The aim of the present in vitro study was to investigate, in different genders, motor responses in surgical colonic specimens from patients with rectal cancer undergoing and not undergoing chemotherapy with capecitabine and radiotherapy.

This in vitro study was conducted from October 2015 to August 2017 at the Experimental Pharmacology Laboratory at the National Institute "S. de Bellis" after collecting samples at the Department of Surgery. Segments of sigmoid colon were obtained from 15 patients (Male (M)/Female (F) = 8/7; control group, CG) operated on for elective colorectal resection for rectal cancer without obstruction and 14 patients (M/F = 7/7; study group, SG) operated on for elective colorectal resection for rectal cancer who also received chemotherapy, based on capecitabine twice daily, and radiotherapy. Isometric tension was measured on colonic circular muscle strips exposed to increasing carbachol or histamine concentrations to obtain concentration-response curves. The motor responses to electrically evoked stimulation were also investigated.

In males, carbachol and histamine caused concentration-dependent contractions in the CG and SG. An increased sensitivity and a higher response to carbachol and histamine were observed in SG than CG (P < 0.01). On the contrary, in females, the response to carbachol was not significantly different in CG from the SG and the maximal responses to carbachol were greater in CG than in SG (P < 0.001). The same applied to histamine for half-maximal effective concentrations and maximal response in that they were not significantly different in CG from the SG. Electrically evoked contractions were significantly more pronounced in males, especially in the SG (P < 0.05).

This preliminary in vitro study has shown gender differences in motor responses of colonic circular muscle strips in patients who had received chemotherapy with capecitabine and radiotherapy.

Murine small intestinal motility consists of phasic contraction from interstitial cells of Cajal (ICC) and migrating motor complexes (MMCs) from the enteric nervous system. The number of ICC is reduced in various gastrointestinal disorders, and this effect can be reversed once the disorder is resolved through cellular and tissue remodelling. Exposure to high-dose radiation can induce inflammation and alter intestinal motility. In this study, we investigated the changes in the small intestinal motility of 8- to 10-week-old male C3H/HeN mice after high-dose (13 Gy) irradiation. The aim of this study was to determine whether those changes are caused by changes in the ICC or enteric nervous system. After irradiation, the small intestine was dissected and stored in oxygenated Krebs-Ringer bicarbonate solution. The tension of contractions and intracellular membrane potentials were recorded at day 0, 1, 3 and 5 after irradiation and compared with those of sham-irradiated mice. Histological evaluation was performed by immunohistochemistry and apoptosis was evaluated. Quantitative real-time polymerase chain reaction (qPCR) for c-kit mRNA was also performed. Phasic contractions were not changed at day 0, 1, 3 and 5 after irradiation and did not significantly differ from those in the control mice. Slow waves were also sustained after irradiation. However, the frequency of migrating motor complexes (MMCs) was significantly higher at day 0 and 1 after exposure and the amplitude and area under the curve were significantly lower at day 3 after exposure compared with control mice. MMCs were recovered at day 5 with no difference from those of the control mice. ICC were detected after irradiation by immunohistochemistry for c-kit, and c-kit mRNA levels did not differ between sham-irradiated and irradiated mice. Histological evaluation showed that the most severe inflammation was detected at day 3 after irradiation, and apoptosis was detected only in the mucosa. Acetylcholine increased the contractility after irradiation, and tetrodotoxin decreased the number of MMCs in sham-irradiated and irradiated mice. N(w)-oxide-l-arginine (L-NA) increased the number of MMCs. MMCs were recovered after L-NA treatment at day 3 after irradiation. Sodium nitroprusside decreased the MMCs in sham-irradiated and irradiated mice. Exposure to high-dose radiation did not alter phasic contractions and slow waves in the small intestine of mice, which suggests that ICC and their functions may be sustained after high-dose irradiation. Mucosal inflammation was severe after irradiation and there were some changes in MMCs related to the enteric nervous system.

