheral afferent nerves by cytokine release, which in turn stimulates the production of cytokines by cells of the CNS. The vagus nerve is widely known to be involved in mediating peripheral inflammatory signals of the CNS. Section of the vagus nerve abrogates IL-1-induced expression of mRNA for IL-1 [22, 23] and C-Fos in the CNS [24], and subdiaphragmatic vagotomy diminishes fever induced by cytokine production [25]. These different pathways of communication between the brain and blood raise the possibility for preferential routes for induction of the radiation-induced inflammatory response in the CNS. Studies using partial body exposures have been reported that suggest that some brain structures react rapidly to peripheral irradiation [26]. Pro-inflammatory cytokines are produced primarily at 6 h post irradiation of the head-protected rat at the level of the hypothalamus (TNF-, IL-6 and IL-1), the thalamus (TNF- and IL-1) and the hippocampus (IL-1) [26].
The increase of IL-1 in the hippocampus is consistent with the well known radiosensitivity of this brain structure. Spike and wave discharges are observed in rabbit electroencephalograph (EEG) recordings at the level of the hippocampus at approximately 4 Gy, and are associated with abnormal spontaneous firing of pyramidal hippocampal neurons [27]. In hippocampal brain slices, persistent changes in neuronal functions (such as a decrease of synaptic efficacy) have been observed [28].
Apoptotic neurons have been detected several hours after irradiation in the granular cell layer of the dentate gyrus and to a lesser extent, in the pyramidal cell layer of the hippocampus [29]. Ionising radiation can trigger the p53 tumour suppressor to induce apoptosis [30]. This transcription factor acts through two major apoptotic pathways: the extrinsic death receptor apoptotic pathway triggering activation of the caspase cascade; and the intrinsic mitochondrial pathway promoting the formation of the apoptosome (caspase 9 activation). Activation of the particular death receptor CD95, which belongs to the TNF receptor family [31], has been shown in radiation-induced apoptosis of brain tumour cells [32]. However, the involvement of this death receptor or other members of the TNF receptor family such as TRAIL-R in the ionising radiation-induced apoptosis in normal brain cells, as described in the dendate gyrus of the adult rat hippocampus, has not yet been determined.
The increase in hippocampal IL-1 6 h after peripheral irradiation may occur in association with functional disturbances, since IL-1 is known to be involved in apoptosis of neuronal cells. Long-term potentiation (LTP) alterations have been also observed 3 weeks after irradiation of the brain [33]. Neuronal apoptosis decreases LTP of the granule cells of the dentate gyrus of the hippocampus [34] and the impairment of LTP causes cognitive deficiencies [35]. Moreover, IL-1 is known to inhibit LTP in the rat dentate gyrus and the pyramidal cells of hippocampus [36, 37]. Finally, intracerebroventricular injection of IL-1 affects the consolidation of hippocampal memory [38]. Taken together, these observations suggest that the functional changes observed after whole body irradiation at the level of the hippocampus could be dependent on the local radiation-induced pro-inflammatory IL-1 response that is caused, in part, by peripheral inputs of the body.
Peripheral pro-inflammatory cytokines are capable of effecting central neurophysiological changes and behavioural responses by direct entry or indirectly via vagal nerve stimulation. IL-1 has been shown to stimulate vagal sensory nerve activity [39], and IL-1 receptors have been detected on vagal afferent neuronal cell bodies [40]. Moreover, peripheral administration of IL-1 induced hippocampal IL-1 production that is blocked by vagotomy [23]. To understand the mechanisms that underlie the radiation-induced inflammation in CNS tissues it is necessary to investigate the role of the vagus nerve in brain cytokine induction in the partial body irradiation model with the head shielded. As illustrated in Figure 5, vagotomy performed prior to irradiation prevents radiation-induced IL-1 production in the hippocampus and hypothalamus. These results were confirmed for induction of TNF- and IL-6 in both brain structures [26]. Thus, comparing vagotomised and non-vagotomised rats, it has been shown that cytokine release in the CNS in the hypothalamus and hippocampus is induced via the vagal afferent pathway. It can be hypothesised that vagal stimulation by a peripheral signal can be promoted by a local inflammatory response of the perivagal immune cells such as macrophages and dendritic cells located around the vagal nerve. Vagal stimulation can in turn activate specific and distinct forebrain structures. Thus, the dorsal vagal complex, which is the location of afferent terminations of the vagus nerve, is known to regulate hypothalamic functions by direct projections to hypothalamic nuclei [41].
Taken together, the bulk of these data suggests that CNS inflammatory response syndrome may be induced either by the direct action of ionising radiation at the level of the brain or by generation of SIRS, as illustrated in Figure 6.
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Figure 6. New approach to the radiation-induced central nervous system (CNS) inflammatory response syndrome and its interactions with the systemic inflammatory response syndrome (SIRS).
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In conclusion, it appears that cytokines play a central role in mediating a CNS response following irradiation. This CNS response syndrome is characterised by local production of pro-inflammatory cytokines (TNF-, IL-6 and IL-1) in different brain structures. The result is stimulation of inflammatory cascades, interaction with other inflammatory mediators and upregulation of the inflammatory process that leads to neurotoxicity. Whether such a radiation-induced CNS inflammatory response syndrome can compromise the functions of various organ systems resulting in MODS, which could in turn progress to develop MOF, is an open question that needs to be explored in future experimental models for the understanding of the pathogenesis of ARS.
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Abstract
Introduction
