British Journal of Radiology (2005) Supplement_27, 89-94
© 2005 British Institute of Radiology
doi: 10.1259/bjr/53186341
British Journal of Radiology Supplement_27 (2005),89-94 © 2005 The British Institute of Radiology
The contribution of radiation-induced injury to the gastrointestinal tract in the development of multi-organ dysfunction syndrome or failure
P Monti1,
J Wysocki1,
A van der Meeren2 and
N M Griffiths1
1 Institut de Radioprotection et de Sûreté Nucléaire, Direction de la Radioprotection de l'Homme, Service de Radiobiologie et d'Epidémiologie, BP 17, F-92262 Fontenay-aux-Roses and 2 Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Département de Radiobiologie et de Radiopathologie Laboratoire de Radiotoxicologie, BP 12, F-91680 Bruyères le Chatel, France
Correspondence: Dr Pascale Monti, Institut de Radioprotection et de Sûreté Nucléaire, DRPH/SRBE, BP N° 17, F-92262 Fontenay-aux-Roses, Cedex, France. E-mail: pascale.monti@irsn.fr
 |
Abstract
|
|---|
Severe damage to the gastrointestinal tract (GIT), such as loss of the gastrointestinal mucosa and haemorrhage, following accidental overexposure to ionising radiation appears to be a determinant feature in patient mortality. Injury to the GIT may be direct, as this tissue is particularly radiation sensitive, as well as indirect as a result of radiation burns and bone marrow aplasia. Similar to other severe trauma situations such as thermal burns, radiation exposure results in reduced intestinal barrier integrity, which initiates and/or perpetuates inflammatory–anti-inflammatory mediator release. This may result in damage to distant organs. In this context, the injured gut may be considered as a "key player" or "motor" in the development of multiple organ dysfunction syndrome or failure. Of note is that radiation exposure elicits similar GIT injury of both mucosal and vascular elements, in contrast to other severe physical insults. Common factors are the intestinal inflammatory response and loss of barrier function. However, bone marrow injury must be taken into account in intestinal responses.
|
Introduction
|
|---|
Injury to the gastrointestinal tract (GIT) following accidental exposure to ionising radiation has been shown in a number of cases to have a significant role in patient survival or mortality. Gastrointestinal dysfunction is also implicated in patient outcome following other types of serious injury such as thermal burns and haemorrhagic shock. Following radiation exposure, GIT injury stems from the direct effects of irradiation owing to the radiation sensitivity of the GIT, as well as from indirect effects associated with radiation effects on other sensitive organs such as the bone marrow and skin. In the second case, for example thermal burns, damage to the GIT is indirect but may be considered as important in the development of multiple organ dysfunction syndrome (MODS) or multiple organ failure (MOF). MOF has been documented to occur after several diverse clinical conditions, including mechanical and thermal trauma, pancreatitis and shock [1].
To date, radiation-induced MOF has not been equivocally added to this list. Thus, it is the aim of this review to examine the similarities of the response of the GIT following radiation exposure with other types of physical insult to address the question of whether the GIT is a key initiator and/or motor in cases of fatal accidental radiation overexposure. In view of the question of multi-organ involvement, the consequences of perturbation of gut homeostasis for distant organ functions will be considered.
|
Evidence for the potential role of the GIT in the development of MODS
|
|---|
Since the recognition of MOF and MODS as clinically defined illnesses, the search for a unifying concept has been the subject of much research and debate [2]. Moreover, there appears to be an ever-increasing interest in this area, which is presumably related to the poor clinical outcome. Much research effort using both experimental animal models and data from clinical studies has been directed towards demonstrating that injury to the GIT, whether direct or indirect, has a key, if not primary, role in the development of MOF. In the early 1980s, the gut was considered as a "sink of infection", with bacterial translocation and subsequent systemic infection being a major hypothesis for the development of MOF. More recently the gut has been defined as becoming a pro-inflammatory organ generating cytokines ("cytokine sink"), biogenic amines, proteases and free radicals, to name but a few, all of which have effects on GIT function as well as on distant organs via the systemic or lymphatic circulation [3]. There are several convincing arguments that reinforce the role of the GIT in MOF: (i) clinical studies that document an association of diminished gut barrier function with systemic infection, acute respiratory distress syndrome (ARDS) or MODS [4, 5]; (ii) clinical trials that indicated that enteral feeding improves clinical outcome [6]; and (iii) experimental animal data that show an association between factors in gut-derived mesenteric lymph following burn injury or haemorrhagic shock and subsequent lung or heart damage [7, 8]. Conversely, other data exist demonstrating that the GIT does not have a major role in MOF, in particular with regard to bacterial translocation where clinical trials have failed to demonstrate endotoxin or bacteria in portal blood [9]. Moreover, selective gut decontamination, which has been clearly shown to reduce infection rates, does not appear to improve patient survival [10].
