A unifying system does the vascular endothelium have a role to play

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					DOI: 10.1259/bjr/24511652

A unifying system: does the vascular endothelium have a role
to play in multi-organ failure following radiation exposure?
                                   ˆ ´       ´
Institut de Radioprotection et de Surete Nucleaire, IRSN, B.P. n˚17, F-92262 Fontenay-aux-Roses Cedex, France

      Abstract. 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.

Multiple organ failure: some definitions                                 different cell types, inflammatory mediators and coagula-
                                                                        tion factors that could lead to organ dysfunction. This
   In 1975, the concept of multiple, progressive or                     review addresses the question of how alterations of the
sequential systems failure was formulated as the basis of               endothelial cell functions could play a critical role in
a new clinical syndrome [1]. Several terms were cloned                  mediating organ dysfunction following radiation exposure?
thereafter, such as multiple organ failure (MOF), multiple              However, the concept of MODS in the context of
system organ failure (MSOF) and multiple organ system                   irradiation is rather a new one, as recovery of the
failure (MOSF), to describe an evolving clinical syndrome               haematological system is only recent, and clinicians are
of otherwise unexplained progressive physiological failure              now presented with failure of other organ systems [4, 5].
of several interdependent organ systems. More recently,                 This review therefore also considers recently published
the acronym MODS (multiple organ dysfunction syn-                       literature on the role of the endothelium in the develop-
drome) has been used first to define a clinical syndrome in               ment of organ failure in other pathologies such as sepsis
which the development of progressive and potentially                    [6–8], which has been also observed in victims of a recent
reversible physiological dysfunction in two or more organs              radiological accident [9].
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             Endothelial cell dysfunction and activation
that homeostasis cannot be maintained without interven-
                                                                           The endothelium has long been viewed as an inert
tion [2]. Alternatively, the acronym MODS may refer to
                                                                        cellophane-like membrane lining the circulatory system,
multiple organ dysfunction score, which represents a
                                                                        with its primary essential function being the maintenance
clinical–biological score that is a reliable descriptor of a
                                                                        of vessel wall permeability. This view changed when it was
complex clinical outcome [3]. It should be pointed out that
                                                                        established that vessels were not merely tunnels bored
alteration in organ function could vary from a potentially
                                                                        through tissues but were lined with cells. In fact, the
reversible organ dysfunction (i.e. MODS) to irreversible                endothelium is a monolayer of endothelial cells (ECs)
and fatal organ failure (i.e. MOF). Depending on a direct               lining the lumen of all blood vessels and is therefore a truly
or indirect effect of the insult, two types of MODS can be              pervasive organ. The endothelial surface in an adult
distinguished. Primary MODS is the direct result of a well              human is composed of approximately 1–661013 cells,
defined insult in which organ dysfunction occurs and can                 weighs approximately 1 kg and covers a surface area of
be directly attributable to the insult itself. Secondary                approximately 4000–7000 m2 [10]. During the last two
MODS is the result of tissue damage in organs distant to                decades, it has become evident that the vascular endothe-
the site of the original injury. In the context of irradiation,         lium is an active paracrine, endocrine and autocrine organ
secondary MODS refers to the abscopal effect, that is the               that is indispensable for the regulation of vascular tone
effect that irradiation of a tissue has on remote non-                  and blood flow, and for maintenance of vascular homeo-
irradiated tissue. All these clinical definitions do not                 stasis (Table 1) [11, 12]. In addition to promoting
describe the highly complex integrated response including               vasodilatation, a healthy endothelium has antioxidant,
                                                                        anti-inflammatory, anti-atherogenic, anticoagulant and
Address correspondence to Dr M H Gaugler, Institut de                   fibrinolytic effects, and inhibits leukocyte adhesion and
                       ˆ ´       ´
Radioprotection et de Surete Nucleaire, B.P. n˚17, F-92262 Fontenay-    migration, smooth muscle cell proliferation and migration,
aux-Roses Cedex, France. E-mail:          and platelet adhesion and aggregation. The myriad of

100                                               Radiation-induced multi-organ involvement and failure: a challenge for pathogenetic,
                                                                                  diagnostic and therapeutic approaches and research
Role of the vascular endothelium in multi-organ failure following irradiation

