Maintenance Of Mucosal Integrity Research Articles

Characterization of monoclonal antibodies raised to C-terminal peptides of pS2: A major trefoil peptide and motility factor expressed in adenocarcinomas and regions of mucosal injury

Two novel monoclonal antibodies, GE1 and GE2 raised against the C-terminal 31 and 28 amino acids of the estrogen-inducible trefoil peptide pS2, are described. Both antibodies are able to detect pS2 in formalin-fixed, paraffin-embedded tissues. Conditions are presented under which pS2 can be shown in cell lines by immunohistochemistry that has previously been problematic. The antibodies can specifically show the presence of pS2 in cell lysates by Western blotting and immunoprecipitation. In the form of an affinity column, the GEl monoclonal antibody can be used to purify pS2 from MCF-7 supernatants. The eluted peptide from the GEl affinity column shows a single band at 6,600 Da (predicted size for pS2) on Western blotting. These antibodies are valuable reagents in the analysis of the role of trefoil peptides in the maintenance of mucosal integrity, and may have applications in the assessment of pS2 expression in chronic gastrointestinal ulceration and adenocarcinomas that secrete pS2, where it may serve as a prognostic marker.

9 Growth factors and ulcerative gastrointestinal disease

A huge variety of peptides and cytokines are involved in the maintenance of mucosal integrity and in the inflammatory response at sites of ulceration. Most studies have focused on the effects of an individual factor in this complex process. However, it is becoming increasingly apparent that, to fully understand their importance in vivo, we should consider their function as part of a highly integrated system. It is also becoming clear that a relatively small number of common pathways are brought into play by the host in response to a wide variety of intestinal insults.

Effect of Sofalcone on Tyrosylprotein Sulfotransferase

1. Gastric mucus glycoproteins are actively involved in the maintenance of mucosal integrity and the impairment in their elaboration is often a prominent feature in gastric pathology. In this study, we investigated the effect of an antiulcer drug, sofalcone, on the activity of tyrosylprotein sulfotransferase enzyme involved in the secretion of proteins and glycoproteins in male 8 week old rats. 2. Using poly-Glu 6, Ala 3, Tyr 1 (EAY) as sulfate acceptor, and 3′phosphoadenosine 5′-phosphosulfate (PAPS) as sulfate donor the optimum Golgi TPST activity was obtained at pH 6.8, in presence of 0.5% Triton X-100, 20 mM MnCl 2, 50 mM NaF and 2 mM 5′-AMP. 3. Introduction of sofalcone to the reaction mixture led to the enhancement in TPST activity. The rate of stimulation was proportional to the drug concentration up to 30 μg, at which concentration, a 55% increase in TPST activity was attained. 4. The results attest further to the value of sofalcone as a potent mucosal strengthening agent, and suggest that the agent may promote mucin secretion via activation of tyrosine sulfation.

Protective effect of epidermal growth factor in an experimental model of colitis in rats

Background/Aims: The role of epidermal growth factor (EGF) in the maintenance of mucosal integrity in the lower gastrointestinal tract is unknown. The aim of this study was to determine the effect of EGF in experimental colitis. Methods: Colitis was induced with 2,4,6-trinitrobenzenesulfonic acid/ethanol enemas. Rats were pretreated with intraperitoneal administration of recombinant human EGF (600 μg/kg) or vehicle 1 hour before induction of colitis and daily thereafter until killed at 8 hours, 48 hours, and 1 week. A separate group received an identical dosage and administration of EGF or vehicle for 1 week with treatment initiated 24 hours after the induction of colitic. Colonic tissue was evaluated macroscopically, histologically, and for myeloperoxidase activity. Results: Pretreatment with EGF reduced microscopic erosions at 8 and 48 hours by 74% and 54%, respectively (P < 0.05). At 1 week, microscopic ulcerations and myeloperoxidase activity were reduced by 65% in the EGF-pretreated group (P < 0.05). No significant difference in macroscopic injury, histological damage, or myeloperoxidase activity was noted when EGF treatment was initiated after the induction of colitis. Conclusions: Systemic EGF administration reduces mucosal damage and inflammation in a trinitrobenzenesulfonic acid/ethanol model of colitis in rats through a mechanism involving mucosal protection.

Interaction of nitric oxide and salivary gland epidermal growth factor in the modulation of rat gastric mucosal integrity.