We investigated the effects of gamma-radiation on cells isolated from the longitudinal smooth muscle layer of the guinea pig ileum, a relatively radioresistant tissue. Single doses (up to 50 Gy) reduced the amount of sarcoplasmatic reticulum and condensed the myofibrils, as shown by electron microscopy 3 days post-irradiation. After that, contractility of smooth muscle strips was reduced. Ca(2+) handling was altered after irradiation, as shown in fura-2 loaded cells, with elevated basal intracellular Ca(2+), reduced amount of intrareticular Ca(2+), and reduced capacitive Ca(2+) entry. Radiation also induced apoptosis, judged from flow cytometry of cells loaded with proprium iodide. Electron microscopy showed that radiation caused condensation of chromatin in dense masses around the nuclear envelope, the presence of apoptotic bodies, fragmentation of the nucleus, detachment of cells from their neighbors, and reductions in cell volume. Radiation also caused activation of caspase 12. Apoptosis was reduced by the administration of the caspase inhibitor Z-Val-Ala-Asp-fluoromethyl-ketone methyl ester (Z-VAD-FMK) during the 3 day period after irradiation, and by the chelator of intracellular Ca(2+), 1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA), from 1 h before until 2 h after irradiation. BAPTA also reduced the effects of radiation on contractility, basal intracellular Ca(2+), amount of intrareticular Ca(2+), capacitative Ca(2+) entry, and apoptosis. In conclusion, the effects of gamma radiation on contractility, Ca(2+) handling, and apoptosis appear due to a toxic action of intracellular Ca(2+). Ca(2+)-induced damage to the sarcoplasmatic reticulum seems a key event in impaired Ca(2+) handling and apoptosis induced by gamma-radiation.

Environmental contamination by 137Cs is of particular public health interest because of the various sources of fallout originating from nuclear weapons, radiological source disruptions, and the Chernobyl disaster. This dispersion may lead to a chronic ecosystem contamination and subsequent ingestion of contaminated foodstuffs. The aim of this study was to thus determine the impact of a chronic ingestion of low-dose 137Cs on small intestine functions in rats. The animals received 150 Bq per day in drinking water over 3 mo. At these environmental doses, 137Cs contamination did not modify the crypt and villus architecture. In addition, epithelial integrity was maintained following the chronic ingestion of 137Cs, as demonstrated by histological analyses (no breakdown of the surface mucosa) and electrical transepithelial parameters (no change in potential difference and tissue conductance). Furthermore, cesium contamination seemed to induce contradictory effects on the apoptosis pathway, with an increase in the gene expression of Fas/FasL and a decrease in the apoptotic cell number present in intestinal mucosa. No marked inflammation was observed following chronic ingestion of 137Cs, as indicated by neutrophil infiltration and gene expression of cytokines and chemokines. Results indicated no imbalance in the Th1/Th2 response induced by cesium at low doses. Finally, evaluation of the functionality of the jejunal epithelium in rats contaminated chronically with 137Cs did not demonstrate changes in the maximal response to carbachol, nor in the cholinergic sensitivity of rat jejunal epithelium. In conclusion, this study shows that chronic ingestion of 137Cs over 3 mo at postaccidental doses exerts few biological effects on the epithelium of rat jejunum with regard to morphology, inflammation status, apoptosis/proliferation processes, and secretory functions.

Intestinal inflammatory conditions are associated with structural and functional alterations of the enteric nervous system (ENS). While injury to the enteric nervous system is well described, the mechanisms of neuronal injury and neuronal cell loss remain unclear. The aim of the present study was to examine the neural consequences of distal colitis and to assess the role of neutrophil granulocytes in mediating these changes. Colitis was induced in C3H/HEN female mice with dinitrobenzene sulfonic acid. The mice were then sacrificed at 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 120 h post instillation of dinitrobenzene sulfonic acid. The inflammatory response was assessed by macroscopic damage score, myeloperoxidase activity and histology. HuC/D and PGP 9.5 immunostaining was used to examine myenteric plexus density and structure, neural cell body numbers and distribution in cross-section and whole mount preparations. Apoptosis was investigated in whole mount preparations double stained with HuC/D and activated caspase-3 or cleaved poly (ADP-ribose) polymerase (PARP). Dinitrobenzene sulfonic acid-induced colitis was associated with a rapid and significant loss of HuC/D immunoreactive myenteric plexus neuronal cell bodies (42% decrease relative to control) that remained unchanged between 6 and 120 h. No change in myenteric plexus density was observed with PGP 9.5 immunostaining. Neuronal apoptosis was evident between 0.5 and 3 h. PARP immunoreactive neurons ranged between 1% and 2.5%. Colitis was associated with significant impairment in colonic propulsive function. Pre-treatment of mice with anti-neutrophil serum attenuated the inflammatory response and partially reduced the extent of myenteric plexus neuronal cell loss. Taken together, these data suggest that acute colitis is associated with loss of myenteric plexus neurons that is partly mediated by neutrophil granulocyte infiltration and is accompanied by impairment of colonic motility.