Table 1. Functions regulated by the vascular endothelium             Link between EC dysfunction and/or activation
Function                  Principal substances
                                                                     and MODS
Vascular tone             Vasodilators: NO, PGI2                        Although the role of the endothelium in severe sepsis
                          Vasoconstrictors: ET-1, Ang II, TXA2       and MODS has been particularly emphasised recently [6–
Coagulation               Anticoagulants: TM, TFPI, PGI2             8], little is known about the mechanisms that ultimately
                          Pro-coagulants: TF, PAR-1, TXA2            lead to organ dysfunction and death. However, what has
Fibrinolysis              Antifibrinolytic: PAI-1                     been described is that, irrespective of the initiating insult
                          Pro-fibrinolytic: tPA                       (including infection, multiple trauma and pancreatitis),
Leukocyte adhesion        Inflammatory mediators:                     circulatory failure, increased endothelial permeability,
  (inflammation)             IL-6, IL-8, MCP-1                        leukocyte accumulation into tissue and coagulation
                          Adhesion molecules: P-selectin,            disorders appear to be critical determinants in the
                            E-selectin, ICAM-1, PECAM-1,
                                                                     development of sequential organ failure. In fact, circula-
Platelet adhesion         VWF, fibrinogen                             tory failure characterised by altered vascular relaxation
  (thrombosis)                                                       and blood flow distribution leads to impaired perfusion
Vascular permeability     RAGE                                       and tissue hypoxia; increased permeability provokes tissue
Vascular growth           VEGF, PDGF, FGF, TGF-b                     oedema; leukocyte accumulation into tissue induces tissue
                                                                     injury through the release of proteases and reactive oxygen
NO, nitric oxide; PGI2, prostacyclin; ET-1, endothelin-1; Ang II,    species (ROS); and coagulation disorders (defined as
 angiotensin II; TXA2, thromboxane A2; TM, thrombomo-                disseminated intravascular coagulation) result in wide-
 dulin; TFPI, tissue factor pathway inhibitor; TF, tissue factor;    spread activation of coagulation, fibrin deposition and
 tPA, tissue plasminogen activator; Il, interleukin; VWF, von        thrombotic occlusion and/or bleeding [6–8]. Furthermore,
 Willebrand factor.                                                  the morphology of necropsy specimens both in animal
                                                                     models and in patients is remarkably constant. There is
functions of ECs makes the endothelium indispensable for             endothelial injury, microvascular occlusion, inflammatory
body homeostasis, as is evident in its many finely                    infiltrates, interstitial oedema, leukostasis, thrombosis,
controlled mechanisms. Local vascular control depends                fibrosis and necrosis. Because all of these disorders
on a balanced release of bioactive factors such as                   could be the consequence of initiation and maintenance
vasodilators and vasoconstrictors. EC dysfunction is                 of alterations in the functions of the endothelium,
characterised by a reduction in the bioavailability of               therefore EC dysfunction and/or activation could be
vasodilators, in particular nitric oxide (NO), which is the          involved in the pathogenesis of MODS.
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).             Radiation-induced endothelial dysfunction and/or
This imbalance leads to an impairment of endothelium-                activation and primary MODS
dependent vasodilatation, which represents the functional
characteristic of EC dysfunction. On the other hand, EC
                                                                     Vascular tone and blood flow
dysfunction also comprises a specific state of ‘‘endothelial             Following irradiation, the endothelium undergoes
cell activation’’, which is characterised by pro-oxidant,            changes that impact the net balance of vasoconstrictor
pro-inflammatory, pro-atherogenic, pro-coagulant and                  and vasodilatory properties. Both early and sustained
antifibrinolytic properties of ECs, and a critical participa-         impairment in endothelium-dependent vasodilatation has
tion of ECs in leukocyte adhesion and migration, smooth              been described following 10–45 Gy doses of irradiation
muscle cell proliferation and migration, and platelet                [16–18], inducing chronic vasoconstriction [19]. This
adhesion and aggregation [11, 12]. EC dysfunction and/               alteration has been related to decreased nitric oxide
or activation occurs as a normal adaptive response for               synthase (NOS) activity and expression [18, 19] as well
tissue repair, the nature and duration of which depends              as synthesis of vasodilators such as prostacyclin (PGI2)
not only on the type of stimulus but also on the spatial             [20, 21], and enhanced synthesis of vasoconstrictors such
and temporal dynamics of the systems. For example, when              as ET-1 and thromboxane A2 (TXA2) [19, 21, 22].
pathogens invade a tissue, ECs are activated locally to              Decrease in blood flow following radiation has also been
release inflammatory mediators and to express adhesion                reported [23–26]. Both radiation-induced alterations in
molecules, in order to promote clotting as a means of                endothelium-dependent vasodilatation and blood flow
walling off the infection and the adhesion and transmigra-           could lead to impaired perfusion and tissue hypoxia.
tion of leukocytes into tissue to eradicate pathogens thus
allowing tissue to be repaired. Normally, negative feed-
back mechanisms are activated to dampen the endothelial              Increased permeability
response. However, a hallmark of many pathological                      In the intact vasculature, the endothelium forms a
states, including atherosclerosis [14] and sepsis [8], is the        continuous and semi-permeable barrier that varies in
maintenance of EC dysfunction and/or activation, which               integrity and control for different vascular beds [27]. A
also plays a central role in the pathogenesis of chronic             central feature of the endothelium irradiated at a single
inflammatory disorders [15]. In fact, when there is a                 dose of 15 Gy or 60–80 Gy in fractionated doses is
sustained dysfunction and/or activation of the endothe-              increased permeability or loss of barrier function, resulting
lium, the threshold from an adaptive to a maladaptive                in a shift of circulating elements and tissue oedema [21, 24,
response is crossed, which favours impaired perfusion,               28]. Emergence of interstitial oedema in the lungs caused
tissue hypoxia and subsequent organ dysfunction.                     by damage to the pulmonary ECs has been reported for

