Mechanism Of Mucosal Damage Research Articles

The effect of dry extract of cabbage garden on the local non-specific proteinase-inhibitory potential of the mucous membrane of the stomach on the model of acute gastric ulcer

Peptic ulcer of the stomach and duodenum is a complex gastroenterological disease multifactorial in pathogenesis. One of the key components of non-specific inflammation in peptic ulcer disease is the activation of proteinases in the gastric mucosa and their interaction with proteinase inhibitors, which determines the degree of proteolytic aggression in terms of the development of destructive changes in the tissues that they damage.
 The aim of the work was to study the effect of dry extract of cabbage garden on the components of the proteinase-inhibitor system in experimental gastric ulcer.
 The effect of dry extract of cabbage garden on the local non-specific proteinase-inhibitory potential of the gastric mucosa was studied on the model of acute alcohol-prednisolone ulcers. Dry extract of cabbage garden at a dose of 50 mg/kg and comparison drugs – omeprazole and altan were administered intragastrically once a day for 7 days from the second day of the experiment. On the 8th day, elastase-like, trypsin-like activity and acid-stable inhibitors in the swabs from the stomach and intestines, biopsy samples of the gastric mucosa from the esophagus and fundus, and small intestine were determined.
 It has been established that with an experimental alcohol-prednisolone gastric ulcer, a local non-specific proteinase-inhibitory system is involved in the mechanism of mucosal damage. At the same time, the level of trypsin-like and elastase-like activity of gastric juice increases and the activity of acid-stable inhibitors decreases, which normally suppress the enzymatic activity of proteinases. According to the effect on the non-specific proteinase-inhibitor system, the dry cabbage extract was significantly superior to altan and not inferior to omeprazole. The most pronounced effect of normalizing the activity of nonspecific proteinases and their inhibitors was established using a combination of dry cabbage extract with omeprazole. One of the mechanisms of the antiulcer action of the dry cabbage extract is its effect on the local nonspecific proteinase-inhibitory potential of the gastric mucosa.
 In the model of acute alcohol-prednisolone gastric ulcer, dry extract of cabbage garden caused a decrease in the activity of local non-specific proteolytic enzymes and activation of proteinase inhibitors of the gastric mucosa and duodenum, exceeding the activity of altan. Under the combined use of the dry extract of cabbage and omeprazole, a complete normalization of the state of the local non-specific proteinase-inhibitory potential of the gastroduodenal zone was observed.

A Crystal in Ulcer

Purpose: A 61-year-old male presented to the ER complaining of fatigue, dizziness, and BRBPR for two days. Past medical history is significant for GERD, Hep C, GIB secondary to NSAID-induced gastric ulcer, and ESRD s/p two failed renal grafts. Current medications include pantoprazole, sevelamer, kayexalate, senna, and metoprolol. On admission, the patient was found to be hypotensive with a hemoglobin (Hb) of 9 g/dl (baseline 10-11 g/dl). His blood pressure responded appropriately to fluid resuscitation. Subsequent EGD revealed a single non-bleeding gastric ulcer (3 mm) in the pre-pyloric region of the stomach with no stigmata of bleeding. The patient continued to have intermittent episodes of BRBPR, necessitating multiple blood transfusions, and a colonoscopy was done, revealing evidence of colitis and localized ulcerations in the proximal ascending colon and cecum status post biopsies. During the hospitalization, an angiography was also performed, which revealed active bleeding from cecal branches of ileocolic artery status post embolization with cessation of bleeding. Biopsy results from the cecal ulcers on colonoscopy revealed single particle of crystalline material in the background of an ulcer consistent with kayexalate-induced ulcers (Image 1). Many drugs can cause non-specific damage in the large intestine, including solitary hemorrhages, erosions, ulcers, and inflammation. The pathogenesis of the lesions caused by drugs is highly variable, with toxic injury and vascular insufficiency thought to be the most common. Kayexalate-induced intestinal injury reveals rhomboid or triangular basophilic crystals adherent to surface epithelium. Kayexalate is a cation exchange resin which acts in the large intestine by exchanging sodium ions for potassium ions. The mechanism of mucosal damage is not clear, and is reported to be more common in patients with renal failure. It is speculated to be caused by its osmotic action and vasospasm of intestinal vasculature. The patient in this case recovered after discontinuation of kayexalate. This case highlights the importance of medication-induced GI tract injury. Physicians should be aware of colonic ulceration and ischemia in renal failure patients taking kayexalate.Figure: Cecal ulcer biopsy.

