Surface Epithelial Cell Damage Research Articles

Ulcerative Colitis with Subsequent Development of Collagenous Colitis: Evolution or Incident

Purpose: Collagenous colitis (CC) is a subclass of microscopic colitis. It has a peak incidence of approximately 25-30 cases per 100,000 in women over the age fifty. Medications, luminal toxins, infections, bile acids, nitric oxide and genetics are etiological contribution. Moreover, autoimmune conditions are reported associations with CC. Most common presentation is watery, non-bloody, chronic diarrhea with normal endoscopic findings. Only one case has been reported of ulcerative colitis (UC) with subsequent development of CC. We describe a case of quiescent UC with symptoms of watery, non-bloody diarrhea; ensuing endoscopic and histologic examinations were consistent with CC. Case Description: The patient is a 72 year old woman with long standing history of UC, which had been in remission over the past few years. Most recently, she developed non-bloody, watery diarrhea without additional symptoms. Her medical history is significant for Graves disease, treatment-induced hypothyroidism, and UC. Medications include Levothyroxine and daily multi-vitamin supplement. No significant findings were observed on the physical exam. Subsequent endoscopic mucosal evaluation was unremarkable. Histological evaluation revealed quiescent colitis, and a subepithelial collagen band with surface epithelial cell damage. Discussion: Evolution of ulcerative colitis to CC seems unlikely given the fibrotic tissue only deposits under the surface epithelium. This pattern of peculiar deposition is seen elsewhere in the autoimmune conditions of the kidney. Similar to pattern of collagen deposition in CC, early periglomerular deposits end up with scarring. Perhaps an autoimmune process is paramount in the development of CC.Figure. 10: x Trichrome Stain. Quiescent ulcerative colitis with marked thickened subepithelial collagen layer (collagenous colitis).

Cathelicidin Mediates Innate Intestinal Defense against Colonization with Epithelial Adherent Bacterial Pathogens

Cathelicidin-related antimicrobial peptide (mCRAMP), the sole murine cathelicidin, is encoded by the gene Cnlp. We show that mCRAMP expression in the intestinal tract is largely restricted to surface epithelial cells in the colon. Synthetic mCRAMP had antimicrobial activity against the murine enteric pathogen Citrobacter rodentium, which like the related clinically important human pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli, adheres to the apical membrane of intestinal epithelial cells. Colon epithelial cell extracts from Cnlp+/+ mice had significantly greater antimicrobial activity against C. rodentium than those of mutant Cnlp-/- mice that lack mCRAMP. Cnlp-/- mice developed significantly greater colon surface and crypt epithelial cell colonization, surface epithelial cell damage, and systemic dissemination of infection than Cnlp+/+ mice after oral infection with C. rodentium. Moreover, Cnlp+/+ mice were protected from oral infections with C. rodentium inocula that infected the majority of Cnlp-/- mice. These results establish cathelicidin as an important component of innate antimicrobial defense in the colon.

Gastric Mucosal Protection Induced by Restraint and Water-Immersion Stress in Rats

We found that the gastric mucosal lesion induced by 60% ethanol containing 150 mM HCI was reduced by pre-loading the rat with restraint and water-immersion stress (22°C). The resistance to ethanol injury was maximal in 1-hr stress loaded rats and gradually decreased with increasing time of stress (2–6 hr). The protective effect of stress was markedly decreased by subdiaphragmatic truncal vagotomy, and electrical stimulation of vagal nerves afforded similar protection as observed after stress. In contrast pretreatment with atropine markedly reduced ethanol injury in both the control and 1 hr stress-loaded rats. One-hour stress produced surface epithelial cell damage in sham vagotomized rats, but the surface cells were almost intact in vagotomized rats. Pretreatment with indomethacin significantly mitigated the protective effect of stress against ethanol injury. However, the level of mucosal prostaglandin E2 was not changed 1 hr after stress, and it tended to decrease 6 hr after stress. Pretreatments with 1-hr stress and vagal stimulation weakly reduced localized staining of gastric mucosa with gentian violet. We conclude that adaptive protection can be achieved by restraint and water-immersion stress.