1. The interaction between endogenous nitric oxide (NO) and factors from the rat submandibular salivary gland such as epidermal growth factor (EGF) on gastric mucosal integrity in the rat has been investigated. 2. Bolus administration of the NO synthase inhibitor, NG nitro-L-arginine methyl ester (L-NAME; 6.25-50 mg kg-1, i.v.) to animals treated intraluminally with 0.15 N HCl resulted in a significant increase in the area of mucosal haemorrhagic damage at doses 12.5 and 50 mg kg-1. Concurrent administration of indomethacin (5 mg kg-1, i.v.) resulted in a significant haemorrhagic mucosal damage in response to L-NAME (12.5-50 mg kg-1). Administration of the highest dose of L-NAME resulted in an increase in histological damage to the rat gastric mucosa. 3. When compared to control animals, the extent of damage produced by L-NAME or L-NAME in combination with indomethacin was significantly exacerbated in rats which had been sialoadenectomized (SALX) by removal of the submandibular salivary glands. The mucosal damage in SALX rats was ameliorated by treatment with EGF (5 and 10 micrograms kg-1, i.v.). 4. L-NAME administration resulted in a small reduction of gastric mucosal blood flow as assessed by laser Doppler flowmetry (LDF). The reduction in LDF by 25 and 50 mg kg-1 L-NAME was significantly greater in SALX rats than in rats with intact salivary glands. Pretreatment of SALX rats with indomethacin did not augment this large decrease in LDF suggesting that endogenous prostanoids do not interact with NO and salivary factors in regulating mucosal microcirculation. 5. Mucosal NO biosynthesis as assessed by ['4C]-citrulline formation was reduced in SALX rats when compared to control animals. Pretreatment of SALX animals with parenterally-administered EGF(10 microg kg-1) was associated with an increase in [14C]-citrulline formation in the gastric mucosa to levels observed in control SALX rats.6. These data suggest that factors which originate from the salivary gland such as EGF interact with NO in the maintenance of mucosal integrity. The effects may be mediated at least in part by changes in gastric mucosal blood flow. Salivary glands and EGF may mediate these effects to some extent via changes in mucosal NO biosynthesis.

Effects of nonsteroidal anti-inflammatory drugs on cell proliferation in gastroduodenal mucosa. A review article

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on gastroduodenal mucosal proliferation remains somewhat controversial. Experiments in rats have shown that acute administration of NSAIDs inhibits cell proliferation in the gastric mucosa while chronic administration of NSAIDs stimulates cell proliferation in gastric fundic and duodenal mucosa but has no effect in the gastric antral mucosa. Studies in humans have demonstrated that NSAIDs stimulate cell proliferation in the gastroduodenal mucosa. The stimulatory effect may be a compensatory reaction to mucosal injury and represent one of the mechanisms of gastric and duodenal mucosal adaptation to continued NSAID exposure. NSAIDs inhibit cell proliferation in the gastric mucosa at the ulcer margin in both rats and humans. This effect may account for the epidemiologic findings of delayed ulcer healing in patients taking long-term NSAIDs therapy. Since cell proliferation and renewal in gastroduodenal mucosa is one of the major mechanisms for the maintenance of mucosal integrity and enables repair of injury and ulcer healing, the effect of NSAIDs on cell proliferation in gastroduodenal mucosa is an important clinical issue.

Dorsal Nasal Cyst Formation: A Rare Complication of Cosmetic Rhinoplasty

A dorsal nasal cyst is a rare complication of cosmetic rhinoplasty. The cause of this complication is unknown; however, entrapment of nasal mucosa and subsequent growth through osteotomy sites are thought to be the basis for formation of these masses. We describe two patients with these dorsal nasal cysts and provide a review of the English-language literature. The maintenance of mucosal integrity together with the meticulous removal of debris from the operative site may prevent postrhinoplasty nasal cysts.

Physiology and pharmacology of prostaglandins.