Apart from bacterial translocation from the gut, another possible major critical factor involving the response of the GIT to a major physical insult is hypoperfusion of the intestine. It has been suggested that persistent gut hypoperfusion is an important inciting event in the development of the systemic inflammatory response syndrome and MOF [11]. The release of pro-inflammatory mediators in addition to increased mucosal permeability, decreased ileal motility and gut-associated lymphoid tissue (GALT) has been observed in different models of GIT ischaemia–reperfusion injury. All these may contribute to the early and/or late development of MOF.
|
Evidence from fatal radiation accidents of significant GIT involvement
|
|---|
It appears that the GIT has a significant role in patient outcome following high dose radiation exposure that leads to major damage to this system. This is demonstrated in Table 1
, which shows different radiation accident scenarios involving both external and internal exposure and for which gastrointestinal damage was considered to have contributed to the final fatal outcome [12]. For the most part, small numbers of people were involved. Both Vinca (Yugoslavia) and Tokai-mura (Japan) were reactor criticality accidents and the personnel (six and three, respectively) were exposed to a mixed neutron/
field irradiation. The fatal accidents that occurred at Soreq (Israel) and Nesvizh (Belarus) involved single operators using industrial sources. For the earlier accident at the Chernobyl nuclear power plant (1986), which involved many more people, an order of priority of organ damage leading to death was ascribed, although there was clearly multi-organ involvement [12]. The one case that cites the "gastrointestinal syndrome" as the cause of death was the accident at Indiana, where a patient undergoing brachytherapy for pelvic tumours received a lethal dose when part of the iridium source was detached during retraction and remained in situ for 4 days.
View this table:
[in this window]
[in a new window]
|
Table 1. Radiation accident scenarios involving both external and internal exposure and for which gastrointestinal damage was considered to have contributed to the final fatal outcome
|
|
It should be noted that the key organs and possibly the life-determining ones appear to be those that provide a primary interface to external aggressions such as the skin, GIT and lungs. Furthermore, given the radiation sensitivity of the haematopoietic system and consequent bone marrow aplasia, tissue defence mechanisms are also significantly reduced following exposure. This degree of aplasia, however, is not generally seen following other types of major injury such as mechanical or thermal trauma and pancreatitis. Initial aplasia and followed by haematopoietic recovery is likely to be important for the clinical course of events leading to "radiation-induced multi-organ involvement". Finally, it is interesting to note that in the case of the Nesvizh accident, which involved high dose exposure (9–16 Gy) to an industrial radiation source (60Co), the patient was declared as having "polyorgan chronic insufficiency syndrome" [15]. This appears to be the first case of fatal radiation overexposure where the notion of multi-organ involvement was clearly stated.
|
Common factors of GIT injury from major physical insults or radiation overexposure
|
|---|
Intestinal epithelial barrier damage
One of the most important properties of both the small and the large intestine is as a barrier between the exterior and the internal milieu, as this organ is constantly challenged by foreign substances as well as by the endogenous microbiota. Under normal circumstances the primary barrier is a physicochemical one provided by the luminal pH and the overlying mucus layer. The main barrier is the single layer of epithelial cells, which is constantly renewed and which allows the passage of small molecules via the paracellular pathway. The tight and adherens junctions between cells maintain epithelial integrity and intestinal functions.
