Hindawi Publishing Corporation
BioMed Research International
Volume 2013, Article ID 123241, 9 pages
Inflammation and Immunity in Radiation Damage to
the Gut Mucosa
Agnès François, Fabien Milliat, Olivier Guipaud, and Marc Benderitter
Laboratory of Radiopathology and Experimental Therapeutics, Institute for Radiological Protection and Nuclear Safety,
31 Avenue de la Division Leclerc, 92262 Fontenay-aux-Roses, France
Correspondence should be addressed to Agn` es Franc ¸ois; email@example.com
Received 30 October 2012; Accepted 18 February 2013
Academic Editor: Silvia Gregori
Copyright © 2013 Agn` es Franc ¸ois et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Erythema was observed on the skin of the first patients treated with radiation therapy. It is in particular to reduce this erythema,
one feature of tissue inflammation, that prescribed dose to the tumor site started to be fractionated. It is now well known that
radiation exposure of normal tissues generates a sustained and apparently uncontrolled inflammatory process. Radiation-induced
The thing with the gut and especially the gut mucosa is that it is at the frontier between the external milieu and the organism, is
in contact with a plethora of commensal and foreign antigens, possesses a dense-associated lymphoid tissue, and is particularly
radiation sensitive because of a high mucosal turnover rate. All these characteristics make the gut mucosa a strong responsive
what remains to be done concerning the immunoinflammatory response following localized radiation exposure.
The objective of radiation therapy is to deliver a dose of
ionizing radiations sufficient to ensure tumor control and
to avoid cancer recurrence. The treatment of malignant
with radiation exposure of surrounding healthy tissues and
the development of acute injury followed by late structural
and/or functional damage, directly or indirectly linked to
the initial trauma. Increased tumor control efficiency and life
expectancy augment the risk to develop radiation sequels in
patients in whom cure has been achieved.
2. Pelvic Radiation Therapy and
‘‘Pelvic Radiation Disease’’
Intestinal tissue is particularly radiosensitive and remains
the limiting factor in the application of radiotherapeutic
schedules for the treatment of tumors located in the pelvis
area. Treatment efficacy relies on a compromise between the
quality of tumor control achieved by radiation therapy and
the damages generated on intestinal healthy tissues; this is
referred to as the benefit/risk ratio . The definition of the
irradiation field is governed by several factors that illustrate
the necessity to include a proportion of normal tissues:
possible tumor extensions undetected by medical imag-
ing techniques, uncertainty concerning patient positioning
reproducibility between each fraction, and the mobility of
tumor and healthy organs during and between each fraction.
Fractionated irradiation reduces the probability of high-dose
exposure for mobile parts of the digestive tract, such as the
small intestine. Conversely, the risk is increased for fixed
segments such as the terminal ileum, colon, or rectum which
are often concerned in irradiation protocols for cervical,
endometrial, rectal, and prostatic cancers treatments. One
strategy to limit normal tissue radiation exposure was to
improve radiation therapy techniques and tumor imaging.
Thus, precise tumor delineation and the use of three dimen-
Modulated Radiation Therapy (IM-RT) reduce normaltissue
volume located in the irradiation field and consequently
treatment side effects.
Radiation gastrointestinal toxicity concerns the majority
of patients treated for pelvic cancers. Acute symptoms are
2 BioMed Research International
declared during or shortly after the end of the radiation
therapy and are characterized by abdominal pain, diarrhoea
and incontinency, less frequently constipation, bleeding, and
mucus discharge. Patient’s clinical status sometimes evolves
through an aggravation of the acute symptoms, with diar-
rhoea alternately with constipation, severe abdominal pain,
and sometimes nausea and vomiting. Clinical expression
of gastrointestinal radiation toxicity often resembles other
pathologies such as Crohn’s disease, ulcerative colitis, or
celiac disease, complicating the diagnosis especially when
there has been a long period of time between radiation
therapy and clinical symptoms expression. To improve the
diagnosis, consideration, and management of the gastroin-
testinal consequences of radiation therapy of pelvic cancers,
and life-strengthening gastrointestinal dysfunction, the term
of “pelvic radiation disease” has been suggested recently by
Andreyev et al. [2, 3].