Radiation-induced diarrhoea is attributed to both mucosal injury and alterations of intestinal motility. Previous reports have indicated that 5-hydroxytryptamine is released following irradiation, which may contribute to these changes.

To investigate the effects of granisetron (5-hydroxytryptamine type-3 receptor antagonist) on colonic motility, fluid absorption and 5-hydroxytryptamine colonic content following abdominal irradiation (10 Gy) in rats.

In vivo measurements of motility and fluid absorption in the proximal and distal colon, respectively, diarrhoea score and 5-hydroxytryptamine tissue levels were performed 3 and 7 days after abdominal irradiation. The effects of post-irradiation granisetron (0.3 mg/kg subcutaneously) were also evaluated.

Colonic motility and fluid/Na(+) absorption were reduced 3 and 7 days after irradiation. All rats developed diarrhoea (3 days) concomitant with increased colonic mucosal 5-hydroxytryptamine levels. Granisetron prevented diarrhoea, attenuated decreased colonic motility and reduced 5-hydroxytryptamine levels on day 3, although fluid absorption was only slightly improved. On day 7, colonic motility and fluid/Na(+) absorption were restored in granisetron-dosed animals.

These results indicate that radiation-induced diarrhoea involves alterations of both colonic motility and fluid/Na(+) absorption. 5-Hydroxytryptamine could be one of the mediators implicated in these alterations, as post-irradiation dosage with a 5-hydroxytryptamine type-3 receptor antagonist improved colonic motility and prevented diarrhoea on day 3.

The current flow of papers on intestinal structure, radiation science, and intestinal radiation response is reflected in the contents of this review. Multiparameter findings and changes in compartments, cells, or subcellular structure all contribute to the overall profile of the response. The well-recognized changes in proliferation, vessels, and fibrogenesis are accompanied by alterations in other compartments, such as neuroendocrine or immune components of the intestinal wall. The responses at the molecular level, such as in levels of hormones, cytokines, or neurotransmitters, are of fundamental importance. The intestine responds to localized radiation, or to changes in other organs that influence its structure or function: some structural parameters respond differently to different radiation schedules. Apart from radiation conditions, factors affecting the outcome include the pathophysiology of the irradiated subject and accompanying treatment or intervention. More progress in understanding the overall responses is expected in the next few years.

Localized application of ionizing radiation to the gastrointestinal tract frequently elicits responses, which include diarrhoea. The origin of this symptom is not clear but has been attributed to loss of epithelial integrity, together with alterations in motility and increased secretion. The purpose of this study was to examine whether a 10 Gy abdominal gamma irradiation leads to an inflammatory reaction, and to compare intestinal and colonic motility in controls and abdominally irradiated rats 1, 3 and 7 days after irradiation, using an electromyographic technique. The motility parameters analysed were the frequency and velocity of propagation of migrating myoelectric complexes (MMC) in the jejunum and colonic spike activity (long spike bursts; LSB) per 10 min in fasted rats. The MMC frequency was significantly reduced on days 1 and 7 after irradiation and the MMC pattern was markedly disrupted on day 3. The frequency of colonic LSB was significantly reduced on days 1, 3 and 7. Mouth to anus transit was significantly accelerated on day 3 only and diarrhoea was observed at this time. Myeloperoxidase activity in the jejunum and colon was also increased on this day only. It is concluded that irradiation-induced diarrhoea occurs contemporaneously with disruption of MMC in the small intestine.