Various studies in man and animals have shown that both small and large intestinal permeability is increased following ionising radiation exposure [16–19]. These alterations are most marked in the acute response period (first 2 weeks) and were associated with epithelial cell loss and modifications in junctional complexes. To date, few studies have addressed the question of intestinal permeability changes at longer times post exposure. Moreover, an important question related to this problem is whether consequential injury stems from initial mucosal breakdown or early responses of the so-called "late responding elements" (blood vessels, myofibroblasts). This would of course be interesting given the clinical manifestation of "late" MOF [11]. It is recognised that although the intestine is particularly sensitive to ionising radiation, like the haematopoietic system it also has a significant capacity for recovery [20, 21]. This was noted at autopsy of the Nesvizh accident patient [15] where partial recovery of the digestive system was recorded.
Renewal of the intestinal epithelial barrier depends upon an active stem cell compartment similar to the haematopoietic system and it is this compartment that has been shown to be particularly sensitive to ionising radiation exposure. With increasing radiation dose, the stem cells cannot produce enough cells to repopulate the villi, which results in blunting and diminution in villus height and eventual functional incapacity. This leads to decreased nutrient absorption and barrier function, loss of fluid and electrolytes, and increased possibility for xenobiotic penetration of the intestinal barrier.
Over many years, Potten and co-workers [22, 23] have shown that the most radiation-sensitive cells are located either at the bottom of small intestinal crypts between positions four and six (above the differentiated Paneth cells) or dispersed throughout the lower third of the large intestinal crypts. This was demonstrated by histological localisation of apoptotic cells in the crypts within hours following radiation exposure. This has become somewhat a hallmark associated with radiation-induced damage. In addition, Potten and co-workers also showed that these cells were sensitive to other types of external aggression such as chemotherapeutic agents and other toxic chemicals.
Similar to radiation-induced GIT injury, thermal burns result in reduced intestinal absorption and increased mucosal permeability. Furthermore, it has been shown in patients that the alterations in intestinal permeability are correlated with the degree of burns [24]. Varedi et al [25] have demonstrated that addition of serum collected from burn-injured rats to an intestinal cell line in culture resulted in disruption of the monolayer integrity. Furthermore, in a more recent study the same group provided evidence for increased apoptosis and reduced cell proliferation in intestinal crypts following burn injury; of note is the fact that the most sensitive cells were in positions 4–6 of the small intestinal crypts where mitosis was significantly reduced at 6 h after burn injury [26]. It is not known which blood- or lymph-borne factors are responsible for these effects on the intestine following skin injury.
These data regarding cellular effects are remarkably similar to those following radiation exposure and are related in both cases to effects on the rapidly dividing and proliferating crypt cells. Moreover, given the different cell types of the intestinal epithelium, cell loss may contribute to a decreased potential capacity to synthesise and secrete naturally occurring mitogenic, motogenic and bacteriostatic factors that would help to restore mucosal homeostasis. Finally, it has been suggested that "intestinal epithelial apoptosis plays an important role in critical illness of infectious and non-infectious origin" [27].
Potential role of changes in intestinal blood and lymphatic circulation
The stem cell compartment is not the only compartment sensitive to ionising radiation exposure. The irrigation of the intestine is extremely important and this organ may require as much as 30% of cardiac output. As a consequence, alterations in local or distant vasoreactivity (vasoconstriction or dilatation) clearly have repercussions on intestinal function. In particular, intestinal absorption of nutriments depends not only on a functional epithelium with resident enzymes but also on an intact functional vasculature. It is important to note that under normal physiological conditions the intestine is an organ that is constantly challenged by ischaemia–reperfusion. Interestingly, a frequently used experimental model with which to study the development of MODS and/or MOF is injury to the intestine following a prolonged period of ischaemia–reperfusion. In a recent review, Bush et al [28] demonstrated that following a period of ischaemia, epithelial barrier properties are modified leading to increased epithelial permeability.