Prostaglandins (PGs) are products of polyunsaturated acid metabolism, particularly arachidonic acid (AA) released from membrane phospholipids by the action of phospholipase A2 in response to a variety of physical, chemical, and neurohormonal factors. AA is rapidly metabolized to oxygenated products by two distinct enzymatic pathways: cyclooxygenase and lipoxygenase. The intermediate cyclooxygenase products are converted to primary PGs, while the lipoxygenase products are converted to leukotrienes. The generation of various cyclooxygenase products varies from tissue to tissue. Aspirin and related antiinflammatory drugs reduce tissue biosynthesis of all cyclooxygenase products; their therapeutic effects and side effects parallel the inhibition of cyclooxygenase. Exogenous PGs exhibit a broad spectrum of effects. PGs of the E series and PGI2 are generated by the endothelium and the vessel wall to maintain the microcirculation and to counteract the vasoconstrictive and proaggregatory actions of thromboxane A2 (TXA2). Exogenous PGs of the E and I series are potent vasodilators in various vascular beds, and result in decreased systemic blood pressure and reflex stimulation of heart rate. PGEs and PGI2 increase renal blood flow and provoke diuresis and natriuresis, partly by modulating the renin-angiotensin-aldosterone system. PGFs contract the bronchial and gut muscle, while PGEs and PGI2 have opposite effects. PGEs and PGFs, but not PGI2, cause a strong contraction of the uterine muscle, hence their undesirable uterotonic effects. PGEs relax bronchial muscle, whereas PGFs cause bronchoconstriction; their imbalance may contribute to the high bronchial tone in bronchial asthma. PGs of the E and I series and TXA2 are generated by the gastrointestinal mucosa and released into the lumen upon neural or hormonal stimulation; they probably participate in the maintenance of mucosal integrity and microcirculation. Exogenous PGs of the E and I series inhibit gastric acid secretion and stimulate alkaline secretion while increasing mucosal blood flow. All PGs, including those noninhibitory for acid secretion, are cytoprotective against various ulcerogens and necrotizing agents. The classic PGs constitute only a small fraction of biologically active products of AA metabolism, and recent studies on the lipoxygenase products emphasize their biological activity and involvement in a variety of pathological conditions.

Prostaglandins in pathophysiology of peptic ulcer disease.

Gastric ulcer (GU) and duodenal ulcer (DU) occur as a result of the imbalance between aggressive and defensive factors affecting the gastroduodenal mucosa. Prostaglandins (PG) of E and I series are generated throughout the gastrointestinal tract, particularly in the gastric and duodenal mucosa, and are released into the gut lumen upon vagal and hormonal stimulation. Endogenous PGs may be involved in the maintenance of mucosal integrity, control of mucosal blood flow and protection against potentially noxious agents. Gastric mucosa of ulcer patients tends to generate smaller amounts of PGs of E and I series and exhibits a reduced ratio of PG to thromboxane generation, which suggests that the deficiency of protective PG may play a role in the pathogenesis of peptic ulcer. Suppression of mucosal generation of PGs by non-steroidal anti-inflammatory compounds causes mucosal damage and increases the risk of the formation or exacerbation of peptic ulcer. Exogenous PGE and its stable analogs have been tested successfully in the treatment of GU and DU and the results so far obtained indicate that these agents significantly increase the ulcer healing rate. Certain anti-ulcer drugs such as carbenoxolone, sucralfate, colloidal bismuth and cimetidine appear to exert their beneficial effects on ulcer healing by mediating the release of endogenous PGs.

Gastric mucosal defence mechanisms.

Gastric mucosa has a particular ability to resist acid/peptic digestion. The nature of the presumed barrier to acid and pepsin has been elusive but recent work suggests that a combination of mechanisms is likely to be involved. Amongst these the mucus gel layer combined with secretion of alkali by the surface epithelium is likely to form a first line defence. The demonstration of a pH gradient within the mucus gel layer supports such a hypothesis. Agents which damage the mucosa such as aspirin and bile salts inhibit the maintenance of the pH gradient allowing the luminal surface of the epithelium to become more acid. Prostaglandins enhance this pH gradient, an observation which may be relevant to the protective properties of prostaglandins. This alkaline zone can be compromised by high levels of luminal acidity and it thus has a limited capacity to prevent acid reaching the mucosa. The local microcirculation is of importance in maintaining surface epithelial metabolic integrity and interstitial fluid bicarbonate may be important in neutralising any acid which may reach the subepithelial layers. This may in part explain the ability of an actively secreting gastric epithelium to resist damage to a greater extent than a resting mucosa. Recent exciting work has focussed on the ability of gastric epithelium to reform by a process which has been termed restitution, after acute mucosal damage. This process appears to be rapid and occurs within an hour or so. Repeated rapid repair may be a common occurrence in the maintenance of mucosal integrity. Finally, it has been proposed that a hydrophobic property of surface epithelium in the stomach may be relevant to mucosal protection.