Gastric surface epithelial cell damage induced by restraint and water-immersion stress in rats. Protective effects of 16,16-dimethyl-prostaglandin E2.

The time course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22 degrees C) in rats was examined, and the prophylactic effects on it of 16,16-dimethyl-prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole, and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 h after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3 and 30 micrograms/kg), papaverine (100 mg/kg), and atropine (1 mg/kg) protected the surface cells against stress-induced (1 h) damage, and inhibited visible lesion formation after 4 h stress. Timoprazole (30 mg/kg s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. DmPGE2, papaverine, and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. DmPGE2, timoprazole, and atropine, but not papaverine, inhibited acid secretion in stress conditions. These results indicated that stress induced damage to the gastric mucosa within 1 h due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.

Effects of 16,16-Dimethyl Prostaglandin E2 on Surface Epithelial Cell Damage in the Rat Stomach Induced by Vagal Nerve Stimulation

The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on gastric surface epithelial cell (SEC) damage induced by vagal nerve stimulation (VS) in urethane-anesthetized rats was studied using scanning electron microscopy. VS (1.25-10 Hz, 0.2 mA, 2 msec, 10 min) resulted in a graded increase in the SEC damage, increased gastric contractions, increased gastric acid secretion, and a decrease in heart rate. Pretreatment with dmPGE2 (0.3-30 μg/kg, s.c.) significantly protected the SEC from VS-induced damage, inhibited the increase in gastric contractions and acid secretion, but had no influence on the decrease in heart rate. Atropine (1 mg/kg, s.c.) also protected the SEC from VS-induced damage and inhibited the alterations in response to VS. Timoprazole (30 mg/kg, s.c.) had no protective effects on SEC from VS-induced damage, no effect on increased gastric contractions and heart rate, but did inhibit the increase in gastric acid secretion, in response to VS. These results suggest that: (A) VS-induced SEC damage was caused by increased gastric contractions and not by increased gastric acid secretion, and (B) dmPGE2 protects against SEC damage by inhibiting gastric contractions.

Effects of 16,16-dimethyl prostaglandin E2 on surface epithelial cell damage in the rat stomach induced by vagal nerve stimulation.

The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on gastric surface epithelial cell (SEC) damage induced by vagal nerve stimulation (VS) in urethane-anesthetized rats was studied using scanning electron microscopy. VS (1.25-10 Hz, 0.2 mA, 2 msec, 10 min) resulted in a graded increase in the SEC damage, increased gastric contractions, increased gastric acid secretion, and a decrease in heart rate. Pretreatment with dmPGE2 (0.3-30 micrograms/kg, s.c.) significantly protected the SEC from VS-induced damage, inhibited the increase in gastric contractions and acid secretion, but had no influence on the decrease in heart rate. Atropine (1 mg/kg, s.c.) also protected the SEC from VS-induced damage and inhibited the alterations in response to VS. Timoprazole (30 mg/kg, s.c.) had no protective effects on SEC from VS-induced damage, no effect on increased gastric contractions and heart rate, but did inhibit the increase in gastric acid secretion, in response to VS. These results suggest that: VS-induced SEC damage was caused by increased gastric contractions and not by increased gastric acid secretion, and dmPGE2 protects against SEC damage by inhibiting gastric contractions.

