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TFF2) and The 516 Gut 1999;45:516–522 Metabolism of oral trefoil factor 2 (TFF2) and the eVect of oral and parenteral TFF2 on gastric and Gut: first published as 10.1136/gut.45.4.516 on 1 October 1999. Downloaded from duodenal ulcer healing in the rat S S Poulsen, J Thulesen, L Christensen, E Nexø, L Thim Abstract which six cysteine residues form three disul- Background—Trefoil factors (TFFs) are phide bonds.1–3 They are produced in exocrine peptides produced by mucus-secreting usually mucus-secreting cells in the gastro- cells in the gastrointestinal tract. A func- intestinal tract,4–8 and there is increasing tional association between these peptides evidence that they are important in the mainte- and mucus, leading to stabilisation of the nance of the integrity of the gastric and intesti- viscoelastic gel overlying the epithelia, has nal mucosa. The peptides are extremely resist- been suggested. Both oral and parenteral ant to degradation by proteases9; they are administration of the peptides increase co-secreted with mucus and are supposed to be the resistance of the gastric mucosa. involved in oligomerisation of mucin polysac- Aim—To study the eVect in rats of oral and charide molecules, processes that lead to the parenteral porcine trefoil factor 2 formation of a gel-like high viscosity mucus.10–12 (pTFF2) on the healing of gastric and Today the mammalian TFF family includes duodenal ulcerations and to clarify the three peptides: TFF1, also named breast distribution and metabolism of orally cancer associated peptide or pS2,6 and TFF2, administered pTFF2 in the gastro- or spasmolytic polypeptide (SP), are both 4 intestinal tract. present mainly in the stomach ; TFF3, or —Gastric ulcers were induced in intestinal trefoil factor (ITF), is present mainly Methods 7813 female Sprague-Dawley rats by indo- in the intestinal goblet cells. methacin and duodenal ulcers by mer- To elucidate the role of the TFFs in the captamine. The rats were treated for up to gastrointestinal tract, their ability to protect the seven days with oral or subcutaneous gastric mucosa against experimental ulceration 14 pTFF2. Ulcer size after treatment was has been investigated. Babyatsky et al showed assessed by stereomicroscopy after whole that oral human TFF2 (hTFF2) and rat TFF3 http://gut.bmj.com/ mount staining with periodic acid-SchiV (rTFF3) given before ulcer induction pro- stain. 125I-labelled pTFF2 was given orally tected against both ethanol induced and indomethacin induced gastric injury. Playford to rats, and tissues were investigated by 15 gamma counting of samples and by auto- et al surprisingly found that even small doses radiography of paraYn embedded sec- of hTFF2 given subcutaneously to rats pre- tions. vented the formation of indomethacin induced gastric ulceration, indicating that TFF2 also Results—pTFF2 accelerated gastric ulcer Department of healing after both oral and subcutaneous can exert its eVect in an endocrine manner, on September 28, 2021 by guest. Protected copyright. Medical Anatomy B, administration. Duodenal ulcers were ag- which may imply the presence of a receptor for University of gravated by both treatments. After oral the peptides. In fact, a putative receptor for Copenhagen, 16 17 administration of 125I-pTFF2, intact pep- TFF3 has recently been characterised, and Copenhagen, Denmark it has been shown that parenterally adminis- S S Poulsen tide was recovered from the superficial J Thulesen part of the mucus layer in the stomach; it tered porcine TFF2 (pTFF2) is taken up by L Christensen passed through the small intestine but was mucus-secreting cells in the stomach and degraded in the caecum. Only a minor secreted into the mucus layer in the same way Department of Clinical as endogenous TFF2.18 Biochemistry, KH part of the labelled pTFF2 entered the 14 colon and was excreted in the faeces. Most In the study of Babyatsky et al, there was no Århus University or very little eVect of intraperitoneally adminis- Hospital, Århus, of the label was excreted in the urine. tered peptide, and Playford 15 found that Denmark —Oral as well as parenteral et al Conclusions oral hTFF2 had no eVect. Thus there are con- E Nexø pTFF2 accelerates the healing of gastric flicting results with respect to the protective ulceration and aggravates duodenal ul- Department of Protein eVect on the gastric mucosa of both oral and cers. Oral pTFF2 binds to the mucus layer Chemistry, Novo systemic TFF. of the stomach and the small intestine but Nordisk A/S, In this study we compared oral and systemic Copenhagen, Denmark does not reach the colonic mucosa. pTFF2 not with respect to the protective L Thim (Gut 1999;45:516–522) eVect, but with respect to the healing of gastric Correspondence to: Keywords: trefoil factors; spasmolytic polypeptide; and duodenal ulcerations, and we describe the Dr S S Poulsen, Institute of ulcer healing; gastric ulcer; duodenal ulcer; rat metabolism and distribution in the gastro- Medical Anatomy B, University of