With regard to ionising radiation exposure, it is not clear from experimental or clinical observations whether ischaemia–reperfusion-induced intestinal injury in the classical sense (splanchnic hypoperfusion) occurs after radiation exposure. However, an interesting dichotomy exists, since ischaemia–reperfusion injury was shown to be attenuated in irradiated animals. This was explained by the reduced numbers of mast cells and neutrophils following irradiation [29]. This observation raises the question of the role of haematopoietic damage and recovery in the generation of MOF following ionising radiation exposure.
Structural and functional modifications of the intestinal circulation and endothelium following radiation exposure have been investigated over many years using a number of techniques. Increased intestinal vascular permeability together with capillary leakage has been observed by a number of workers in the early period after irradiation [30–32]. In the elegant study using both histology and microangiography of rat intestinal blood vessels, Eddy and Casarett [31] demonstrated several post-irradiation alterations including moderate to marked dilatation, shortening and tortuosity of small arterial vessels, reduction in numbers and/or lengths of vessels and later occurring haemorrhagic patterns. In addition, swelling or hypertrophy of endothelial nuclei was also observed. The conclusion from this early work was that "there was an apparent relationship between the degree and rate of development of radiation damage of the mucosal epithelial structure and the degree and time of development of obstructive changes in the fine vasculature".
Vascular permeability, like epithelial permeability, is also increased following irradiation and this has been demonstrated using a number of experimental approaches, from in vivo [33–35] to ultrastructural analyses using electron microscopy [36]. Similar to the epithelium, which provides a barrier between the exterior and interior, the endothelium provides a barrier between tissue and blood (or lymph). Changes in vascular permeability to either cells and/or molecules play a fundamental role in the initiation of inflammatory responses. In agreement with this, several experimental studies have shown increased pro-inflammatory cytokines, biogenic amines and nitric oxide as well as increased adhesion molecule expression in intestinal tissue following radiation exposure [33, 34, 37, 38]. These arguments reinforce the hypothesis cited earlier that gut hypoperfusion may lead to the gut being "a generator" of inflammatory mediators with consequences for the intestine and distant organs indicating a key role, at least, in the development of early MOF.
The question of the primary lesion — epithelial stem cell death or endothelial cell death — has been the subject of much debate, and some 30 years on from Eddy and Casarett's publication, Fuks, Kolesnick and co-workers, using a number of different approaches, have demonstrated that endothelial apoptosis does play a key role in the loss of the intestinal mucosa and survival [39–41]. The results showed that protection of endothelial cells with basic fibroblast growth factor (bFGF) had a beneficial effect on mouse survival, crypt survival and mucosal morphology. The authors concluded, "the data suggest that microvascular function regulates expression of radiation-induced crypt stem cell clonogen damage in the evolution of radiation injury to the GIT mucosa" [41]. Interestingly, they did not show an increased number of regenerating crypts with bFGF treatment or with any other procedure designed to protect the endothelium. Conversely, Eddy and Casarett proposed that "obstruction to arterial perfusion can result in serious impairment of the regenerative capability of the epithelium". For improved treatment of accidental radiation-induced injury to the gut it would surely be advantageous to increase regenerating crypt numbers. Perhaps a better localisation of blood vessel type — arteriole or venule — in combination with identification of bFGF and other growth factor receptor spatial heterogeneity merits investigation.
Transport of mediators (cellular or chemical) released by the injured gut may not only be via blood vessels but also via intestinal lymphatics. The implication of lymphatic drainage has been a matter of controversy initiated in the late 19th century by Starling, who proposed that in cases of haemorrhage, lymph flow was decreased and that interstitial fluid was reabsorbed directly into intravascular spaces across the capillaries. This was later challenged by Cope and Litwin, who claimed that lymphatic vessels do have a major role in fluid reabsorption. Clearly following radiation exposure where hypovolaemia, necrotic cells and toxic accompanying products are problems, the aspect of lymphatic drainage requires further investigation. In addition to the regulation of intratissue/intertissue homeostasis, intestinal lymphatic vessels are important for absorption of lipid-soluble nutriments from the intestine.