Effects of 16,16-Dimethyl Prostaglandin E2 on Surface Epithelial Cell Damage in the Rat Stomach Induced by Vagal Nerve Stimulation

The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on gastric surface epithelial cell (SEC) damage induced by vagal nerve stimulation (VS) in urethane-anesthetized rats was studied using scanning electron microscopy. VS (1.25–10 Hz, 0.2 mA, 2 msec, 10 min) resulted in a graded increase in the SEC damage, increased gastric contractions, increased gastric acid secretion, and a decrease in heart rate. Pretreatment with dmPGE2 (0.3–30 μg/kg, s.c.) significantly protected the SEC from VS-induced damage, inhibited the increase in gastric contractions and acid secretion, but had no influence on the decrease in heart rate. Atropine (1 mg/kg, s.c.) also protected the SEC from VS-induced damage and inhibited the alterations in response to VS. Timoprazole (30 mg/kg, s.c.) had no protective effects on SEC from VS-induced damage, no effect on increased gastric contractions and heart rate, but did inhibit the increase in gastric acid secretion, in response to VS. These results suggest that: (A) VS-induced SEC damage was caused by increased gastric contractions and not by increased gastric acid secretion, and (B) dmPGE2 protects against SEC damage by inhibiting gastric contractions.

Surface epithelial cell damage induced by restraint and water-immersion stress in rats effects of 16,16-dimethyl prostaglandin E2 on stress-induced gastric lesions.

The time-course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22 degrees C) in rats was examined, and the effects on it of 16,16-dimethyl prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 hr after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3, 30 micrograms/kg), papaverine (100 mg/kg) and atropine (1 mg/kg) protected the surface cells against stress (1 hr)-induced damage, and inhibited visible lesion formation after 4 hr stress. Timoprazole (30 mg/kg, s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. dmPGE2, papaverine and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. dmPGE2, timoprazole and atropine, but not papaverine, inhibited acid secretion in stress-conditions. These results indicated that stress induced damage to the gastric mucosa within 1 hr due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.

Surface Epithelial Cell Damage Induced by Restraint and Water-Immersion Stress in Rats Effects of 16,16-Dimethyl Prostaglandin E2 on Stress-Induced Gastric Lesions

The time-course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22°C) in rats was examined, and the effects on it of 16,16-dimethyl prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 hr after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3, 30 μg/kg), papaverine (100 mg/kg) and atropine (1 mg/kg) protected the surface cells against stress (1 hr)-induced damage, and inhibited visible lesion formation after 4 hr stress. Timoprazole (30 mg/kg, s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. dmPGE2, papaverine and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. dmPGE2, timoprazole and atropine, but not papaverine, inhibited acid secretion in stress-conditions. These results indicated that stress induced damage to the gastric mucosa within 1 hr due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.

Effect of 16,16-dimethyl prostaglandin E2 on gastric surface epithelial cell damage induced by 20% ethanol in rats.

Prostaglandins protect against the gross damage of gastric mucosa induced by 50-100% ethanol, but do not protect surface epithelial cells (SEC) from necrosis. Since this induced damage to SEC is so severe, we attempted to determine the effects of a prostaglandin on slightly induced SEC damage and gastric potential difference (PD) in response to low concentrations of ethanol. The necrotizing effects of graded concentrations of ethanol (10-50%) to SEC on the rat gastric mucosa were studied by scanning electron and light microscopy. Intragastric instillation of 20% ethanol (v/v, 1 ml/100 g body wt.) to pylorus-ligated rats for 10 min induced slight and reproducible SEC damage consisting mainly of the apical cell membrane erosion of SEC. Pretreatment with 16,16-dimethyl prostaglandin E2 (dmPGE2, 3 or 30 micrograms/kg, p.o. or s.c.) afforded protection of the SEC from 20% ethanol-induced damage. However, the cytoprotective effects of dmPGE2 were abolished when gastric contents were emptied prior to 20% ethanol instillation. Intragastric instillation of ethanol immediately reduced PD in a concentration-related manner. dmPGE2 (3 or 30 micrograms/kg, s.c.) had no effect on the reduction of gastric PD after 20% ethanol treatment and the recovery of reduced PD to normal levels. We conclude that dmPGE2 has no cytoprotective effect on 20% ethanol-induced SEC damage in rat gastric mucosa.

