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PubMed1993

Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium.

alpha 1-Antitrypsin (alpha 1-AT) is an acute phase plasma protein predominantly derived from the liver which inhibits neutrophil elastase. Previous studies have suggested that alpha 1-AT is also expressed in human enterocytes because alpha 1-AT mRNA could be detected in human jejunum by RNA blot analysis, and alpha 1-AT synthesis could be detected in a human intestinal adenocarcinoma cell line Caco2, which spontaneously differentiates into villous-like enterocytes in tissue culture. To definitively determine that the alpha 1-AT gene is expressed in human enterocytes in vivo, we examined tissue slices of human jejunum and ileum by in situ hybridization. The results demonstrate specific hybridization to enterocytes from the bases to the tips of the villi. Although there was no hybridization to enterocytes in most of the crypt epithelium, there was intense specific hybridization in one region of the crypt. Double-label immunohistochemical studies showed that alpha 1-AT and lysozyme co-localized to this region, indicating that it represented Paneth cells. Finally, there was a marked increase in hybridization to alpha 1-AT mRNA in villous enterocytes and Paneth cells in Crohn's disease. The results of this study provide definitive evidence that alpha 1-AT is expressed in human jejunal and ileal enterocytes in vivo, and show that alpha 1-AT is also a product of Paneth cells. Together with the results of other studies, these data raise the possibility that alpha 1-AT detected in fecal alpha 1-AT clearance assays for diagnosing protein-losing enteropathies is predominantly derived from sloughed enterocytes.

Adenocarcinoma↗
PubMed2006

Reduced gene expression of intestinal alpha-defensins predicts diarrhea in a cohort of African adults.

BACKGROUND: Human defensin (HD) 5 and HD6, both Paneth cell alpha-defensins, contribute to the antimicrobial barrier against intestinal infection. We have previously demonstrated that levels of both HD5 and HD6 mRNA were reduced in adults living in urban Zambia, compared with those in adults living in London. The aim of the present study was to determine, during 2 years of follow-up, whether alpha-defensin expression in Zambian adults is related to susceptibility to diarrhea. METHODS: We analyzed intestinal biopsy samples from a longitudinal cohort study conducted in 83 Zambian adults by quantitative reverse-transcription polymerase chain reaction, Western blotting, immunohistochemistry, and in situ hybridization, and we measured the incidence of diarrhea. RESULTS: Levels of HD5 and HD6 mRNA in Paneth cells varied between participants, over time, and seasonally and were strongly correlated with mucosal architecture. Gene expression was almost exclusively restricted to Paneth cells. The median (interquartile range) HD5 mRNA level was 6.0 (5.6-6.7) log10 transcripts/microg of total RNA among 18 participants who experienced diarrhea within 2 months after biopsy-sample collection, compared with 6.8 (6.2-7.3) log10 transcripts/microg of total RNA among 94 participants who did not (P=.006). A similar observation was made for HD6. CONCLUSIONS: These data indicate that intestinal alpha-defensin expression is dynamic and seasonal and suggest that susceptibility to intestinal infection is related to alpha-defensin expression.

Adult↗
PubMed2001

Cellular localization of group IIA phospholipase A2 in rats.

It has been known that group II phospholipase A2 (PLA2) mRNA and protein are present in the homogenates of the spleen, lung, liver, and kidney in normal rats, but the cellular origin of this enzyme has not been yet identified. At present, five subtypes of group II PLA2 have been identified in mammals. Antibodies or mRNA probes previously used for detecting group II PLA2 need to be evaluated to identify the subtypes of group II PLA2. In this study we tried to identify group IIA PLA2-producing cells in normal rat tissues by in situ hybridization (ISH) using an almost full-length RNA probe for rat group IIA enzyme. Group IIA PLA2 mRNA was detected in megakaryocytes in the spleen and Paneth cells in the intestine by ISH. These cells were also immunopositive for an antibody raised against group IIA PLA(2) isolated from rat platelets. Group IIA PLA2 mRNA-positive cells were not detected in lung, liver, kidney, and pancreas. Under normal conditions, group IIA PLA2-producing cells are splenic megakaryocytes and intestinal Paneth cells in rats.

Animals↗
PubMed1985

A comparison of several fixative solutions for histochemical studies on human gastric mucosa.