3. Radiation-Induced Breakdown
of the Fragile Balance Governing
The intestine is a hierarchised self-renewing tissue, the entire
mucosa being replaced every 3–5 days. Cell production is
assumed by stem cells residing at the crypt bottom. The
number of stem cells is estimated between 4 to 6 cells per
crypt . Daughter cells exit the stem cell compartment,
reaching the transit amplifying compartment in which they
achieve several divisions and are also named as committed
precursors or progenitors cells. New produced cells then
lineages of the intestinal mucosa, that is, epithelial bordering
cells, goblet cells, and enteroendocrine cells. The fourth cell
lineage, the Paneth cells, also derives from stem cells but
migrates toward the bottom of the crypts.
properties to kill cells by energy deposition in tissues, water
radiolysis, and production of free radicals damaging DNA,
proteins and lipids. Radiation-induced molecular damage on
DNA can induce cell phenotypic modifications and/or death
by apoptosis, necrosis, or mitotic catastrophe. Indirect bio-
logical effects consist in cell water radiolysis and generation
of a burst of free radicals responsible for multiple damages to
The target cell concept [5, 6] states that tissue response
to radiation exposure is governed by cell death in a target
radiosensitive compartment, often the stem cell compart-
ment, and that tissue regeneration depends on the surviving
and proliferation of stem or progenitor cells. Thus in the
case of intestinal mucosa, the severity of radiation damage
and its regeneration capacity have long been paralleled to the
level of cell death in the stem cell compartment. R-spondin-
1, a potent intestinal stem cell growth factor and ligand of
[7, 8] and GLP-2, an intestinal growth factor, reduces both
acute and late small intestinal damages following localized
high-dose radiation exposure in the rat . However, the
increasing knowledge in radiation biology showed that the
target cell concept does not reflect what is really happening
in the vicinity of irradiated organs. All cell types are sensitive
to ionizing radiations, and tissue scaring process initiates
immediately after radiation exposure, involving all cell types
and compartments of the tissue. Reduction of endothelial
cells radiation-induced apottosis by basic fibroblast growth
reduced small intestinal tissue damage following localized
radiation exposure in PAI-1 −/− mice is associated with less
events and late tissue fibrosis. Conversely to normal scaring,
tissue response to ionizing radiation can be considered as
a chronic and self-maintained scaring process leading to
fibrosis. The acute or prefibrotic phase is characterized by an
inflammatory process with tissue damage essentially visible
in the mucosal compartment. The young fibrosis shows
immunocompetent cells accumulation and mesenchymal
cells activation (fibroblasts and smooth muscle cells). Estab-
lished fibrosis is paucicellular, with densification of scaring
tissue and continuous matrix remodelling (Figure 1).
endothelial cells apoptosis . Tissue response to radiation
exposure is considered as a continuum between very acute
4. Radiation-Induced Inflammation
Ionizing radiations can be considered as a proinflammatory
signal, and normal tissue response to radiation exposure
is immediate and endures with time. Radiation-induced
inflammatory response is initiated by the production of reac-
tive oxygen/nitrate species, the induction of apoptosis and
of the transcription of several proinflammatory cytokines,
chemokines, and growth factors in the microvascular and
mucosal compartments, presumably by recruited immune
cells but also by enterocytes and residing cells, depending on
the severity of tissue trauma [12, 13].
The vascular endothelium is a critical target compart-
ment involved in tissue response to radiation exposure and
strongly participates in the initiation and development of
radiation lesions [5, 14]. Irradiation of the vascular endothe-
lium leads to endothelial cell apoptosis and the acquisition
of a proinflammatory, prothrombotic, and antifibrinolytic
phenotype, with increased secretion of soluble mediators
such as cytokines, chemokines, and growth factors . The
increase in adhesion molecules expression such as VCAM-
1, ICAM-1, PECAM-1 as well as E and P selectins ,
and the expression of proinflammatory soluble mediators
by irradiated endothelial cells activate resident macrophages
and favour the early recruitment of polymorphonuclear
neutrophils from the bloodstream. Neutrophils are recruited
within minutes following tissue trauma, and their presence is
characteristic of acute inflammation. Inflammatory process
is then amplified by the recruitment and transmigration of
monocytes and the activation of resident mast cells, both
as IL-1훽, IL-6, IL-8, CXCL-1, CXCL-2, TNF-훼, or TGF-
훽 [17–20]. The innate immune response carried out by
BioMed Research International3
Figure 1: Continued.
4 BioMed Research International
Figure 1: Left panel ((a) to (e)): Radiation-induced damage to the rectal wall following localized exposure to 27Gy single dose in the rat.