The Prevention of Oral Mucositis in Patients with Blood Cancers: Current Concepts and Emerging Landscapes

The prevention of oral mucositis (OM) in the management of hematological malignancies continues to represent an unmet clinical need. Addressing this issue has major clinical implications as OM can also greatly impair patient's quality of life. To review currently available measures and investigational agents to prevent OM in hematological patients. we searched for OM and related issues using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. Many agents targeting different mechanisms of mucosal damage have been applied in order to prevent OM; most of them have failed or its efficacy has not been fully demonstrated. Palifermin is the first pharmaceutical/biological agent approved for the prevention of OM; its use is currently restricted to patients who have received radiotherapy-containing conditioning regimens prior to autologous hematopoietic stem cell transplantation. No clear benefit by this agent has been demonstrated outside of this specific setting and its application should be limited to clinical trials. Other interventions, such as other growth factors and non mitogenic measures are under investigation or in development and their application in the hematological setting is expected in the short term.

Overexpression of cyclin‐dependent kinase (CDK) inhibitors p21 and p27 is a common mechanism of experimental duodenal ulcer and ulcerative colitis

Recently we demonstrated that increased expression of cyclin‐dependent kinase inhibitors p21 and p27 is an early event in duodenal ulceration (DU) induced by cysteamine or mepirizole and in indomethacin‐caused gastric erosions. We hypothesized that overexpression of p21, p27 and p16 may be involved in the mechanisms of mucosal damage in both DU and ulcerative colitis (UC). To compare the effect of chemically‐induced injury in duodenal and colonic mucosa, Sprague‐Dawley rats were treated with cysteamine (85 mg/100 g, intragastrically) or with 6% iodoacetamide (0.1 ml, intracolonically). Animals were euthanized at 0.5, 2, 6, 12, 24 hr after treatment. Mucosal scrapings of proximal duodenum and distal colon were used for RNA isolation; p16, p21 and p27 were detected by Real‐time polymerase chain reaction. The results demonstrated that cysteamine enhanced duodenal p21 and p27 mRNA expression at 2 hr by 2.9‐ and 4.6‐fold, respectively. In colonic mucosa iodoacetamide increased p21 by 4.2‐fold and p27 expression by 1.5‐fold. Expression of p16 changed in neither DU nor UC.Conclusions1) Expressions of p21 and p27 were significantly increased in rat duodenal and colonic mucosa in the early stages of DU and UC formation. 2) Thus, both p21 and p27 but not p16 seem to be a common mechanism involved in the pathogenesis of DU and UC.(This study was supported by Dept of Veterans Affairs, Medical Research Service Merit Reviews)

Gastric stem cells: an update.

Cells of the gastric mucosa undergo constant renewal, the rate depending on the health of the tissue (inflammation, ulceration, carcinogenesis). While much attention has been focused on the mechanism of mucosal damage and the pathogenesis of ulceration, there has recently been the recognition that elucidation of the nature of the gastric stem cell lineages as well as the regulators of phenotype expression of this system may yield considerable biological information as well as open the door to the identification of areas of therapeutic relevance. Chimeric and X-inactivation studies in mice and humans demonstrate that each region of the gastric mucosa is morphologically diverse (antrum is different to the fundus), with its own repertoire of cell types and glandular structures. The current evidence suggests that a single stem cell in every gastric gland indirectly gives rise to a clone of all differentiated cells, by production of committed progenitor cells. It is also this multipotential cell that produces new crypts by crypt fission, repairs entire crypts when damaged, and gives rise to the ulcer-associated cell lineage and gastric carcinomas. It is likely that this stem cell occupies a niche in the isthmus composed of mesenchymal cells and extracellular matrix factors, which regulates the function of the cell via mesenchymal-epithelial cross talk. The molecular events (IGF-signaling) that regulate the development of the gastric gland in the mice have begun to be understood. Ultimately, the identification of these pathways will play an important role in identifying new molecular targets for the treatment of gastric disease.

