British Journal of Radiology (2005) Supplement_27, 100-105
© 2005 British Institute of Radiology
doi: 10.1259/bjr/24511652
British Journal of Radiology Supplement_27 (2005),100-105 © 2005 The British Institute of Radiology
A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure?
M-H Gaugler, PhD
Institut de Radioprotection et de Sûreté Nucléaire, IRSN, B.P. n°17, F-92262 Fontenay-aux-Roses Cedex, France
Correspondence: Dr M H Gaugler, Institut de Radioprotection et de Sûreté Nucléaire, B.P. n°17, F-92262 Fontenay-aux-Roses Cedex, France. E-mail: marie-helene.gaugler@irsn.fr
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Abstract
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Over the past two decades, investigators have increasingly recognised the importance of the endothelium as a central regulator of vascular and body homeostasis. The vascular endothelium is versatile and multifunctional. In addition to its role as a selective permeability barrier, it has many synthetic and metabolic properties, including modulation of vascular tone and blood flow, regulation of immune and inflammatory responses, and regulation of coagulation, fibrinolysis and thrombosis. Perturbations of endothelial structure and function result in pathological states. Following radiation exposure, changes of the vasculature and more specifically of the endothelial cells were a prominent histological finding dating back more than a century. Since then, there have been numerous studies detailing the morphological and functional changes seen in all types of vessels following irradiation of critical organ systems. This review addresses the question of how alterations in endothelial cell functions could play a critical role in mediating organ dysfunction following radiation exposure.
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Multiple organ failure: some definitions
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In 1975, the concept of multiple, progressive or sequential systems failure was formulated as the basis of a new clinical syndrome [1]. Several terms were cloned thereafter, such as multiple organ failure (MOF), multiple system organ failure (MSOF) and multiple organ system failure (MOSF), to describe an evolving clinical syndrome of otherwise unexplained progressive physiological failure of several interdependent organ systems. More recently, the acronym MODS (multiple organ dysfunction syndrome) has been used first to define a clinical syndrome in which the development of progressive and potentially reversible physiological dysfunction in two or more organs or organ systems induced by a variety of acute insults is characteristic. MODS is also defined as the presence of altered organ function in a patient who is acutely ill such that homeostasis cannot be maintained without intervention [2]. Alternatively, the acronym MODS may refer to multiple organ dysfunction score, which represents a clinical–biological score that is a reliable descriptor of a complex clinical outcome [3]. It should be pointed out that alteration in organ function could vary from a potentially reversible organ dysfunction (i.e. MODS) to irreversible and fatal organ failure (i.e. MOF). Depending on a direct or indirect effect of the insult, two types of MODS can be distinguished. Primary MODS is the direct result of a well defined insult in which organ dysfunction occurs and can be directly attributable to the insult itself. Secondary MODS is the result of tissue damage in organs distant to the site of the original injury. In the context of irradiation, secondary MODS refers to the abscopal effect, that is the effect that irradiation of a tissue has on remote non-irradiated tissue. All these clinical definitions do not describe the highly complex integrated response including different cell types, inflammatory mediators and coagulation factors that could lead to organ dysfunction. This review addresses the question of how alterations of the endothelial cell functions could play a critical role in mediating organ dysfunction following radiation exposure? However, the concept of MODS in the context of irradiation is rather a new one, as recovery of the haematological system is only recent, and clinicians are now presented with failure of other organ systems [4, 5]. This review therefore also considers recently published literature on the role of the endothelium in the development of organ failure in other pathologies such as sepsis [6–8], which has been also observed in victims of a recent radiological accident [9].