In addition to its beneficial effects on small intestinal mucosal development and repair, insulin-like growth factor (IGF)-I has also been reported to improve neural function in toxic neuropathies. It has recently been recognized that enteric neural abnormalities contribute to the small intestinal dysmotility observed during and after abdominal radiotherapy for gynecological and pelvic malignancy. The aim of the present study was to evaluate the effects of IGF-I (5 mg/kg per day) and the more potent analog LR3IGF-I (5 mg/kg per day) on neurally mediated ileal dysmotility following irradiation.

Intestinal motor activity was recorded from 6-8 cm segments of explanted rat ileum using a miniaturized manometric technique during arterial perfusion with oxygenated fluorocarbon solution. Studies were performed 4 days after treatment with 10 Gy abdominal irradiation. At the time of irradiation, all rats underwent implantation of an osmotic mini-pump that contained 100 mmol/L acetic acid vehicle (n = 8), IGF-I (n = 8) or LR3IGF-I (n = 7). For each experiment, the total number of pressure waves, high-amplitude long-duration (defined as > 20 mmHg, > 6 s; HALD) pressure waves and long bursts (> 20) of pressure waves were determined. Ileal segments from 12 non-irradiated rats were used as controls for manometric studies. In radiotherapy treated animals, the degree of mucosal damage was determined using a standardized histologic scoring system.

The HALD pressure waves were infrequent in non-irradiated rats but occurred in all irradiated animals. Insulin-like growth factor-I and LR3IGF-I had no effect on the frequency, amplitude or migration characteristics of HALD pressure waves compared with vehicle. Histologic damage was reduced in animals that received IGF-I and LR3IGF-I compared with vehicle-treated animals.

In radiation enteritis, IGF-I has no effect on neurally mediated small intestinal dysmotility while improving mucosal histology. The disparity between these results suggests that parallel but separate pathologic processes underlie mucosal and motor abnormalities in radiation enteritis.

Exposure of the abdomino-pelvic region to ionizing radiation, such as that received during radiotherapy, is associated with the development of a number of untoward symptoms which may limit the course of therapy or which may involve serious chronic intestinal disease. While the mucosal dysfunction surrounding acute radiation enteritis is generally ascribed to the effects of ionizing radiation on the cell cycle of epithelial stem cells of the intestinal crypts and subsequent epithelial loss, recent evidence suggests that other, earlier events also play a role. The severity of these early events may determine the incidence and severity of chronic enteritis. The mechanism for this is unclear, but may relate to radiation-induced compromise of host defence responses to luminal pathogens or antigens. This review will address the current state of knowledge of the pathogenesis of radiation-induced intestinal dysfunction, focusing on events which occur in the mucosa, and will discuss what the future may hold with respect to the treatment of radiation-associated diseases of the intestinal tract.

The aim of this study was to determine whether ionizing radiation modifies muscarinic regulation of intestinal mucosal function. Rats exposed to total body 8-Gy gamma-irradiation or sham irradiated were studied up to 21 days after irradiation. Basal and carbachol-stimulated short-circuit current (Isc) and transepithelial conductance (Gt) of stripped ileum were determined in Ussing chambers. Muscarinic receptor characteristics using the muscarinic antagonist [3H]quinuclidinyl benzilate and three unlabeled antagonists were measured in small intestinal plasma membranes together with two marker enzyme activities (sucrase, Na+-K+-ATPase). Enzyme activities were decreased 4 days after irradiation (day 4). Basal electrical parameters were unchanged. Maximal carbachol-induced changes in Isc and Gt were increased at day 4 (maximal DeltaIsc = 195.8 +/- 14.7 microA/cm2, n = 19, vs. 115.4 +/- 8.2 microA/cm2, n = 63, for control rats) and unchanged at day 7. Dissociation constant was decreased at day 4 (0.73 +/- 0.29 nM, n = 10, vs. 2.14 +/- 0.39 nM, n = 13, for control rats) but unchanged at day 7, without change in binding site number. Thus total body irradiation induces a temporary stimulation of cholinergic regulation of mucosal intestinal function that may result in radiation-induced diarrhea.