Effect of 16,16-Dimethyl Prostaglandin E2 on Gastric Surface Epithelial Cell Damage Induced by 20% Ethanol in Rats

Prostaglandins protect against the gross damage of gastric mucosa induced by 50–100% ethanol, but do not protect surface epithelial cells (SEC) from necrosis. Since this induced damage to SEC is so severe, we attempted to determine the effects of a prostaglandin on slightly induced SEC damage and gastric potential difference (PD) in response to low concentrations of ethanol. The necrotizing effects of graded concentrations of ethanol (10–50%) to SEC on the rat gastric mucosa were studied by scanning electron and light microscopy. Intragastric instillation of 20% ethanol (v/v, 1 ml/100 g body wt.) to pylorus-ligated rats for 10 min induced slight and reproducible SEC damage consisting mainly of the apical cell membrane erosion of SEC. Pretreatment with 16,16-dimethyl prostaglandin E2 (dmPGE2, 3 or 30 μg/kg, p.o. or s.c.) afforded protection of the SEC from 20% ethanol-induced damage. However, the cytoprotective effects of dmPGE2 were abolished when gastric contents were emptied prior to 20% ethanol instillation. Intragastric instillation of ethanol immediately reduced PD in a concentration-related manner. dmPGE2 (3 or 30 μg/kg, s.c.) had no effect on the reduction of gastric PD after 20% ethanol treatment and the recovery of reduced PD to normal levels. We conclude that dmPGE2 has no cytoprotective effect on 20% ethanol-induced SEC damage in rat gastric mucosa.

Protective effect of dicloguamine maleate (MN-1695) on HCl-induced gastric mucosal damage in rats--histologic studies

Effect of MN-1695, a new cytoprotective antiulcer agent, on 0.2 N HCl-induced gastric surface epithelial cell damage was investigated by optical and transmission electron microscopy in rats. Tissue examination after five minutes exposure to 0.2 N HCl showed extensive damage of the surface epithelial cells: dilatation of intercellular spaces including marked edema of lamina propria. It was found that MN-1695 (3 mg/kg) pretreatment prevented such 0.2 N HCl-induced damage of the surface epithelial cells, and it reduced the percentage of damaged mucosa, but not significantly.

Role of mucus in the repair of gastric epithelial damage in the rat: Inhibition of epithelial recovery by mucolytic agents

A role for mucus in providing a microenvironment over sites of gastric damage, which is conducive to reepithelialization, has been proposed. We tested this hypothesis by examining the effects of disruption of such mucus on the recovery of epithelial integrity after damage induced by 50% ethanol. Exposure of an ex vivo chambered gastric mucosa to topically applied 50% ethanol resulted in copious release of mucus, cellular debris, and plasma, which formed a continuous cap over the mucosal surface. Ethanol-induced gastric damage was accompanied by extensive surface epithelial cell damage and a marked decrease in transmucosal potential difference. During the 30 min after ethanol was removed from the chamber, the epithelium became reestablished and the potential difference gradually recovered to 94% of the level before ethanol treatment. However, if the mucolytic agents N-acetylcysteine (5%) or pepsin (0.5%) were added to the bathing solutions, the “mucoid cap” disintegrated and the recovery of potential difference was significantly retarded (recovering to only 51% and 52% of levels before ethanol treatment). Histologic evaluation confirmed that mucosae treated with either agent had significantly less (p < 0.005) intact epithelium at the end of the experiment. Removal of the mucoid cap with forceps caused a similar inhibition of the repair of the epithelium and the recovery of potential difference. Both mechanical and chemical (N-acetylcysteine) disruption of the mucoid cap resulted in a significant increase in the mucosal leakage of albumin and hemoglobin, supporting previous histologic evidence that the mucoid cap traps blood components over the damaged mucosa. These studies support the hypothesis that mucus released in response to topical application of an irritant plays an important role in the repair of epithelial damage through the process of restitution.