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Endothelial cell dysfunction and activation
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The endothelium has long been viewed as an inert cellophane-like membrane lining the circulatory system, with its primary essential function being the maintenance of vessel wall permeability. This view changed when it was established that vessels were not merely tunnels bored through tissues but were lined with cells. In fact, the endothelium is a monolayer of endothelial cells (ECs) lining the lumen of all blood vessels and is therefore a truly pervasive organ. The endothelial surface in an adult human is composed of approximately 1–6 x 1013 cells, weighs approximately 1 kg and covers a surface area of approximately 4000–7000 m2 [10]. During the last two decades, it has become evident that the vascular endothelium is an active paracrine, endocrine and autocrine organ that is indispensable for the regulation of vascular tone and blood flow, and for maintenance of vascular homeostasis (Table 1
) [11, 12]. In addition to promoting vasodilatation, a healthy endothelium has antioxidant, anti-inflammatory, anti-atherogenic, anticoagulant and fibrinolytic effects, and inhibits leukocyte adhesion and migration, smooth muscle cell proliferation and migration, and platelet adhesion and aggregation. The myriad of functions of ECs makes the endothelium indispensable for body homeostasis, as is evident in its many finely controlled mechanisms. Local vascular control depends on a balanced release of bioactive factors such as vasodilators and vasoconstrictors. EC dysfunction is characterised by a reduction in the bioavailability of vasodilators, in particular nitric oxide (NO), which is the best characterised and probably the most important [13], and an increase in endothelium-derived contracting factors such as endothelin-1 (ET-1) and angiotensin II (Ang II). This imbalance leads to an impairment of endothelium-dependent vasodilatation, which represents the functional characteristic of EC dysfunction. On the other hand, EC dysfunction also comprises a specific state of "endothelial cell activation", which is characterised by pro-oxidant, pro-inflammatory, pro-atherogenic, pro-coagulant and antifibrinolytic properties of ECs, and a critical participation of ECs in leukocyte adhesion and migration, smooth muscle cell proliferation and migration, and platelet adhesion and aggregation [11, 12]. EC dysfunction and/or activation occurs as a normal adaptive response for tissue repair, the nature and duration of which depends not only on the type of stimulus but also on the spatial and temporal dynamics of the systems. For example, when pathogens invade a tissue, ECs are activated locally to release inflammatory mediators and to express adhesion molecules, in order to promote clotting as a means of walling off the infection and the adhesion and transmigration of leukocytes into tissue to eradicate pathogens thus allowing tissue to be repaired. Normally, negative feedback mechanisms are activated to dampen the endothelial response. However, a hallmark of many pathological states, including atherosclerosis [14] and sepsis [8], is the maintenance of EC dysfunction and/or activation, which also plays a central role in the pathogenesis of chronic inflammatory disorders [15]. In fact, when there is a sustained dysfunction and/or activation of the endothelium, the threshold from an adaptive to a maladaptive response is crossed, which favours impaired perfusion, tissue hypoxia and subsequent organ dysfunction.
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Link between EC dysfunction and/or activation and MODS
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Although the role of the endothelium in severe sepsis and MODS has been particularly emphasised recently [6–8], little is known about the mechanisms that ultimately lead to organ dysfunction and death. However, what has been described is that, irrespective of the initiating insult (including infection, multiple trauma and pancreatitis), circulatory failure, increased endothelial permeability, leukocyte accumulation into tissue and coagulation disorders appear to be critical determinants in the development of sequential organ failure. In fact, circulatory failure characterised by altered vascular relaxation and blood flow distribution leads to impaired perfusion and tissue hypoxia; increased permeability provokes tissue oedema; leukocyte accumulation into tissue induces tissue injury through the release of proteases and reactive oxygen species (ROS); and coagulation disorders (defined as disseminated intravascular coagulation) result in widespread activation of coagulation, fibrin deposition and thrombotic occlusion and/or bleeding [6–8]. Furthermore, the morphology of necropsy specimens both in animal models and in patients is remarkably constant. There is endothelial injury, microvascular occlusion, inflammatory infiltrates, interstitial oedema, leukostasis, thrombosis, fibrosis and necrosis. Because all of these disorders could be the consequence of initiation and maintenance of alterations in the functions of the endothelium, therefore EC dysfunction and/or activation could be involved in the pathogenesis of MODS.
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Radiation-induced endothelial dysfunction and/or activation and primary MODS
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Vascular tone and blood flow
Following irradiation, the endothelium undergoes changes that impact the net balance of vasoconstrictor and vasodilatory properties. Both early and sustained impairment in endothelium-dependent vasodilatation has been described following 10–45 Gy doses of irradiation [16–18], inducing chronic vasoconstriction [19]. This alteration has been related to decreased nitric oxide synthase (NOS) activity and expression [18, 19] as well as synthesis of vasodilators such as prostacyclin (PGI2) [20, 21], and enhanced synthesis of vasoconstrictors such as ET-1 and thromboxane A2 (TXA2) [19, 21, 22]. Decrease in blood flow following radiation has also been reported [23–26]. Both radiation-induced alterations in endothelium-dependent vasodilatation and blood flow could lead to impaired perfusion and tissue hypoxia.