Copenhagen, intestinal tract of orally administered pTFF2 in The Panum Institute, 3 Blegdamsvej, 2200 The trefoil factors (TFFs) constitute a family Copenhagen N, Denmark. of mucin associated gastrointestinal peptides Abbreviations used in this paper: TFF, trefoil Accepted for publication that create a characteristic three leafed struc- factor; pTFF, porcine TFF; hTFF, human TFF; rTFF, 30 March 1999 ture because of the existence of domains in rat TFF. EVect of TFF2 in the rat 517 were fasted for five hours in raised mesh bottom cages and thereafter given 30 mg/kg mercaptamine hydrochloride (Sigma Chemical Gut: first published as 10.1136/gut.45.4.516 on 1 October 1999. Downloaded from Co, St Louis, Missouri, USA) subcutaneously. Gastric ulceration was induced by means of indomethacin and restraint.20 Rats were fasted for 12 hours and given indomethacin 20 mg/kg subcutaneously. They were restrained by being placed in Bolmann cages for three hours. The rats were killed after being anaesthetised with barbiturate (Brietal, methohexital; 50 mg/kg intraperitoneally; Eli Lilly, Indiana, USA). The stomach and duodenum were removed, the distal end of the oesophagus and the duodenum were ligated, and the organs were fixed by intraluminal injection of 10% formalin for 10 minutes. Thereafter the stomach was opened along the greater curva- ture and suspended on a polyethylene plate and fixed for a further 24 h. The specimens were Figure 1 Rat stomach with indomethacin induced ulcers after whole mount staining with periodic acid-SchiV. The specimen has been photographed with a Wild photomacroscope. then flushed with water and stained as whole The borderline of the rumen is in the upper part of the photograph. The gastro-oesophageal mounts with periodic acid-SchiV (PAS).21 After junction is indicated by a large arrow and the ulcers are seen as well defined white areas × staining they were rinsed with tap water and (small arrows). Original magnification 4. stored in 70% ethanol. The surface of the gas- order to elucidate the possible role of oral tric and duodenal mucosa, immersed in 70% TFFs in gastrointestinal disorders. ethanol, was investigated and photographed We report that pTFF2 accelerates gastric with a Wild photomacroscope (fig 1). Determi- ulcer healing after both oral and subcutaneous nation of the number and size of the ulcers was administration. Only very small doses are nec- performed using an image analysis program essary to obtain an eVect of oral treatment. (NIH Image 1.59) run on a Power Macintosh Surprisingly, duodenal ulcers are aggravated by (8500/120) computer with a high resolution both treatment regimens. Orally administrated camera (Hamamatsu C2400, Hamamatsu pTFF2 binds in the mucus layer of the stomach Photonics KK, Hamamatsu, Japan). and also in the intestine. It seems to be degraded in the caecum, and only very small ULCER HEALING amounts enter the colon. Gastric and duodenal ulceration was induced as described above. Treatment was not initi- http://gut.bmj.com/ Materials and methods ated until 48 hours after ulcer induction to ULCER INDUCTION make sure that ulceration had developed fully Female Sprague-Dawley rats weighing 180– at the onset of treatment. 200 g were used throughout the study. They were fed a standard laboratory diet (Altromin Oral treatment with pTFF2 1314, Lage, Germany). The study was ap- Gastric ulceration was induced with indometh- proved by the Danish National Committee for acin in 14 rats. Seven were given pTFF2 in the on September 28, 2021 by guest. Protected copyright. Animal Studies. drinking water (2 mg pTFF2 in 20 ml water Duodenal ulceration was induced with per rat per day). They drank all the water, and mercaptamine.19 For ulcer induction, the rats to ensure that they were not dehydrated, they were allowed to drink water ad libitum for one * hour every morning. Controls received tap water following the same schedule. The rats were killed after seven days of treatment (nine ABControls pTFF2 days after ulcer induction). Duodenal ulceration was induced in 32 rats. 600 Half of them received pTFF2, 3 mg in 20 ml water per rat per day as described above, and 20 ) ) 2 the rest received tap water. The rats were 2 divided into groups of eight and killed after one 400 15 or three days of treatment. * 10 Subcutaneous treatment with pTFF2 Gastric ulceration was induced with indometh- 200 acin in 84 rats. The rats were divided into four 5 groups of 21. One group received 50 µg/kg Ulcerated area (mm Ulcerated area (mm pTFF2 in 1 ml saline subcutaneously three 0 0 times a day, one received 1 mg/kg three times a 7 days 1 day 3 days day, one served as controls which were given 1 Figure 2 (A) The eVect of oral treatment with porcine trefoil factor 2 (pTFF2) on the ml saline × 3, and one served as positive healing of gastric ulceration expressed as the total area of ulceration in mm2 in the stomach controls for the eVect of treatment and received after seven days of treatment (mean (SD), n = 7).
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