A role for lymphatics in interorgan communication pathways has been proposed in uncontrolled inflammatory responses initiated in the skin following thermal burns that in turn affect gastrointestinal and pulmonary function [7]. Deitch and co-workers have investigated the role of intestinal lymph in several different models using either lymphatic diversion or collection of lymph following thermal burns, ischaemia–reperfusion or haemorrhagic shock. Mesenteric lymph in these cases has been shown to have effects on distant organs such as the lungs (increased permeability and adhesion molecule expression [7, 42]) and heart (decreased cardiac contractility [8]) as well as on endothelial cells in culture (HUVECs, upregulation of adhesion molecule expression [43]) and bone marrow (suppressed haematopoiesis [44]). If indeed the constituents of mesenteric lymph are similar following radiation overexposure, which may also involve radiation burns, then haematopoiesis even in non-exposed areas may be further compromised. This may be particularly important since most accidental radiation exposures are heterogeneous, thus some functional bone marrow remains. In several accident cases (Nesvizh, Tokai-mura) it was observed that, although there was haematopoietic recovery, circulating white cells for example did not attain normal levels. This may be associated in part with perpetuation of the release of lymph-borne toxic factors from the intestine or indeed the skin as proposed following other physical insults [45, 46]. The aspect of intestinal lymphatic drainage has been investigated, seemingly with an ever-increasing interest, in cases of trauma and thermal burns, but to date not following irradiation. Thus, the concept of lymphatic trafficking of injurious cells/mediators that may have detrimental effects on distant organs and in the development of MOF remains to be elucidated in the case of ionising radiation exposure.
|
Conclusion
|
|---|
Under normal physiological conditions, the GIT, skin and haematopoietic system interact with each other to maintain "homeostasis". Following radiation overexposure and disruption of one or more of these systems, these homeostatic mechanisms are severely disturbed leading to inappropriate responses. It is clear from data obtained from radiation accidents and from other physical insults that the "injured gut" has a pivotal role in the course of development of multi-organ involvement and indeed in patient survival. The GIT is sensitive to ionising radiation per se and additionally is affected by the responses of other organs such as the skin. The question of the importance of lymph-borne cells/molecules post radiation exposure remains to be investigated. It is possible that even if the intestinal stem cell compartment recovers from the initial radiation damage, additional factors related to the scale of radiation burn injury may aggravate and perpetuate reduced intestinal function and/or integrity. These inappropriate responses evolve with time and are undoubtedly affected by different therapeutic regimens, including transplantation of blood elements (bone marrow graft, peripheral blood stem cells, transfusions). These interventions may also be important in the development of MOF.
In comparison with responses of the GIT to other severe physical insults, radiation exposure elicits similar responses for both mucosal and vascular elements. Thus, in terms of GIT responses, MOF induced by ionising radiation exposure could be added to the list cited earlier. However, a caveat to this should be considered: in the accidental situation, overexposure may be total or localised, with a heterogeneous dose distribution and by association, the radiation effects on haematopoiesis–lymphopoiesis. This must surely influence intestinal inflammatory–anti-inflammatory responses, which are either beneficial (counteract infection) or deleterious (uncontrolled inflammatory responses).
|
References
|
|---|
- Deitch EA. Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 1992;216:117–34.[Medline]
- Baue AE. MOF/MODS, SIRS: an update. Shock 1996;6:S1–5.
