Intestinal Radiation Syndrome Research Articles

ROS-Responsive and pH-Sensitive Aminothiols Dual-Prodrug for Radiation Enteritis.

Radiation exposure can immediately trigger a burst of reactive oxygen species (ROS), which can induce severe cell death and long-term tissue damage. Therefore, instantaneous release of sufficient radioprotective drugs is vital to neutralize those accumulated ROS in IR-exposed areas. To achieve this goal, we designed, synthesized, and evaluated a novel oral ROS-responsive radioprotective compound (M1) with high biocompatibility and efficient ROS-scavenging ability to act as a promising oral drug for radiation protection. The compound is stably present in acidic environments and is hydrolyzed in the intestine to form active molecules rich in thiols. M1 can significantly remove cellular ROS and reduce DNA damage induced by γ-ray radiation. An in vivo experiment showed that oral administration of M1 effectively alleviates acute radiation-induced intestinal injury. Immunohistochemical staining showed that M1 improved cell proliferation, reduced cell apoptosis, and enhanced the epithelial integrity of intestinal crypts. This study provides a promising oral ROS-sensitive agent for acute intestinal radiation syndrome.

Radiation-induced changes in intestinal and tissue-nonspecific alkaline phosphatase: implications for recovery after radiation therapy

BackgroundExogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. MethodsWAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. ResultsIntestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. ConclusionsSupplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome.

Acute Gastrointestinal Syndrome in High-Dose Irradiated Mice

The most detailed reports of the response of the gastrointestinal system to high dose acute radiation have focused mainly on understanding the histopathology. However, to enable medical countermeasure assessment under the animal rule criteria, it is necessary to have a robust model in which the relationship between radiation dose and intestinal radiation syndrome incidence, timing, and severity are established and correlated with histopathology. Although many mortality studies have been published, they have used a variety of mouse strains, ages, radiation sources, and husbandry conditions, all of which influence the dose response. Further, it is clear that the level of bone marrow irradiation and supportive care can influence endpoints. In order to create robust baseline data, the authors have generated dose response data in adult male mice maintained under identical conditions and exposed to either total or partial-body irradiation. Partial-body irradiation includes both extensive (40%) and minimal (5%) bone marrow sparing models, the latter designed to correlate with an established primate model and allow assessment of effects of any medical countermeasure on all three major radiation syndromes (intestinal, bone marrow, and lung) in the surviving mice. Lethal dose (LD(30), LD(50), and LD(70)) data are described in the various models, along with the impact of enteric flora and response to supportive care. Correlation with diarrhea severity and histopathology are also described. These data can be used to aid the design of good laboratory practice (GLP)-compliant Animal Rule studies that are reflective of the conditions following accidental radiation exposure.

Effect of irradiation on morphology and motility of canine small intestine.

In addition to severe damage to the intestinal mucosa, there is evidence based on altered transit that irradiation affects intestinal motor function. A single dose of 938 cGy to the intestine of dogs consistently produced an acute intestinal radiation syndrome consisting of vomiting and diarrhea but was not lethal. In the fasting state, the migrating myoelectric complex was uniformly interrupted. After a meal, jejunal myoelectric activity analyzed by a computer program showed a progressive decline in the number, duration, and length of migration of spike bursts. There were occasionally bizarre motility patterns consisting of clusters of migrating spike bursts. Slow waves demonstrated irregular rhythm and nonuniform morphology. They occasionally migrated in an orad direction and at times were totally uncoupled. At 24 hr and four days after irradiation, the muscle and the neural plexus were nearly normal by light microscopy, but the mucosa exhibited severe necrosis. Therefore, irradiation produces profound functional abnormalities in intestinal muscle even though the morphology is minimally altered.