Role of mucus in the repair of gastric epithelial damage in the rat

Abstract A role for mucus in providing a microenvironment over sites of gastric damage, which is conducive to reepithelialization, has been proposed. We tested this hypothesis by examining the effects of disruption of such mucus on the recovery of epithelial integrity after damage induced by 50% ethanol. Exposure of an ex vivo chambered gastric mucosa to topically applied 50% ethanol resulted in copious release of mucus, cellular debris, and plasma, which formed a continuous over the mucosal surface. Ethanol-induced gastric damage was accompanied by extensive surface epithelial cell damage and a marked decrease in transmucosal potential difference. During the 30 min after ethanol was removed from the chamber, the epithelium became reestablished and the potential difference gradually recovered to 94% of the level before ethanol treatment. However, if the mucolytic agents N -acetylcysteine (5%) or pepsin (0.5%) were added to the bathing solutions, the cap disintegrated and the recovery of potential difference was significantly retarded (recovering to only 51% and 52% of levels before ethanol treatment). Histologic evaluation confirmed that mucosae treated with either agent had significantly less (p N -acetylcysteine) disruption of the mucoid resulted in a significant increase in the mucosal leakage of albumin and hemoglobin, supporting previous histologic evidence that the mucoid traps blood components over the damaged mucosa. These studies support the hypothesis that mucus released in response to topical application of an irritant plays an important role in the repair of epithelial damage through the process of restitution.

All that flattens is not “sprue”

The loss of normal villous architecture of the mucosa with some degree of flattening is a characteristic response of the small intestine to many forms of mucosal injury. Indeed, the height of the villi and the depth OF the crypts represent important markers for identifying morphologic abnormalities in the small intestine.* Nevertheless, little is known about the mechanisms of villous flattening or its reversal. Normally, a continuous, single layer of epithelium covers the villi and lines the crypts of the small intestine. Epithelial cell renewal occurs in the proliferative zone in the crypts where undifferentiated cells divide to provide a constant source of new cells which migrate toward the gut lumen and are extruded.’ Ci:ll migration time from crypt to villous tip in the human proximal small bowel is 5-6 days.” The paradigm of the flat villous lesion is that which occurs in gluten-sensitive enteropathy or celiac sprue.” The gluten-induced lesion results in damage to the surface epithelial cells, reducing their life span and increasing their shedding into the intestinal lumen. This results in eventual villous flattening with compensatory lengthening of the crypts.5-8 It is now well established that many disorders which result in surface epithelial cell damage lead to a lesion similar to that observed in gluten-sensitive enteropathy” (see Table 1). Some of these disorders are more prevalent in infancy and include: acute’” and chronic” infectious enteritis, cow’s milk protein sensitivity,12 soy protein enteropathy,13 eosinophilic gastroenteritis,“’ tropical sprue,l’ immunodeficiency syndromes,” collagenous or unclassified sprue,j7 malnutrition, most notably kwashiorkor,” bacterial overgrowth,” giardiasis,“” and dermatitis herpetiformis.” Villous shortening has also been reported in association with certain drugs” and radiation.23 Many of these conditions, unlike gluten-sensitive en-

Effect of glucagon on aspirin-induced gastric mucosal damage in man

The effect of glucagon on aspirin-induced damage to human gastric mucosa and its effect on gastric mucosal potential difference were studied in 29 healthy volunteers. Intragastric instillation of 600 mg of aspirin suspended in 100 ml of isotonic saline caused significant damage to 21 ± 3% of surface epithelial cells and a marked reduction in gastric potential difference within 15 min of aspirin instillation. Glucagon, 2 mg given intravenously, caused hyperglucagonemia, hypophosphatemia, hyperinsulinemia, increased blood glucose levels and gastric pH, as well as significant prolonged elevation of gastric potential difference. Glucagon injection given 15 min before aspirin instillation effectively prevented surface epithelial cell damage, decreasing percentage of damaged cells to 3.5%. Glucagon did not prevent the drop in gastric potential difference evoked by aspirin, but did, however, prevent potential difference from falling below base line values after aspirin. This study showed in man that glucagon protects gastric mucosa against aspirin damage and suggests possible therapeutic value in clinical situations requiring prevention of aspirin-induced gastric mucosal damage.