(a) Healthy mucosa. (b) Two weeks after exposure, tissue shows mucosal and submucosal inflammation, with mucosal ulceration (u) and
submucosal (sm) oedema. Glandular recovering (arrow) alternates with ulcerated areas. (c) Height weeks after exposure, underlying the
ulcerated areas, the entire rectal wall is pathologic. The mucosa and submucosa show still severe inflammation, with tissue necrosis at the
mucosa disappeared. (e) Eight weeks after exposure, severe epithelial, submucosal, and muscular damage is associated with dystrophic
submucosal and mesenteric vessels. The elastic layer is dystrophic (arrow) compared to the healthy vessels ((d), arrow) and, neointimal
in the vessel wall and neointimal hyperplasia reducing the vascular lumen. (f), (g), (h) HeS staining, (i), (j) Sirius Red staining. Original
Francois. Right panel radiation-induced damage to the rectal wall in patients treated for rectal adenocarcinoma, 5 to 7 weeks following the
end of radiation therapy (45Gy). (f) Healthy rectal mucosa. (g): Epithelial atypia with mucosal oedema and inflammation. Crypt positioning
magnification ×40, pictures Agn` es Franc ¸ois.
macrophages, neutrophils, and mast cells is supported by
the adaptative immune response assumed by the B and T
lymphocytes (Figure 2).
4.1. Innate or Unspecific Immune Response. Innate immunity
insures organismsagainst pathogens. The first line of defence
implicated in the immediate unspecific reactions to antigens
shared by a plethora of pathogens.
4.1.1. Macrophages. Resident macrophages and circulating
monocytes are the sensors of tissue homeostasis breakdown.
Upon tissue injury, activated macrophages release a cytokine
and chemokine “soup” to recruit neutrophils . Once in
the injured tissue, neutrophils can in turn emit signals to
favour monocyte recruitment from the bloodstream. Fol-
lowing extravasation, monocytes differentiate into dendritic
cells, resident macrophages (M2 type), or inflammatory
mation but also in its resolution and tissue regeneration,
notably in clearing out tissues from apoptotic neutrophils,
bacteria, and cells and tissue debris. The termination of
inflammation is orchestrated by many factors. For example,
neutrophil apoptosis can trigger several feed-back signals
which dampen further neutrophil recruitment, and neu-
ones a switch in the nature of secreted mediators toward
alpha and increased TGF-beta and IL-10 secretions) .
Fibrotic small bowel of patients with radiation enteritis
show altered expression of many genes implicated in stress
them is increased expression of MIP-2, a member of C-X-C
chemokine family secreted by monocytes and macrophages
and chemoattractive for neutrophils . Rectal biopsies
from 33 patients treated with radiotherapy for nongas-
trointestinal pelvic carcinoma show increased density of
macrophages at the end of the second week of treatment
mainly in the mucosal compartment . In 17 patients
of radiotherapeutic treatment . Macrophage immunos-
taining is increased in the rat small intestine 2 weeks after
of X-radiation (8 × 5.6Gy) . Finally, radiation proctitis
all tissue compartments .
Broadly, authors often report macrophage invasion in
irradiated intestine in human tissues as well as in preclinical
played by macrophages in the initiation and development
of gut radiation damage. Macrophages, but also neutrophils,
are followed in radiation lesions to establish radiation injury
scores and put in evidence eventual beneficial effects asso-
ciated with therapeutic strategies. The understanding of
the roles played by macrophages in radiation damage may
in mice 2 and 14 weeks following 27Gy single-dose radiation
exposure is associated with increased macrophage density in
BioMed Research International5
Intestinal stem cells and
endothelial cells apoptosis
Adhesion molecules and
Immune cells recruitment
Activation of resident
(IL-6, IL-8, IL-1훽, ...)