Increased permeability
In the intact vasculature, the endothelium forms a continuous and semi-permeable barrier that varies in integrity and control for different vascular beds [27]. A central feature of the endothelium irradiated at a single dose of 15 Gy or 60–80 Gy in fractionated doses is increased permeability or loss of barrier function, resulting in a shift of circulating elements and tissue oedema [21, 24, 28]. Emergence of interstitial oedema in the lungs caused by damage to the pulmonary ECs has been reported for patients irradiated in the Tokai-mura accident [5]. Redistribution of fluid from the intravascular to the extravascular compartment contributes to hypovolaemia, haemoconcentration and stasis of blood flow [7].
Endothelial cell apoptosis
Radiation (doses ranging from 2 Gy to 50 Gy) has been shown to induce EC apoptosis in vitro [29, 30] or in vivo [31, 32]. Because of the close apposition of ECs and parenchymal cells in a tissue such as the epithelium, there is strong communications between these two types of cells. It has been reported that inhibition of radiation-induced apoptosis of ECs prevents the development of lethal radiation pneumonitis [33] and death from gastrointestinal syndrome [34], and suggests that EC apoptosis represents the primary lesion involved in organ failure following radiation exposure.
Pro-adhesive properties
The endothelium responds to 5–30 Gy doses of irradiation by expressing adhesion molecules on the EC surface, including P-selectin [35], E-selectin [36], ICAM-1 [37], PECAM-1 [38, 39] and VCAM-1 [40, 41], and by producing inflammatory cytokines (interleukin-6 (IL-6)) and chemokines (IL-8, MCP-1) [38, 42]. Collectively, these alterations result in increased rolling, firm adhesion and transmigration of leukocytes into underlying tissue. Persistent inflammatory infiltrates following radiation exposure up to 40 Gy have been reported [26, 41, 43], which could contribute to fibrosis and induce tissue injury through the release of proteases and ROS. ECs irradiated at 20 Gy release von Willebrand factor (VWF) [43] and recruit increased numbers of platelets to the blood vessel wall and promote platelet thrombus [26, 44–46]. Maintenance of the prothrombotic property of ECs causes occlusion of the vascular lumen [47] and impaired tissue perfusion.
Abnormal coagulation and fibrinolysis
The outer membrane of ECs normally expresses various membrane-associated components with anticoagulant properties, among which are thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI). The effects of ionising radiation on endothelial functions associated with blood coagulation have been studied in vitro and in vivo and include early and sustained decreased TM production following fractionated irradiation up to 67.2 Gy [48, 49], and increased tissue factor (TF) activity following a 20 Gy exposure [50]. The pro-fibrinolytic property of ECs following radiation is blunted because of reduced fibrinolytic activity [44, 51–53] and decreased release of tissue plasminogen activator (tPA) [53–55]. When the endothelium is viewed in the context of its native environment, additional properties emerge that contribute to a pro-coagulant state. In fact, NO and PGI2 not only control vascular tone but also have tPA-like properties, and decrease of NO and PGI2 production following radiation up to 50 Gy [20, 21] facilitates aggravation of coagulopathy. Platelets and leukocytes adhere to irradiated ECs and these blood cells are capable of initiating or amplifying coagulation. ECs undergoing apoptosis expresses an increasingly pro-coagulant phenotype [56]. Activation of coagulation concomitant with impaired fibrinolysis is associated with fibrin deposition, tissue ischaemia and tissue necrosis, and with increased risk of death in critically ill patients [8].
In summary, radiation-induced EC dysfunction, activation or injury contributes to circulatory failure, increased permeability, leukocyte accumulation into tissue and coagulation disorders. Because ECs are present in every organ, this EC dysfunction could be a common initial and perpetuating pathway contributing to organ dysfunction.
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Radiation-induced endothelial cell dysfunction and/or activation and secondary MODS
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Different factors could be implicated in the induction of EC dysfunction and/or activation in organs distant to the site of the original insult.
Environmental factors
Environmental factors, such as hypoxia, changes in blood flow, temperature, oxygenation, acid–base/electrolyte abnormalities and hyperglycaemia contribute to EC dysfunction [7].
Activated blood cells
Activated platelets and leukocytes are known to activate ECs [57].
