Effects of a novel histamine H2-receptor antagonist, lafutidine, on the mucus barrier of human gastric mucosa

BACKGROUND AND AIM: Lafutidine is a novel histamine H(2)-receptor antagonist used primarily as an antisecretory agent in Japan. Previous human studies have not assessed its gastroprotective effects. The purpose of the present study was to determine the effects of lafutidine on the human gastric mucus layer using both histological and biochemical methods. METHODS: Of the 14 patients scheduled for gastrectomy who consented to participate, seven were given 14 days of lafutidine 20 mg/day (lafutidine group) and the others received no medication (control group). The surface mucus gel layer in Carnoy-fixed tissue sections was examined immunohistochemically. Both the thickness of the mucus layer and its mucin content were measured in gastric corpus mucosa. RESULTS: There was no detectable difference between the groups in the grade of gastritis or the immunohistochemical staining characteristics. The laminated structure of the surface mucus gel layer was retained after administration of lafutidine and it was thicker than the layer in the control group. The surface layer in the lafutidine group had three-fold more mucin than that in the control group. There was no difference between the two groups in the mucin content of the deep mucosa. CONCLUSION: Lafutidine, given at clinical dosages, not only inhibits acid secretion but also strengthens the mucus barrier of the human gastric mucosa.     

Effects of baicalin and wogonin on mucin release from cultured airway epithelial cells

Scutellaria baicalensis Georgi has been used for the treatment of diverse chronic inflammatory diseases including respiratory disease in oriental medicine and its major components - baicalin, baicalein and wogonin - were reported to have various biological effects. This study investigated whether baicalin, baicalein and wogonin affect basal and ATP-induced mucin release from cultured airway epithelial cells. Confluent primary hamster tracheal surface epithelial (HTSE) cells were metabolically radiolabeled using (3)H-glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of each agent to assess the effects on (3)H-mucin release. The results were as follows: (1) Baicalein did not affect both basal and ATP-induced mucin release significantly. (2) Baicalin and wogonin increased basal mucin release at the highest concentrations (10(-3) m). (3) However, baicalin and wogonin significantly inhibited ATP-induced mucin release. It is concluded that baicalin and wogonin can slightly increase basal mucin release whereas they can inhibit ATP-induced mucin release, by directly acting on airway mucin-secreting cells. It is suggested that baicalin and wogonin be further investigated for the possible use as mucoregulators during the treatment of chronic airway diseases.     

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells

MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4alpha, and a membrane-bound growth factor-like subunit, MUC4beta. MUC4 mRNA contains unique 5' and 3' coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7-19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer. To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is comparable with that of wild-type MUC4 (930 kDa) but represents only 10% of VNTR. Stable ectopic expression of mini-MUC4 in two human pancreatic cancer cell lines, Panc1 and MiaPaCa, showed that MUC4 minigene expression follows a biosynthesis and localisation pattern similar to the wild-type MUC4. Expression of MUC4 resulted in increased growth, motility, and invasiveness of the pancreatic cancer cells in vitro. Ultra-structural examination of MUC4-transfected cells showed the presence of increased number and size of mitochondria. The MUC4-expressing cells also demonstrated an enhanced tumorigenicity in an orthotopic xenograft nude mice model, further supporting a direct role of MUC4 in inducing the cancer properties. In conclusion, our results suggest that MUC4 promotes tumorigenicity and is directly involved in growth and survival of the cancer cells.     

Depleted intestinal goblet cells and severe pathological changes in SCID mice infected with Heligmosomoides polygyrus

To determine the role of T cells and mast cells in intestinal pathology and immune expulsion of intestinal nematodes, worm burdens, goblet cell responses and villus structures were analysed in T- and B-cell-deficient severe combined immunodeficiency (SCID) mice, athymic nu/nu mice and mast cell deficient W/W^v mice after infection with the nematode Heligmosomoides polygyrus. SCID and nu/nu mice showed significantly higher worm burdens at week 9 post-infection compared with the wild-type controls. SCID and nu/nu mice showed compromised goblet cell hyperplasia and/or Muc 2 expression, indicating that both events are T-cell dependant. On the other hand, the SCID mice showed increased pathology (villus atrophy and crypt hyperplasia) and increased numbers of proliferating cell nuclear antigen positive cells compared to the wild-type controls. W/W^v mice, conversely, were able to expel the worms normally, had normal goblet cell hyperplasia, and did not demonstrate the changes in mucosal architecture seen in SCID mice, confirming that a normal mast cell response is not necessarily required for these changes. These results suggest that a functional T-cell response, but not a mast cell response, is necessary for anti-parasite responses, goblet cell function, and maintaining normal mucosal architecture.     