Figure 2: Radiation exposure to the gut mucosa induces epithelial stem cells apoptosis and clonogenic cell death, endothelial cells death and
activation, and mucosal barrier breakdown. Innate immunity: resident immune cells such as macrophages and mast cells are activated by
DAMPs generated by dead cells and PAMPs coming from mucosal breakdown. Activated endothelial cells express adhesion molecules and
cytokines favouring immune cells recruitment into the injured tissue. Activated macrophages increase neutrophil recruitment, which in turn
emit signals favouring monocytes recruitment from the blood stream. The radiation-induced tissue M1/M2 balance is unknown. Adaptative
immunity: Th1 lymphocytes can activate innate immune cells and favour cell-mediated immunity, whereas Th2 favour humoral immunity
via B cells. The balance in irradiated gut tissue is in favour of a Th2 orientation. Treg maintain immune tolerance. Resident and recruited
dendritic cells are activated and carry out the link with lymph nodes and the establishment of specific immune response. PAMPs are also
detected by TLRs, whose activation can protect epithelium against radiation damage. ILCs play a role in epithelial homeostasis, but their role
after radiation exposure is unknown.
help to find new therapeutic options. For instance, to favour
macrophage M2 phenotype or neutrophil apoptosis may
help macrophages to dampen inflammation and would be
an interesting therapeutic option but necessitate a refined
knowledge of the roles of the different cell types in the
successive phases of intestinal tissue response to radiation
4.1.2. Polymorphonuclear Neutrophils. Neutrophils, with
their phagocytic and microbicidal capacities, play a key role
in the protection of organisms against infections and partici-
pate to the inflammatory response of injured tissues. Radi-
ation-induced intestinal mucosal and vascular barrier break-
down leads to bacterial translocation and to immediate
recruitment of neutrophils to the site of injury. The
microbicidal properties of the reactive oxygen species (ROS)
produced by the so-called neutrophils “respiratory burst”
 are crucial in the management of the first steps of
gastrointestinal infections and inflammation. However,
excessive and sustained ROS production may damage
healthy cells and tissues and participate in the progression
and the chronicity of radiation injury to the intestinal
wall. Radiation-damaged tissues, included during the late
fibroatrophic phase, often present sustained oxidative
stress , and the protective effects of probiotics in the
pathogenesis of radiation injury to the digestive tract
may in part rely on their antioxidant properties .
Neutrophil influx is observed in the rat small intestine until
26 weeks after exposure to localized single (18, 21, 29.6Gy)
or fractionated (16 × 4.2Gy) X-radiation [30, 31]. In mice,
radiation proctitis following 27Gy single-dose exposure
shows increased neutrophil numbers in the inflamed and
6BioMed Research International
fibrosed areas 2 and 14 weeks postirradiation. The expression
of CXCL-1 and CXCL-2, both having a strong neutrophil
chemoattractant activity, is increased in irradiated tissues as
soon as 3 hours postirradiation, . In humans, biopsies
from rectal mucosa of patients at 2 and 6 weeks during the
course of ongoing radiotherapy for prostate carcinoma show
increased neutrophil numbers .
The precise roles of neutrophils in radiation enteritis
and proctitis are still unknown and remain ambiguous.
Neutrophils are generally considered deleterious in intestinal
inflammation. However, in radiation-induced proctitis in
mice, increased neutrophil chemoattractant expression and
subsequently higher neutrophil numbers were associated
with less tissue damage in mast cells-deficient mice .
Several studies have reported a potential role of acute neu-
trophil influx in tissue protection. In Smad3 knockout mice
receiving 30Gy on the flank skin, reduced tissue radiation
damage is associated with increased acute neutrophil influx
. In a model of septic shock following cecal ligation
and puncture in mice, Alves-Filho et al. noticed that IL-
33 favours neutrophils chemotaxis to the site of infection
and reduces animal mortality. IL-33-treated animals exhibit
bacterial clearance . Neutrophil infiltration is a hallmark
of irradiated tissues, and several studies are necessary to
in the initiation and progression of radiation damage to the
located in tissues in close contact with the external milieu
(gut, lung, and skin) thus participating in innate and adapta-
tive immune reactions [34, 35]. Mast cells are able to secrete
a huge number of proinflammatory, profibrosing, vasoactive,
and mitogenic soluble mediators (stocked in their granules
or newly synthesized) in response to various physiological
and pathological situations. Mast cells have been known for
a long time to be implicated in allergic reactions but are also
involved in several inflammatory and fibrotic disorders .