Preface

The 8th Taisho International Symposium on Gastroenterology was held in Shimoda, Japan, on 16–17 April 1999. Shimoda is the original home of the Taisho International Symposia, the first meeting of which was held 12 years ago, in 1987. Since then, these symposia have been held in Shimoda on three additional occasions. In May of 1997, the meeting's tenth anniversary was celebrated in Lansdowne, Virginia, USA. For this meeting, we invited approximately 100 Japanese doctors as well as six world-famous doctors from overseas. The contents of that meeting were published in a distinguished journal after strict peer review. This current meeting, however, has shifted toward a more 21st century orientation, and the organizers have been drawn from a younger generation. Here, we extend our cordial appreciation to the previous organizing committee, especially Professor Tadayoshi Takemoto, Professor Gregory L. Eastwood and Professor Kenzo Kobayashi, as well as Professor Andrzej S. Tarnawski, for their great dedication to these symposia. We should cherish the saying to ‘explore the old to understand the new’–‘onko-chisin’ in Japanese. The main themes of this symposium were ‘Mechanisms of mucosal damage and repair in the gastrointestinal tract’ and ‘Gastrointestinal carcino-genesis’, and nearly 100 papers on these subjects were presented and extensively discussed among the young Japanese doctors present, as well as by the invited speakers from all over the world. It was great to see young Japanese doctors raising many questions in English, which has been one of the goals for these symposia. The Proceedings of the 8th Taisho International Symposium on Gastroenterology have finally reached the stage of publication in Alimentary Pharmacology and Therapeutics. We cordially thank Professor Roy Pounder for his kind offer to publish the proceedings in this prestigious journal. We would like to express our sincere gratitude to all the staff engaged in the work of editing, reviewing and publishing for their tremendous efforts. Finally, we cordially thank Taisho Pharmaceutical for its great support to this symposium.

Experimental esophagitis induced by acid and pepsin in rabbits mimicking human reflux esophagitis

Background & Aims: The lack of appropriate animal models might explain the paucity of information on the mechanisms of mucosal damage and defense in reflux esophagitis. The aim of this study was to develop a model of esophagitis in rabbits mimicking human reflux esophagitis. Methods: New Zealand white rabbits underwent surgery for placement of a plastic tube into the cervical esophagus. Acidified pepsin (AP) was intermittently perfused for different periods. Esophageal injury was assessed by macroscopic and microscopic examination, including the cell proliferation immunohistochemical parameter mib1. Results: Rabbit losses (20%) were attributable mostly to postsurgical mortality and tube displacement. Perfusion of AP for 60 min/12 h or 45 min/12 h induced high-grade esophagitis by days 3 and 5, respectively, characterized by diffuse erosion/ulceration, inflammation, bleeding, and reactive epithelial changes. Perfusion of acidified pepsin for 60 min/day, especially at 30 min/12 h, induced low-grade esophagitis characterized by superficial epithelial loss, mild/absent inflammation, and epithelial reactive changes including increased cell proliferation, basal hyperplasia, and papillomatosis, which reached maximal expression by day 7. This perfusion regimen induced mucosal adaptation to damage. Conclusions: Different and highly reproducible esophageal mucosal lesions mimicking human reflux esophagitis can be induced in rabbits with repetitive acid and pepsin exposure. GASTROENTEROLOGY 1999;116:97-107

Commentary: Helicobacter pylori and Mechanisms of Mucosal Damage

Commentary: Helicobacter pylori and Mechanisms of Mucosal Damage

Quantitative Analysis and Immunohistochemical Studies on Small Intestinal Mucosa of Food-Sensitive Enteropathy

Quantitative analysis and immunohistochemical studies of small intestinal mucosa were performed to investigate the mechanism of mucosal damage in 10 patients with food-sensitive enteropathy. Jejunal biopsy specimens were taken before and after treatment and after clinical relapse following a challenge test. The low villous height of untreated patients normalized after introduction of an elimination diet but declined again to subnormal level after a challenge test. Several other types of cells were significantly increased in the untreated patients in comparison to controls. These included HLA-DR+ (DR+) CD4+ cells in the lamina propria and intraepithelial CD8+ cells. Moreover, those cell patterns, such as increased DR+ CD4+ cells and CD8+ cells, normalized with treatment but regressed to pretreatment levels when the patients were challenged. These findings suggest that activated CD4+ cells in the lamina propria of the small intestinal mucosa, probably by releasing cytokines, may play an important role in contributing to mucosal damage in patients with food-sensitive enteropathy.