Bile Loss in the Acute Intestinal Radiation Syndrome in Rats

The effects of bile duct ligation (BDL), choledochostomy, bile acid sequestering within the intestinal lumen by cholestyramine, and fluid and electrolyte replacement on survival time and development of diarrhea after whole-body exposure to doses of ionizing radiation that result in death from acute intestinal injury were studied. BDL significantly prolonged survival and delayed the onset of diarrhea after exposure to 137Cs gamma rays, fission neutrons, or cyclotron-produced neutrons in the range of doses that produce intestinal death or death from a combination of intestinal and hematopoietic injuries. Cannulation of the bile duct with exteriorized bile flow (choledochostomy) to protect the irradiated intestine from the mucolytic action of bile salts did not duplicate the effect of BDL in increasing survival time. Choledochostomy without fluid replacement eliminated the occurrence of diarrhea in 15.4 Gy irradiated rats. Diarrhea did occur in irradiated animals with choledochostomy if they received duodenal injections of fluid and electrolytes to replace the fluid lost as a result of bile drainage. Duodenal injection of fluid and electrolytes, however, had no significant effect on survival time in irradiated rats. In contrast, injection of fluid and electrolytes into the peritoneal cavity of irradiated rats resulted in an increase in survival time that was comparable to that observed after BDL. Addition of antibiotics to the peritoneally injected fluid and electrolytes further increased survival time (up to 9 days). This survival time approached that seen in animals receiving the same radiation dose but which had the intestine exteriorized and shielded to minimize radiation injury to the intestine. Postmortem histological examinations of the irradiated small intestine showed mucosal regeneration in these long-term survivors receiving fluid and antibiotic therapy. In contrast, duodenal injection of cholestyramine post irradiation to bind bile acids had no effect on survival time or diarrhea incidence. The conclusions from these experiments are that BDL prolongs survival and postpones the onset of diarrhea in irradiated rats dying from acute intestinal injury primarily by slowing down the loss of fluid and electrolytes and that bile acids play no significant role.

The Intestinal Radiation Syndrome: Sepsis and Endotoxin

Rats were whole-body irradiated with 8-MeV cyclotron-produced neutrons and 137Cs gamma rays to study the role of enteric bacteria and endotoxin in the intestinal radiation syndrome. Decrease in intestinal weight was used as an index of radiation-induced breakdown of the mucosa. Neutron and gamma-ray doses that were sublethal for intestinal death resulted in a dose-dependent decrease in intestinal weight, reaching minimal values 2 to 3 days after exposure, followed by recovery within 5 days after irradiation. Neutron and photon doses that caused intestinal death resulted in greater mucosal breakdown with little or no evidence of mucosal recovery. The presence of fluid in the intestine and diarrhea, but not bacteremia or endotoxemia, were related to mucosal breakdown and recovery. Neither sepsis nor endotoxin could be detected in liver samples taken at autopsy from animals which died a short time earlier from intestinal injury. These results suggest that overt sepsis and endotoxemia do not play a significant role in the intestinal radiation syndrome.

Conjugated dihydroxy bile salt inhibition of glucose influx in rat jejunum in vitro.

Effects of bile salts on intestinal transfer differ in diverse animal preparations exposed to various bile acids. Radiolabeled glucose influx into rat jejunum in vitro was studied in buffer and compared to taurodeoxycholate, taurochenodeoxycholate, taurocholate, and deoxycholate. Jejunum was obtained from intact, bile-diverted, and colestipol-treated rats and in similar categories after abdominal x-irradiation. Taurodeoxycholate but not taurocholate inhibited glucose influx only in bile-fistula and colestipol-treated rats. Bile diversion increased and colestipol decreased glucose uptake from buffer. Added inhibitory effects of irradiation and bile salts were seen in bile-fistula animals. These data suggest that normal exposure to bile is chronically inhibiting jejunal glucose transport and that dihydroxy bile salts are responsible for this effect. They do not provide an explanation for the role of bile in the intestinal radiation syndrome.

