Kinetics, localization, and mechanism of 5-aminolevulinic acid-induced porphyrin accumulation in normal and Barrett's-like rat esophagus
Jolanda van den BoogertAdriaan B. HoutsmullerFelix W.M. de RooijRon W.F. de BruinPeter D. SiersemaRichard van Hillegersberg
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Photodynamic therapy may selectively destroy Barrett's epithelium in the esophagus. To optimize photosensitizer administration, the kinetics of 5-aminolevulinic acid (ALA)-induced porphyrin accumulation in the normal and Barrett's-like esophagus were studied in the rat.Animals received 200 mg/kg ALA intravenously (n = 21) or orally (n = 21). Six rats served as controls. At t = 1, 2, 3, 4, 6, 12, and 24 hr, porphyrin concentration in the esophagus was measured by using chemical extraction, and porphyrin localization was determined by laser scanning microscopy (LSM). In addition, in 20 animals, porphobilinogen deaminase, ferrochelatase, and iron concentration were determined. In a second group (n = 24), an esophagojejunostomy was performed to induce a Barrett's-like esophagus. After 18 weeks, animals received ALA, and LSM was performed at t = 1, 2, 3, 4, 6, 8, and 12 hr.Porphyrin accumulation in normal mucosa was 3.5-fold higher than in muscularis, with a maximum at 3 hr after ALA administration. With LSM, strong homogeneous fluorescence of the squamous epithelium was shown, with minor fluorescence of submucosa and muscularis. In Barrett's-like epithelium, fluorescence was heterogeneous but was also restricted to epithelial cells. There was no difference in fluorescence intensity between Barrett's-like and adjacent squamous epithelium. Porphobilinogen deaminase activity was higher and iron concentration was lower in the mucosa than in the muscularis (P < 0.001).ALA-induced porphyrin accumulation selectively occurs in esophageal mucosa, whether normal or Barrett's-like, compared with the muscularis, with a maximum at 3 hr after ALA administration. Selectivity may be caused by a different activity of heme-synthetic enzymes or relative iron deficiency in the mucosa.Keywords:
Porphobilinogen deaminase
Muscularis mucosae
Submucosa
Barrett's esophagus
To the best of our knowledge, this is the first report of ectopic gastric mucosa appearing between muscularis mucosae and submucosa, at esophagogastric junction. Currently there are two theories explaining the mechanism. The most widely accepted one is that Ectopic gastric mucosa is an embryological remnant, and an alternative theory is abnormal proliferation under inflammation1.Although we don't have many evidences to clarify this case into specific mechanism mentioned above, Nomura et reported two cases of Adenocarcinoma of the cervical esophagus arising from ectopic gastric mucosa, Completely resected by ESD with no signs of recurrence2. Therefore, In this present case, the lesion was successfully managed with ESD. The symptoms were released after the operation and the patient remained well during a year follow-up. Long-term follow-up is recommended in case of recurrence or gastric cancer.
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Herniation of the glandular epithelium into the submucosa has been observed in 11 out of 27 cases of chronic ulcerative colitis. Glandular herniation was associated with thickening of the muscularis mucosae, with interruption of the muscularis mucosae by lymphoid follicles, and, in five of the 11 cases, with significant crowding of the glands of the mucosa. This study strongly suggests that sustained contraction of the muscularis mucosae, which has been shown by others to be a major feature of chronic ulcerative colitis, is the prime factor in the formation of downgrowths or herniations of the glandular epithelium into the submucosa. Comparison of the cases in which cancer developed with those where there was glandular herniation led to the conclusion that they are independent associations of chronic ulcerative colitis, and that glandular herniation plays no part in the development of dysplasia or cancer.
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Ten cases of endoscopically removed colorectal polypoid tumors exhibiting lobular growth patterns in the submucosa without prominent desmoplastic changes in the interstitium were investigated using serial sections, and four cases were confirmed to be pseudoinvasion. The growth pattern of these four cases (pseudoinvasive tumors) was morphologically compared with the other six tumors (microinvasive tumors) in which obviously infiltrating foci were seen in minimal ranges. In the pseudoinvasive tumors, intramucosal tumor tissue spread into the submucosa through the narrow gap of the muscularis mucosae and formed a lobulated nodule larger than the gap of the muscularis mucosae. This suggested that squeezing of the herniated tumor tissue by muscularis mucosae at the gap was crucial to forming a typical feature of pseudoinvasion. The maximum diameters of the gap of the muscularis mucosae (G) and the submucosal tumor nodule (N) were measured under a microscope and compared between both groups. The mean N/G ratio of the pseudoinvasive tumors (1.73 ± 0.46) indicated a significantly higher value than that of the microinvasive tumors (1.04 ± 0.06; P < 0.01). The N/G ratio could be one of the indices used to distinguish a pseudoinvasive tumor from a microinvasive tumor in colorectal polypoid tumors.