Numerous studies remain necessary to define the precise
roles of mast cells in the initiation and development of
and the diversity of irradiation models generates controversy
about mast cells response to irradiation in vitro and in
vivo. Globally, in vitro, mast cells are rather radioresistant
compared to other immune cells . In vivo, mast cells also
appear quite radioresistant in mice following 20Gy fraction-
ated total body irradiation, with no evidence of radiation-
induced degranulation . Conversely in the rat, intestinal
mast cells are severely depleted after 3.5, 5, or 10Gy single-
dose total body radiation exposure [39, 40]. Human proctitis
following radiation therapy for rectal adenocarcinoma is
associated with mast cell hyperplasia in the mucosa and
submucosa, in muscularis propria, in the dystrophic vessel
wall, and more globally in the areas of inflammation and
collagen deposition . Mast-cells-deficient rats develop
severe acute mucosal damage compared to wild-type ani-
mals following localized radiation exposure of the small
intestine to 21Gy-single dose but are protected from late
tissue fibrosis . Despite reduced collagen accumulation
in fibrotic lesions of mast-cells-deficient rats, TGF훽-1 mRNA
expression in irradiated tissues is similar to their control
littermates. Authors suggest that mast cells participate to
the profibrosing effect of TGF훽-1. Experimental radiation
chronic (14 weeks) rectal damage , suggesting again that
mast cells play a role in the radiation-induced inflammatory
and fibrosing processes in the gut.
Besides a wide range of proinflammatory and profibros-
ing mediators, mast cells also secrete chymase and tryptase,
two proteases implicated in numerous biological processes.
Mast cell chymase is involved in vascular, inflammatory,
and fibrosing diseases. Chymase can activate matrix met-
alloproteases, degrades matrix proteins such as fibronectin
and vitronectin, and potentiates the biological actions of IL-
deficient mice are protected from both acute (2 weeks) and
1훽, TGF훽-1, endothelin-1, and angiotensin II . Mast cell
genesis, inflammation and fibrosis . Mast cell tryptase
are G-protein-coupled receptors expressed on the surface of
many cell types including enterocytes, smooth muscle cells,
immune cells, endothelial cells, and stromal cells. PAR-2 is
implicated in various biological functions such as intestinal
ion transport, motility, vascular tone, inflammation, and cell
migration and proliferation in response to various traumas
. PAR-2 expression and activation are increased after
radiation exposure of the small intestine of the wild-type
rat, with significant attenuation in mast cells-deficient rats,
proliferative phase of intestinal radiation injury may partly
occur via PAR-2 activation [45, 46]. In vitro, exogenously
added mast cell chymase or tryptase can turn human colonic
muscularis propria smooth muscle cells toward a migrat-
ing/proliferating and proinflammatory phenotype, making
mast cells putative participants in the in vivo radiation-
induced inflammatory process and dystrophy of the muscu-
induced overexpression of inflammatory genes such as IL-6,
IL-8, CXCL-2, and E-selectin , suggesting that mast cells
may participate in the activation of vascular endothelium
and in the global tissue inflammation following radiation
exposure. There is still a lot to be done to understand the
when chronicity takes hold.
proliferation, and contraction of smooth muscle cells, angio-
phoid cells populations, among which NK cells implicated
in the maintenance of epithelial homeostasis and integrity.
They produce numerous cytokines and growth factors as
IL-22, expressed by Th cells and ILCs and with a recep-
tor located on stromal mesenchymal and epithelial cells,
triggers the production of genes involved in epithelial cell
BioMed Research International7
differentiation and survival and has been shown to protect
intestinal Paneth and stem cells against immune-mediated
tissue damage in a model of graft-versus-host disease in
mice. Reciprocally, deficiency in IL-22 led to loss of ILCs and
subsequent intestinal barrier disruption and increased tissue
damage, showing mutual interactions between immune and
epithelial compartments . To our knowledge, no data
damage following localized exposure.
4.1.5. Pattern Recognition Receptors (PRRs). Innate response
relies on the activation of receptors recognizing pathogens
molecular motifs (for Pathogen-Associated Molecular Pat-
terns (PAMPS)) and referred to as Pattern Recognition
Receptors (PRRs). Among the different PRRs, Toll-Like
Receptors (TLRs) are able to recognize Damage-Associated
damaged and activated cells, thus playing a putative role in
tissue homeostasis and repair such as postradiation exposure
. TLRs are expressed on the surface of multiple cell
cells. Pretreatment with the TLR5 receptor ligand flagellin is
protective against sublethal doses of whole body irradiation
in mice and primates  and protects gut mucosal tissue
from apoptosis following 8Gy total body irradiation in
mice . In the same way, probiotics inhibit TLR4/NFkB
Probiotics also reduce radiation-induced epithelial injury
and improve crypt survival in mice following 12Gy whole
There are still no data on the role of TLRs signalling and
high-dose localized intestinal radiation exposure. Working
in this direction would warranty interesting breakthroughs
and probably open new therapeutic windows to prevent or
mitigate severe gut radiation injury.