Effect of Exposure Conditions on the Production of Radiation Lesions in Rat Small Intestine

ConclusionsThe 2000 R X-irradiation of small gut of the rat in general produces a shortening of the viscus which is time dependent. This dose, when delivered either to the whole-body or to the abdomen only, produces in the small gut of the rat the uniform classic lesion of the acute intestinal radiation syndrome, but without generalized denudation. The characteristic, foamy, epithelial cells that line most of the luminal surface after the third day are packed with large lipid droplets. The same dose, when applied to the exteriorized gut produces patchy lesions with areas similar to the above, interspersed with apparently intact areas usually concentrated in the upper small intestine. There are indications that the intact areas might have escaped the full effect of the dose delivered due to some interference with their blood supply resulting from the process of exteriorization.

Anoxic protection of small intestine of dogs by intra-arterial catheterization.

Repression of the immune response by whole-body irradiation makes possible homografting of various organs, including bone marrow. For the most part, such grafts are temporary, a primary factor in their destruction being recovery of the immune response of the host. This recovery is delayed as the amount of whole-body irradiation is increased (1). Untreated dogs receiving 1,000 to 1,100 r whole-body irradiation in one sitting usually die the intestinal type of death within three to five days. Dogs receiving a lesser though lethal dose die after five days but within thirty days. Death has been associated with bone-marrow failure. Swift and Taketa (2) shielded 6 to 8 per cent of the small intestine of rats, thereby protecting them from intestinal death. Osborne (3) removed the irradiated segment of the small intestine of rats and prevented intestinal death. From these experiments it seems likely that the immediate cause of death from the intestinal radiation syndrome may be electrolyte loss. If the animal survives beyond five days, healing of the intestinal mucosa can take place rapidly. Successful homografting of bone marrow might permit increased doses of whole-body irradiation in the treatment of leukemia and disseminated cancer. The technic might also be used in conjunction with increased amounts of chemotherapeutic agents. These last are frequently toxic to the bone marrow and small intestine. The objective of the present experiment was to determine the degree of protection against whole-body irradiation afforded by intraarterial occlusion of the superior mesenteric artery. The effect would be mediated through anoxia. Procedure Balloons, distensible to 2 c.c, were placed 2 cm. from the blind end of Ödman catheters (Fig. 2). After these were soaked in heparin, they were introduced into the femoral arteries of 4 dogs and passed into the superior mesenteric arteries under fluoroscopic guidance, using an image intensifier. The adjacent femoral vein was catheterized so that the location of the balloon could be proved by intravenous aortography. The balloon was inflated with a mixture of Hypaque and methylene blue. Hypaque permitted post-irradiation checking of the position and competence of the balloon. Appearance of the blue dye at the exterior end of the catheter during irradiation would indicate loss of distention. The balloon was distended five minutes before irradiation to allow time for the tissues to become anoxic. A plain Ödman catheter was passed into the aorta of 3 control dogs via the femoral artery. Irradiation was delivered at 250 kvp, h.v.l. of 1.75 mm. Cu, and target-skin distance of 100 cm. As can be seen in Figure 1, the animal is placed in a curved container so that one entire side is 100 cm. from the target. After 550 r in air was delivered, the dogs were turned so that the opposite side faced the target, and another 550 r was delivered. The dogs were anesthetized during irradiation with sodium pentobarbital.

The effect of D.F.P. on the acute intestinal radiation syndrome in the rat.

The administration of D.F.P. either before or up to 24 hours after abdominal irradiation reduced mortality after 1,050 and 1,334 r. D.F.P. had no effect on irradiation induced leucopenia nor on the later deaths (“bone-marrow death”) that occur after whole body irradiation. The effect of D.F.P. treatment on histological changes in the intestine has been studied. D.F.P. appears to have an anti-inflammatory action on radiation injury to the intestine. The mode of action of D.F.P. has been discussed and it is suggested that this drug might act by preventing the formation of vasoactive polypeptides (kallikrein and kinins).