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Proliferating patterns of acetylcholinesterase (AChE) positive nerve fibres were investigated in 23 neonates with Hirschsprung's disease. All subjects were separated into three groups, according to age. In group A (0-10 days old) adn groups B (11-20 days old, no increase in AChE positive nerve fibres was evidenced in the lamina propria mucosae, whereas 7 out of 9 cases in group C (21-28 days old) showed a moderate or marked increase in AChE positive nerve fibres in the lamina propria mucosae. A typical pattern of this proliferation up to the lamina propria mucosae was seen in 30.4% only of all cases in the series, and was limited to group C, where the positive AChE reaction from the submucosa to the muscularis mucosae (including the submucosa only), the rate was 91.3%. Re-examination was preformed in 14 cases over sthe neonatal period. All showed a positive AChE reaction up to the lamina propria mucosae. Suction biopsy specimen from neonates is sometimes inadequate with respect to the lack of inclusion of the muscularis mucosae and submucosa, as a result of a weakly negative pressure by suction. The normal reactions of AChE activity in the lamina propria mucosae do not exclude Hirschsprung's disease in neonates. Therefore, when a histochemical diagnosis of Hirschsprung's disease using rectal suction biopsy for staining of AChE activity is required in the neonatal period, the diagnosis is safe and relatively easy at least over three weeks of age as mentioned above.
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Electrolyte transport across two preparations of mucosa from rat colon descendens was compared to determine what influence the submucosal plexus has on electrolyte transport. One preparation consisted of the mucosa, muscularis mucosae, and the submucosal tissue and is referred to as the mucosa‐submucosa preparation. The second preparation obtained by further blunt dissection of the mucosa‐submucosa preparation consisted of only the mucosa and the circular muscle layer of muscularis mucosae and is referred to as the mucosa preparation. Histological studies showed that the submucosal tissue and the longitudinal layer of muscularis mucosae could be removed leaving only the mucosa and the circular layer of muscularis mucosae. The extensive neuronal network of the submucosa was shown when the submucosal tissue and longitudinal muscle layer of muscularis mucosae, which were removed, were stained histochemically for acetylcholinesterase activity. Both the mucosa‐submucosa and mucosa preparations absorbed Na+ and Cl‐ when short‐circuited. However, Na+ and Cl‐ absorption were significantly higher in the mucosa preparation. The increase in Na+ and Cl‐ transport in the mucosa preparation was accompanied with a decrease in the short‐circuit current (Isc), the open‐circuit potential difference (p.d.) and the transmural tissue conductance (Gt) when compared to the mucosa‐submucosa preparation. Tetrodotoxin (TTX), a neurotoxin which blocks specifically the propagation of action potentials in excitable tissues, dose‐dependently decreased Isc and p.d. in the mucosa‐submucosa preparation when added to the serosal solution. The half‐maximal effective concentration of TTX was 5 nM and maximal effective concentration 100 nM. TTX (1 microM) had no effect on Isc or p.d. when added to the mucosal solution. The decrease in Isc and p.d. caused by TTX in the mucosa‐submucosa preparation was accompanied with an increase in Na+ and Cl‐ absorption. TTX caused only a small decrease in Isc and p.d. in the mucosa preparation. However, there was no measurable change in Na+ and Cl‐ transport in the mucosa preparation. The results suggest that spontaneously active neurones from the submucosal plexus have an inhibitory influence on the mucosa. Physical removal of the submucosal plexus or pharmacological blockade of the neurones within the mucosa‐submucosa preparation by TTX led to enhanced absorption, suggesting that the set point of the mucosa for electrolyte transport is at or near a maximal absorptive state. Regulation or modulation of the mucosa may therefore occur by mechanisms that lower this set point, causing an inhibition of absorption of electrolytes.
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