4.2. Adaptative Immune Response. The adaptative immunity
consists of immune cell response to specific antigens. This
specific response necessitates the presentation to B and T
lymphocytes of antigens coming from pathogens by special-
ized presenting cells such as dendritic cells. The rapid innate
response following tissue radiation exposure changes the
composition of the microenvironment and favours dendritic
cells maturation, antigens presentation and the induction
of clonal proliferation of selected immune cells. Adaptative
immunity amplifies the first line innate response, so innate
and adaptative immunities complement to each other.
Lymphocyte infiltrate is a common feature of irradiated
matory phases of radiation damage. Following antigen pre-
sentation, na¨ ıve CD4+T cells can differentiate into different
T cells subsets such as Th1, Th2, Th17, or Treg, each showing
specific cytokine expression profiles controlled by distinct
transcription factors, and assuming various redundant or
opposed roles in the tissue immune response to injury.
Immune-modulation properties of ionizing radiation are
used in the context of antitumor radiation therapy .
In normal tissues, even if lymphocytes subsets have differ-
ent radiation sensitivities, radiation exposure in total body
configuration is used for its immune-suppressive properties.
The effects of localized irradiation on lymphocytes are more
complex and depend on the irradiated organ, the size of
the irradiation field, and the delivery protocol (fraction
cell to produce antibodies, activate CD8+cytotoxic T cells,
and are implicated in the recruitment of innate immune cells
such as neutrophils and monocytes/macrophages to the site
schedule and total administered dose). CD4+T cells are
crucial in the adaptative immune response as they help B-
of tissue damage. CD4+T cells polarisation into Th1, Th2,
Th17, and Treg subsets is acquired depending on the tissue
cytokine context and is revealed by the activation of specific
transcription factors, the expression of several chemokine
receptors, a specific cytokine expression profile for each sub-
set, and the activation of preferential partner cells triggering
specific immunity . Briefly, Th1 cells are responsible for
cell-mediated immunity, stimulate macrophages, and thus
contribute to the elimination of intracellular pathogens and
promote tumoricidal activity. The Th1 profile is mainly asso-
ciated with autoimmune diseases. Th2 cells mainly stimulate
humoral immunity with B-cell activation and are implicated
in allergic reactions. Th17 cells recruit neutrophils and are
implicated in the elimination of extracellular pathogens and
also participate in the development of autoimmune dis-
exposure, by its direct effects on adaptative immune cells
and by the generation of innate immune response and
inflammation, triggers an imbalance in immune populations
which still remains obscure . For example, abdominal
irradiation in the rat increases Treg populations in the
intestine with impaired ability to control effectors T cells
and compromise normal tissue repair . Still in the rat,
the CD4+T helper polarization through a Th2 profile. The
imbalance in favour of Th2 cells persists until 6 months post-
the development of a Th1 profile in Crohn’s disease and a Th2
profile in ulcerative colitis. Continuing immune imbalance
may play a significant role in the chronicity of radiation
the nature of infiltrating immune cells, to understand the
modalities of their recruitment, and finally to highlight the
roles played by adaptativeimmunityin the context of normal
digestive tissue response to radiation exposure.
In conclusion, normal gut tissue response to radiation
exposure is the result of cell death and activation in all tissue
compartments, with a strong oxidative and immunoinflam-
and recruited immune cells described in irradiated normal
tissues are still obscure, as well as the part played by innate
and adaptative immunities. Strong evidence suggests that
ongoing researches in this direction warranty opportunities
to discover new therapeutic tools to manage normal tissue
radiation damage. Given the relatively poor therapeutic
efficiency of “classic” anti-inflammatory strategies, it appears
8 BioMed Research International
necessary to increase the knowledge concerning enduring
oxidative stress, vascular endothelial cell activation, immune
cells recruitment and their phenotypic orientations such as
M1/M2 macrophages and lymphocytes Th1/Th2/Th17/Treg
balances, and finally the conditions necessary to the res-
olution of radiation-induced inflammation. This may help
the understanding of the benefit/risk ratio of the radiation-
induced immunoinflammatory response and offer consider-
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