Effects of Gamma Radiation on Calves

Twenty-seven calves were exposed to whole-body gamma radiation from a Co/sup 60/ source with a skin exposure dose rate of about 6.6 r per minute. The tissue exposure doses at the midline ranged from 150 to 360 r. All except one animal receiving a tissue exposure dose at the midline of 250 a or more developed acute hypoplasia of the bone marrow and a hemorrhagic syndrome and died after 14 to 24 days. One caif exposed to 350 r developed an acute intestinal radiation syndrome and died on the fifth day. Two calves exposed to 150 r developed a severe blood dyscrasia between the twentieth and thirtieth day, from which they recovered. They appeared to be normal by 270 days. The time sequence and extent of the changes in the circulating derivatives of the hematopoietic tissues werc essentially the same as those described in other mammalian species. (auth)

A Comparative Histological Study of Duodenal Damage Produced by Fission Neutrons and Co 60 Gamma-Rays

During the past several years experiments have been carried out at the Argonne National Laboratory to test the relative effectiveness of Co60 y-rays and fission neutrons on a number of biological objects (1). One of the comparative criteria utilized was the acute lethal action on mice exposed to single doses of these two radiations (2). After exposures to fission neutrons, mice showed a much earlier mortality mode than after comparable irradiation with Co60 y-rays. After neutron doses that were high enough to kill mice within the 30-day period after irradiation, a mortality peak was observed on the fifth or sixth day after exposure; a great majority of these neutron-irradiated mice died between the fourth and the ninth days. In contrast, the pattern after y-irradiation showed a pronounced peak of mortality around the thirteenth or fourteenth day after exposure. A specific intestinal radiation syndrome leading to death in 3 to 5 days has been described in several species of laboratory animals after exposure to large doses (1000 to 10,000 r) of X-rays (3-8). It seemed of interest to determine whether or not the early mortality mode characteristically following fission neutrons was also produced chiefly by intestinal damage. The object of this experiment was to compare both histologically and cytologically the small intestine of mice exposed to fission neutrons with that of animals exposed to Co60 y-irradiation.

Effect on Circulating Blood Volume of Partial Shielding of Rat Intestine during X-Irradiation

A lethal acute intestinal radiation syndrome was produced in rats by 100 r of x irradiation. All animals were exposed with head and thoracic regions leadshielded in order to minimize hematopoietic damage. By using the P/sup 32/- tagged red cell dilution method, circulating blood volume changes were studied in groups of animals that had been exposed with or without additional lead-shielding of a very short segment of ileum, a procedure which decreases intestinal radiation mortality significantly. Total circulating blood volume decreased markedly in both groups after irradiation, but the loss was significantly less severe in rats exposed with the ileal segment shielded. Four days after irradiation, blood volumes averaged 63 and 78% of normal in control irradiated and ileal segment-shielded groups, respectively. Although both groups sustained some loss of red cells, the total blood volume losses measured were mainly due to loss of plasma, presumably reflecting fluid loss by way of the intestinal lumen. Plasma volumes averaged 40 and 66% of normal on the fourth day in control and ileal segment-shielded groups, respectively. Rats surviving the critical period for intestinal radiation deaths showed blood volumes approaching normal levels on the sixth day. With the hematocrit taken as an approximate indexmore » of plasma volume change, serial determinations made on individual animals of both groups showed that mortality and survival time were closely related to the degree and rate of plasma loss. (auth)« less

Modification of acute intestinal radiation syndrome through shielding.

Mortality associated with intestinal injury in rats occurring 3–5 days after 1000 r x-irradiation was significantly decreased by shielding, during exposure, a small exteriorized section of duodenum or ileum. Protection was not obtained by shielding either the distal half of the cecum or the whole stomach. Beginning recovery of radiation-induced small intestine weight loss was observed 4 days after 1000 r in rats irradiated with a section of ileum shielded, whereas no recovery had occurred by this time in nonshielded controls. This effect was not demonstrable at 875 r, a dose that produced no acute intestinal deaths in either control or experimental group. An intermediate dose of 500 r to the ileal section under exposure conditions otherwise identical to the 1000-r experiment decreased the incidence of early deaths but failed to affect intestinal weight significantly as compared with controls without ileal shielding.