- Deitch EA, Xu D, Franko L, Ayala A, Chaudry IH. Evidence favoring the role of the gut as a cytokine-generating organ in rats subjected to hemorrhagic shock. Shock 1994;1:141–5.[Medline]
- Goris RJ, Beokhorst PA, Nuytinck KS, et al. Multiple organ failure: generalized autodestructive inflammation. Arch Surg 1985;120:1109–15.[Abstract]
- Ziegler TR, Smith RJ, O'Dwyer ST, Demling RH, Wilmore DW. Increased intestinal permeability associated with infection in burn patients. Arch Surg 1988;123:1313–9.[Abstract]
- Kompan L, Kremzar B, Gadzijev E, Prosek M. Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 1999;25:157–61.[Medline]
- Magnotti LJ, Xu DZ, Deitch EA. Gut-derived mesenteric lymph: a link between burn and lung injury. Arch Surg 1999;134:1333–41.[Abstract/Free Full Text]
- Sambol JT, White J, Horton JW, Deitch EA. Burn-induced impairment of cardiac contractile function is due to gut-derived factors transported in mesenteric lymph. Shock 2002;18:272–6.[Medline]
- Moore FA, Moore EE, Poggetti R, McAnena O, Peterson V, Abernathy CM, et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 1991;31:629–38.[Medline]
- Reidy JJ, Ramsey G. Clinical trials of selective decontamination of the digestive tract: a review. Crit Care Med 1990;18:1449–56.[Medline]
- Moore FA. Role of gut hypoperfusion in the development of Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Failure (MOF). Am J Surg 1999;178:449–53.[Medline]
- Baranov AE. Allogeneic bone marrow transplantation after severe uniform total body irradiation: experience from recent (Nyasvizh, Belarus) and previous radiation accidents. Adv Biosci 1994;94:281–93.
- Flynn DF, Mihalakis I, Mauceri T, Pins MR. Gastrointestinal syndrome after accidental exposure during radiotherapy. In: Dubois A, King GL, Livengood DR. Radiation and the gastrointestinal tract. Boca Raton, FL: CRC, 1995:225–34.
- Hirama T, Tanosaki S, Kandatsu S, Kuroiwa N, Kamada T, Tsuji H, et al. Initial medical management of patients severely irradiated in the Tokai-mura criticality accident. Br J Radiol 2003;76:246–53.[Abstract/Free Full Text]
- International Atomic Energy Agency. The radiological accident at the irradiation facility in Nesvizh. Vienna, Austria: IAEA, 1996:46–65.5.
- Solheim KE, Laerum F, Stordahl A, Aase S. Urinary excretion of iohexol after enteral administration in rats with radiation injury of the small intestine. Scand J Gastroenterol 1991;26:1097–106.[Medline]
- Nejdfors P, Ekelund M, Westrom BR, Willen R, Jeppsson B. Intestinal permeability is increased after radiation therapy. Dis Colon Rectum 2000;43:1582–8.[Medline]
- Thiagarajah J, Gourmelon P, Griffiths NM, Lebrun F, Naftalin RJ, Pedley KC. Radiation-induced cytochrome c release causes loss of colonic fluid absorption by damage to crypts and pericryptal myofibroblasts. Gut 2000;47:675–84.[Abstract/Free Full Text]
- Vigneulle RM, Rao S, Fasano A, MacVittie TJ. Structural and functional alterations of gastrointestinal tract following radiation-induced injury in the rhesus monkey. Dig Dis Sci 2002;47:1480–91.[Medline]
- De Both NJ, Verney M. Epithelial regeneration of transposed intestine after high doses of X-irradiation. Int J Radiat Res 1976;29:17–26.
- Lamerton LF, Lord BI. Studies of cell proliferation under continuous irradiation. Natl Cancer Inst Monogr 1964;14:185–98.[Medline]
- Potten CS. A comprehensive study of the radiobiological response of the murine (BDF1) intestine. Int J Radiat Biol 1990;58:925–73.[Medline]
- Potten CS, Grant HK. The relationship between ionising radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer 1998;78:993–1003.[Medline]
- Ryan CM, Yarmush ML, Burke JF, Tompkins RG. Increased gut permeability early after burns correlates with the extent of injury. Crit Care Med 1992;20:1508–12.[Medline]
- Varedi M, Greeley GH, Herndon DN, Englander EW. A thermal injury-induced circulating factor(s) compromises intestinal cell morphology, proliferation and migration. Am J Physiol 1999;277:G175–82.[Medline]
- Varedi M, Chinery R, Greeley GH, Herndon DN, Englander EW. Thermal injury effects on intestinal crypt cell proliferation and death are cell position dependent. Am J Physiol 2001;280:G157–63.