E 2005 The British Institute of Radiology                                                                                     101
                                                                                                                  M-H Gaugler

patients irradiated in the Tokai-mura accident [5].              amplifying coagulation. ECs undergoing apoptosis
Redistribution of fluid from the intravascular to the             expresses an increasingly pro-coagulant phenotype [56].
extravascular compartment contributes to hypovolaemia,           Activation of coagulation concomitant with impaired
haemoconcentration and stasis of blood flow [7].                  fibrinolysis is associated with fibrin deposition, tissue
                                                                 ischaemia and tissue necrosis, and with increased risk of
                                                                 death in critically ill patients [8].
Endothelial cell apoptosis                                          In summary, radiation-induced EC dysfunction, activa-
                                                                 tion or injury contributes to circulatory failure, increased
   Radiation (doses ranging from 2 Gy to 50 Gy) has been
                                                                 permeability, leukocyte accumulation into tissue and
shown to induce EC apoptosis in vitro [29, 30] or in vivo
                                                                 coagulation disorders. Because ECs are present in every
[31, 32]. Because of the close apposition of ECs and
                                                                 organ, this EC dysfunction could be a common initial and
parenchymal cells in a tissue such as the epithelium, there
                                                                 perpetuating pathway contributing to organ dysfunction.
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-induced endothelial cell dysfunction and/
radiation pneumonitis [33] and death from gastrointestinal       or activation and secondary MODS
syndrome [34], and suggests that EC apoptosis represents
the primary lesion involved in organ failure following              Different factors could be implicated in the induction of
radiation exposure.                                              EC dysfunction and/or activation in organs distant to the
                                                                 site of the original insult.