The effects of different fixative solutions on the staining of polyanions and Paneth cell granules and on alkaline phosphatase activity were evaluated in surgical specimens of human gastric mucosa with areas of intestinal metaplasia, which were dehydrated and embedded with routine procedures. Alcohol-formol proved to be particularly advisable for studies on the epithelial mucins, buffered formol with cetylpyridinium chloride for the connective tissue polyanions and the fluid of Mota et al. (1956) for the mast cells. In areas of complete intestinal metaplasia, the Paneth cell granules were destroyed by acidic fixative mixtures and 95% ethanol; in the same areas, alkaline phosphatase activity was well demonstrated after fixation with formol, alcohol-formol, or 95% ethanol.

Adult↗
PubMed1996

Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships.

Defensins, a family of antimicrobial peptides isolated from several mammalian species, have a proposed functional role in innate host defense. In humans, certain defensin genes are expressed in phagocytic cells of hematopoietic origin, while others are expressed in Paneth cells, epithelial cells of the small intestine. In this study, we determined the chromosomal localization of the human defensin (HD) genes expressed in Paneth cells, HD-5 and HD-6. Analysis of a panel of human/hamster hybrids localized both HD-5 and HD-6 to chromosome 8. Southern blot analysis of DNA from cell lines that contain either chromosome 8 deletions or duplications further localized these two genes to 8p21-pter. Fluorescence in situ hybridization analysis of metaphase chromosomes using an HD-5 probe further supported the regional map assignment. Previous studies had localized the hematopoietic genes to chromosome 8p23, and the current work is consistent with both the enteric and the myeloid defensin genes being located at the same cytogenetic region of chromosome 8. In addition, the evolutionary relationships of this gene family were addressed using dot matrix sequence analysis. From this analysis, a model for the possible evolutionary history of the human defensin genes is proposed. According to this model, an early duplication of a primordial defensin gene yielded the ancestral genes of present day HD-5 and HD-6. The model further suggests that a subsequent unequal meiotic crossover event had generated an additional gene, comprised of a hybrid of sequences from the two parental genes, and that this hybrid gene then served as the ancestor to present day hematopoietic defensin genes.

Amino Acid Sequence↗
PubMed2005

Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease.

BACKGROUND AND AIMS: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation. PATIENTS AND METHODS: Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor kappaB (NFkappaB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo. RESULTS: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn's disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-alpha induced NFkappaB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression. CONCLUSIONS: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFkappaB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.

Analysis of Variance↗
PubMed2003

Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin.

Genetically encoded antibiotic peptides are evolutionarily ancient and widespread effector molecules of immune defence. Mammalian defensins, one subset of such peptides, have been implicated in the antimicrobial defence capacity of phagocytic leukocytes and various epithelial cells, but direct evidence of the magnitude of their in vivo effects have not been clearly demonstrated. Paneth cells, specialized epithelia of the small intestinal crypt, secrete abundant alpha-defensins and other antimicrobial polypeptides including human defensin 5 (HD-5; also known as DEFA5). Although antibiotic activity of HD-5 has been demonstrated in vitro, functional studies of HD-5 biology have been limited by the lack of in vivo models. To study the in vivo role of HD-5, we developed a transgenic mouse model using a 2.9-kilobase HD-5 minigene containing two HD-5 exons and 1.4 kilobases of 5'-flanking sequence. Here we show that HD-5 expression in these mice is specific to Paneth cells and reflects endogenous enteric defensin gene expression. The storage and processing of transgenic HD-5 also matches that observed in humans. HD-5 transgenic mice were markedly resistant to oral challenge with virulent Salmonella typhimurium. These findings provide support for a critical in vivo role of epithelial-derived defensins in mammalian host defence.

Animals↗
PubMed1997

Induction of epithelial chloride secretion by channel-forming cryptdins 2 and 3.

Salt and water secretion from intestinal epithelia requires enhancement of anion permeability across the apical membrane of Cl- secreting cells lining the crypt, the secretory gland of the intestine. Paneth cells located at the base of the small intestinal crypt release enteric defensins (cryptdins) apically into the lumen. Because cryptdins are homologs of molecules known to form anion conductive pores in phospholipid bilayers, we tested whether these endogenous antimicrobial peptides could act as soluble inducers of channel-like activity when applied to apical membranes of intestinal Cl- secreting epithelial cells in culture. Of the six peptides tested, cryptdins 2 and 3 stimulated Cl- secretion from polarized monolayers of human intestinal T84 cells. The response was reversible and dose dependent. In contrast, cryptdins 1, 4, 5, and 6 lacked this activity, demonstrating that Paneth cell defensins with very similar primary structures may exhibit a high degree of specificity in their capacity to elicit Cl- secretion. The secretory response was not inhibited by pretreatment with 8-phenyltheophyline (1 microM), or dependent on a concomitant rise in intracellular cAMP or cGMP, indicating that the apically located adenosine and guanylin receptors were not involved. On the other hand, cryptdin 3 elicited a secretory response that correlated with the establishment of an apically located anion conductive channel permeable to carboxyfluorescein. Thus cryptdins 2 and 3 can selectively permeabilize the apical cell membrane of epithelial cells in culture to elicit a physiologic Cl- secretory response. These data define the capability of cryptdins 2 and 3 to function as novel intestinal secretagogues, and suggest a previously undescribed mechanism of paracrine signaling that in vivo may involve the reversible formation of ion conductive channels by peptides released into the crypt microenvironment.