Soluble mediators
Soluble mediators such as inflammatory mediators (cytokines, chemokines), TF, complement and various components of the coagulation cascade (thrombin, fibrin) function in a paracrine loop to further activate endothelium and to trigger protease-activated receptors (PARs) on the surface of the endothelium in organs distant to the site of original insult. Inflammatory mediators such as IL-6 and tumour necrosis factor-
(TNF-) are described as being released following irradiation [58, 59] and to activate ECs. Thrombin and fibrin are capable of interacting with PARs on the surface of ECs, leading to activation and additional inflammation [60, 61]. Because ECs are in permanent contact with the blood circulation, ECs could participate in the induction of EC dysfunction and/or activation in organs distant to the site of the original insult. In fact, local response of ECs to an injury such as irradiation results in release into the systemic circulation of mediators such as cytokines, chemokines and coagulation factors, which can in turn contribute to systemic dysfunction and/or activation of ECs in organs distant to the original insult. Two studies have provided evidence of brain microvascular dysfunction following experimental intestinal inflammation. Induction of an experimental colitis resulted in increased blood–brain barrier permeability and brain endothelial VCAM-1 and ICAM-1 expression [62, 63]. More recently, Van der Meeren et al [64] have shown that abdominal irradiation increased an endothelial adhesion molecule PECAM-1 in the lung. This activation of lung ECs following abdominal irradiation, i.e. in an organ outside of the field of irradiation, is the result of a gut-induced distant organ injury and could be mediated, as has been recently proposed, through the release of gut-derived factors carried in the mesenteric lymph rather than the portal blood [65]. Changes in EC functions in organs distant to the site of the original injury help to perpetuate cycles of inflammation, coagulation and cellular interactions that ultimately lead to impaired perfusion, tissue hypoxia and organ dysfunction.
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How is endothelial function assessed?
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Endothelium-dependent vasomotion can be assessed in the coronary and peripheral circulations [11, 66, 67]. Invasive assessment of coronary endothelial function by quantitative coronary angiography and intracoronary Doppler flow measurements, along with graded intracoronary infusions of endothelium-dependent vasodilators such as acetylcholine, were considered the gold standard for endothelial function testing. However, during the last decade, other less invasive or non-invasive techniques for the assessment of endothelial-dependent vasodilatation in the coronary circulation, including Doppler echocardiography, positron emission tomography (PET) and phase-contrast magnetic resonance imaging (MRI), have been developed. Regarding the peripheral circulation, high resolution external vascular ultrasound is a widely used non-invasive technique to measure flow-mediated endothelium-dependent dilatation, especially when examining brachial arteries. Importantly, endothelial dysfunction assessed by this technique correlates with measures of coronary endothelial dysfunction [66], and peripheral resistance vessel function can be assessed by strain gauge venous impedance plethysmography. What is missing from these assessments is an evaluation of other aspects of endothelial function including antithrombotic, anti-inflammatory, anticoagulant and fibrinolytic functions [11]. A number of circulating molecules such as soluble cellular adhesion molecules and C-reactive protein (CRP) have been examined over the past few years as surrogate markers of endothelial dysfunction and vascular inflammation [68]. With the exception of soluble E-selectin, which is specific to ECs, other soluble adhesion molecules can also be produced by leukocytes or platelets and therefore, cannot be used to reflect endothelial dysfunction/activation. Interestingly, elevated serum levels of soluble E-selectin have been observed in non-human primates following irradiation (pers. comm., D Agay). On the other hand, several large-scale studies have shown that plasma levels of CRP are a strong but independent predictor of endothelial dysfunction [69]. Finally, circulating ECs have been described in several pathological conditions that have in common the presence of vascular injury [70–72], but no data are available in irradiated patients. Thus, there is work to do in developing improved non-invasive imaging that can evaluate endothelial function in arteries throughout the body and in identifying biomarkers with sensitivity and specificity for detection of early and progressive endothelial dysfunction and/or activation, especially following radiation exposure.
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Conclusion
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Following radiation exposure, endothelial dysfunction and/or activation play a central role in initiating and perpetuating local and systemic responses that could ultimately lead to the development of organ dysfunction and failure. Therefore, the endothelium should be considered as a therapeutic target, not alone but rather integrated with others entities participating in organ dysfunction. For doses of irradiation that cause endothelial destruction, endothelial progenitor cells may provide an opportunity for therapeutic intervention to restore endothelial integrity [73, 74]. For doses of irradiation that cause endothelial dysfunction and/or activation, pharmacological agents such as statins, which have been described to limit endothelial dysfunction and/or activation, should be included in combined therapeutic intervention following radiation exposure [75].
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Abstract
Multiple organ failure: some...