Pro-adhesive properties
                                                                 Environmental factors
   The endothelium responds to 5–30 Gy doses of irradia-
tion by expressing adhesion molecules on the EC surface,            Environmental factors, such as hypoxia, changes in
including P-selectin [35], E-selectin [36], ICAM-1 [37],         blood flow, temperature, oxygenation, acid–base/electro-
PECAM-1 [38, 39] and VCAM-1 [40, 41], and by                     lyte abnormalities and hyperglycaemia contribute to EC
producing inflammatory cytokines (interleukin-6 (IL-6))           dysfunction [7].
and chemokines (IL-8, MCP-1) [38, 42]. Collectively, these
alterations result in increased rolling, firm adhesion and
transmigration of leukocytes into underlying tissue.             Activated blood cells
Persistent inflammatory infiltrates following radiation             Activated platelets and leukocytes are known to activate
exposure up to 40 Gy have been reported [26, 41, 43],            ECs [57].
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            Soluble mediators
recruit increased numbers of platelets to the blood vessel
                                                                    Soluble mediators such as inflammatory mediators
wall and promote platelet thrombus [26, 44–46].
                                                                 (cytokines, chemokines), TF, complement and various
Maintenance of the prothrombotic property of ECs
                                                                 components of the coagulation cascade (thrombin, fibrin)
causes occlusion of the vascular lumen [47] and impaired
                                                                 function in a paracrine loop to further activate endothe-
tissue perfusion.
                                                                 lium 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
Abnormal coagulation and fibrinolysis
                                                                 and tumour necrosis factor-a (TNF-a) are described as
   The outer membrane of ECs normally expresses various          being released following irradiation [58, 59] and to activate
membrane-associated components with anticoagulant                ECs. Thrombin and fibrin are capable of interacting with
properties, among which are thrombomodulin (TM) and              PARs on the surface of ECs, leading to activation and
tissue factor pathway inhibitor (TFPI). The effects of           additional inflammation [60, 61]. Because ECs are in
ionising radiation on endothelial functions associated with      permanent contact with the blood circulation, ECs could
blood coagulation have been studied in vitro and in vivo         participate in the induction of EC dysfunction and/or
and include early and sustained decreased TM production          activation in organs distant to the site of the original
following fractionated irradiation up to 67.2 Gy [48, 49],       insult. In fact, local response of ECs to an injury such as
and increased tissue factor (TF) activity following a 20 Gy      irradiation results in release into the systemic circulation of
exposure [50]. The pro-fibrinolytic property of ECs               mediators such as cytokines, chemokines and coagulation
following radiation is blunted because of reduced fibrino-        factors, which can in turn contribute to systemic dysfunc-
lytic activity [44, 51–53] and decreased release of tissue       tion and/or activation of ECs in organs distant to the
plasminogen activator (tPA) [53–55]. When the endothe-           original insult. Two studies have provided evidence of
lium is viewed in the context of its native environment,         brain microvascular dysfunction following experimental
additional properties emerge that contribute to a pro-           intestinal inflammation. Induction of an experimental
coagulant state. In fact, NO and PGI2 not only control           colitis resulted in increased blood–brain barrier perme-
vascular tone but also have tPA-like properties, and             ability and brain endothelial VCAM-1 and ICAM-1
decrease of NO and PGI2 production following radiation           expression [62, 63]. More recently, Van der Meeren et al
up to 50 Gy [20, 21] facilitates aggravation of coagulo-         [64] have shown that abdominal irradiation increased
pathy. Platelets and leukocytes adhere to irradiated ECs         an endothelial adhesion molecule PECAM-1 in the
and these blood cells are capable of initiating or               lung. This activation of lung ECs following abdominal

102                                        Radiation-induced multi-organ involvement and failure: a challenge for pathogenetic,
                                                                           diagnostic and therapeutic approaches and research
Role of the vascular endothelium in multi-organ failure following irradiation

irradiation, i.e. in an organ outside of the field of                 Conclusion
irradiation, is the result of a gut-induced distant organ
injury and could be mediated, as has been recently                      Following radiation exposure, endothelial dysfunction
proposed, through the release of gut-derived factors                 and/or activation play a central role in initiating and
carried in the mesenteric lymph rather than the portal               perpetuating local and systemic responses that could
                                                                     ultimately lead to the development of organ dysfunction
blood [65]. Changes in EC functions in organs distant to
                                                                     and failure. Therefore, the endothelium should be
the site of the original injury help to perpetuate cycles of
                                                                     considered as a therapeutic target, not alone but rather
inflammation, coagulation and cellular interactions that
                                                                     integrated with others entities participating in organ
ultimately lead to impaired perfusion, tissue hypoxia and
                                                                     dysfunction. For doses of irradiation that cause endothe-
organ dysfunction.
                                                                     lial destruction, endothelial progenitor cells may provide
                                                                     an opportunity for therapeutic intervention to restore
                                                                     endothelial integrity [73, 74]. For doses of irradiation that
How is endothelial function assessed?                                cause endothelial dysfunction and/or activation, pharma-
                                                                     cological agents such as statins, which have been described
   Endothelium-dependent vasomotion can be assessed in               to limit endothelial dysfunction and/or activation, should
the coronary and peripheral circulations [11, 66, 67].               be included in combined therapeutic intervention following
Invasive assessment of coronary endothelial function by              radiation exposure [75].
quantitative coronary angiography and intracoronary
Doppler flow measurements, along with graded intracor-
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E 2005 The British Institute of Radiology                                                                                           105

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