- Husain KD, Coopersmith CM. Role of intestinal apoptosis in survival. Curr Opin Crit Care 2003;9:159–63.[Medline]
- Bush KT, Keller SH, Nigam SK. Genesis and reversal of ischaemic phenotype in epithelial cells. J Clin Invest 2000;106:621–6.[Medline]
- Harari Y, Weisbrodt NW, Moody FG. Ileal mucosal response to bacterial toxin challenge. J Trauma 2000;49:306–13.[Medline]
- Willoughby DA. Pharmacological aspects of the vascular permeability changes in the rat's intestine following abdominal irradiation. Br J Radiol 1960;23:515–9.
- Eddy HA, Casarett GW. Intestinal vascular changes in the acute radiation syndrome. In: Sullivan MF. Gastrointestinal radiation injury. Amsterdam, The Netherlands: Excerpta Medica Foundation, 1968:385–95.
- Cockerham LG, Doyle TF, Trumbo RB, Nold JB. Acute post-irradiation canine intestinal blood flow. Int J Radiat Biol Relat Stud Phys Chem Med 1984;45:65–72.[Medline]
- Buell MG, Harding RK. Proinflammatory effects of local abdominal irradiation on rat gastrointestinal tract. Dig Dis Sci 1989;34:390–9.[Medline]
- Panés J, Anderson DC, Miyasaka M, Granger DN. Role of leukocyte–endothelial cell adhesion in radiation-induced microvascular dysfunction in rats. Gastroenterology 1995;108:1761–9.[Medline]
- Van der Meeren A, Mouthon MA, Vandamme M, Squiban C, Aigueperse J. Combinations of cytokines promote survival of mice and limit acute radiation damage in concert with amelioration of vascular damage. Radiat Res 2004;161:549–59.[Medline]
- Debbage PL, Seidl S, Kreczy A, Hutzler P, Pavelka M, Lukas P. Vascular permeability and hyperpermeability in a murine adenocarcinoma after fractionated radiotherapy: an ultrastructural tracer study. Histochem Cell Biol 2000;114:259–75.[Medline]
- Freeman SL, MacNaughton WK. Ionizing radiation induces iNOS-mediated epithelial dysfunction in the absence of an inflammatory response. Am J Physiol 2000;278:G243–50.
- Linard C, Ropenga A, Vozenin-Brotons, Chapel A, Mathe D. Abdominal irradiation increases inflammatory cytokine expression and activates NF-kappaB in rat ileal muscularis layer. Am J Physiol 2003;285:G556–65.
- Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, et al. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 1997;186:1831–41.[Abstract/Free Full Text]
- Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001;293:293–7.[Abstract/Free Full Text]
- Maj JG, Paris F, Haimovitz-Friedman A, Venkatraman E, Kolesnick R, Fuks Z. Microvascular function regulates intestinal crypt response to radiation. Cancer Res 2003;63:4338–41.[Abstract/Free Full Text]
- Zallen G, Moore EE, Johnson JL, Tamura DY, Ciesla DJ, Silliman CC. Post hemorrhagic shock mesenteric lymph primes circulating neutrophils and provokes lung injury. J Surg Res 1999;83:83–8.[Medline]
- Adams CA, Sambol T, Xu DZ, Ly Q, Granger DN, Deitch EA. Hemorrhagic shock induced upregulation of P-selectin expression is mediated by factors in mesenteric lymph and blunted by mesenteric lymph duct interruption. J Trauma 2001;51:625–31.[Medline]
- Anjaria DJ, Rameshwar P, Deitch EA, Xu DZ, Adams CA, Forsythe RM, et al. Hematopoietic failure after hemorrhagic shock is mediated partially through mesenteric lymph. Crit Care Med 2001;29:1780–5.[Medline]
- Deitch EA. Role of the gut lymphatic system in multiple organ failure. Curr Opin Crit Care 2001;7:92–8.[Medline]
- Deitch EA. Bacterial translocation or lymphatic drainage of toxic products from the gut: what is important in human beings? Surgery 2002;131:241–4.[Medline]
Top
Abstract
Introduction