Gefarnate increases PAS positive cell density in rabbit conjunctiva

AIMS—The effects of three drugs for the treatment of gastritis and gastric ulcer—gefarnate, ecabet sodium, and troxipide—on periodic acid Schiff (PAS) positive cell density in rabbit conjunctiva in vivo were investigated.
METHODS—Eye drops containing gefarnate (0.1%, 1%), ecabet sodium (0.1%, 1%), or troxipide (0.1%, 1%) were instilled in both eyes of rabbits, six times a day for 7 days. On the eighth day, filter paper was gently pressed on the bulbar and palpebral conjunctiva, and impression cytology was performed with PAS staining. Three points in each specimen were selected randomly, and PAS stained cells were counted.
RESULTS—The instillation of gefarnate increased PAS positive cell density significantly at the concentration of 1% (p <0.05). In contrast, instillation of ecabet sodium or troxipide failed to change PAS positive cell density.
CONCLUSIONS—These results demonstrated that gefarnate stimulates PAS positive cell density in rabbit conjunctiva.

Keywords: gefarnate; goblet cell; mucin; conjunctiva; rabbit     

Preclinical evaluation of copper-67 labelled anti-MUC1 mutin antibody C595 for therapeutic use in bladder cancer

Transitional cell carcinoma of the bladder is the fifth commonest cause of death from cancer in men in the United Kingdom. Most patients present early with superficial disease, though with current treatment up to 20% progress to invasive disease, which has a poor prognosis. Better local treatments are required to limit this tumour progression. The ease of access to the bladder via a catheter provides the ideal opportunity for antibody (Ab) targeted therapy. We have previously shown that indium-111 labelled anti-MUCI mucin Ab C595 selectively localises to bladder tumours after intravesical administration. We have selected copper-67 as an alternative radiolabel with suitable physical characteristics for radioimmunotherapy. This communication demonstrates that C595 can be reproducibly labelled with⁶⁷Cu and that the radioimmunoconjugate is both stable and maintains high immunoreactivity. Pilot studies on cystectomy specimens in a novel ex vivo system and in one patient confirmed the ability of this conjugate to localise to tumour after intravesical administration. On the basis of these studies we are now in a position to study the intravesical administration of⁶⁷Cu-labelled C595 in patients with bladder cancer with a view to a therapeutic trial.     

Intracytoplasmic lumina–a useful diagnostic feature of adenocarcinomas

The monoclonal antibody NCRC-11, which has epithelial membrane antigen (EMA)-like immunoreactivity, was used to identify intracytoplasmic lumina in a series of 105 adenocarcinomas from various sites and in 283 breast carcinomas; 55% of the non-breast carcinomas and all breast carcinomas except one of spindle cell type contained intracytoplasmic lumina. The highest frequency (16.4% of tumour cells) was found in invasive lobular carcinoma of the breast. The use of antibodies with EMA reactivity is advocated in the routine investigation of metastatic and undifferentiated tumours.     

Thyroglobulin in human thyroid follicles with acid mucin.

The minority of human thyroid follicles that contain acid mucin are often grouped in the C-cell area of the gland, and are lined by abundant C cells. They are thought to be derived from the ultimobranchial contribution to the thyroid gland. This study demonstrates the presence of thyroglobulin reactive follicular cells and colloid as well as calcitonin and CGRP in these ultimobranchial-related thyroid follicles. These findings add further support to the belief that the ultimobranchial body is a source of at least some C cells and follicular cells, and support the view that thyroid mixed medullary follicular neoplasia may originate from an ultimobranchial stem cell line.     

Scanning Microscopy of Colonic Mucin during Carcinogenesis: Is It Clinically Applicable?

The integrity of the colonic mucin layer has been reported to be altered during carcinogenesis in both humans and rodents. Prior to attempting scanning microscopic techniques on colonic mucosa of patients at high risk to develop colorectal cancer, these procedures were performed on colonic mucosa from rats with chemically induced colon cancers. Substantial technical difficulties in preparation and serious subjectivity in interpretation of the scanning micrographs were encountered. The major technical problem was the unpredictable retention of the mucin layer upon both normal and cancerous mucosae. Visual interpretation of the integrity or disruption of the mucin layer with the scanning electron microscope revealed variable fenestration and fraying of the mucin in both normal and cancerous colons. Our findings suggest that scanning electron microscopy of colonic mucin may not be a reliable screening procedure for (pre)cancerous changes in human colonic mucosae.     

Breast epithelial antigen levels and breast tumor antigen content

The relationship between the primary tumor expression of a breast epithelial antigen, called non-penetrating glycoprotein (NPGP) or breast epithelial mucin, and the same patient's serum level of this antigen at the time of relapse was studied in 23 cases. The expression of NPGP on breast tumors was measured by immunoperoxidase staining using monoclonal antibody Mc5, and quantitated by a histopathological index created for this purpose. Serum levels were measured by a competitive RIA using the same monoclonal antibody. An inverse correlation between these parameters was found, such that tumors having high NPGP levels in serum had a low index, while low NPGP serum levels had a high index. These results show that cellular events in breast tumors could participate in determining NPGP serum levels in breast cancer.