Amino Acid Sequence↗
PubMed2004

Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine.

We recently reported the inflammation of the cystic fibrosis (CF) mouse small intestine, and we hypothesized bacterial overgrowth as a possible cause. Quantitative PCR of bacterial 16S genomic DNA in the CF mouse small intestine revealed an increase of greater than 40-fold compared to controls. Sequencing of 16S PCR products and Gram staining showed that the majority of bacteria in the CF mouse intestine were gram negative. Bacteria were observed to colonize the mucus that accumulates in the intestinal lumen of mice with CF. Impaired Paneth cell defenses were suggested by observation of partially dispersed Paneth granules in the mucus plugs of CF mouse intestinal crypts, and this mucus was strongly immunoreactive for Paneth cell bactericidal products. The role of bacterial overgrowth in intestinal inflammation in CF was tested by treating mice with oral antibiotics (ciprofloxacin and metronidazole) for 3 weeks, which reduced bacterial load in the CF mouse small intestine over 400-fold. Antibiotic treatment decreased the expression of the inflammation-related genes mast cell protease 2, leucine-rich alpha2 glycoprotein/leucine-rich high endothelial venule glycoprotein, suppressor of cytokine signaling 3, hematopoietic cell transcript 1, and resistin-like molecule beta/found in inflammatory zone 2, all of which were no longer expressed at levels significantly different from control levels. The reduction of intestinal bacteria also significantly improved the growth of CF mice but had no effect on the growth of wild-type mice. These data suggest that bacterial overgrowth in the CF mouse small intestine has a role in inflammation and contributes to the failure to thrive in this mouse model of CF.

Animals↗
PubMed1997

Antimicrobial protection of the mouse testis: synthesis of defensins of the cryptdin family.

We report the synthesis by mouse testicular cells of antibiotic peptides related to the defensins secreted by the Paneth cells of the intestinal epithelium. A Sertoli cell-derived line (15P-1), Sertoli cells in primary cultures, and explanted testicular tissue in culture medium were observed to release protease-sensitive material with a broad-spectrum antibacterial activity. The activity of 15P-1 culture medium was increased 10- to 50-fold in the presence of fractions enriched in round spermatids and of nerve growth factor. Two series of results suggest that this activity may correspond to the release by testicular cells of defensin peptides, and specifically, of peptides of the cryptdin family first identified in the Paneth cells of intestinal crypts. First, a characteristic nucleotide sequence corresponding to the conserved first exon of the mouse cryptdin and cryptdin-related (CRS) genes was evidenced in the RNA of 15P-1 cells and of the testis. Second, immunohistochemical analysis demonstrated the presence of cryptdins of the cryp-1, -2, -3, -6 group in 15P-1 cells, and identified two distinct localizations in the testis. Inside the seminiferous tubule, these cryptdins were found accumulated in Sertoli cells at stages corresponding to the maturation of spermatids. In the interstitial space, Leydig cells also contained immunoreactive cryptdins.

Animals↗
PubMed1987

Induction of gastric tumor and intestinal metaplasia in rats exposed to localized X-irradiation of the gastric region.

The induction of gastric tumor and intestinal metaplasia was examined in 8-week-old male JCL/SD rats exposed to localized X-irradiation of the gastric region. The animals were each given two 20 Gy fractions of X-rays, with a one-week interval between fractions (total, 40 Gy). Nine atypical hyperplasias (20%) and 13 adenocarcinomas (28%) in the pyloric mucosa of the glandular stomach were found in 46 animals with X-irradiation. The incidence of intestinal metaplasia was 93% in the pyloric mucosa, 50% in the fundic mucosa and 96% in both the pyloric and fundic mucosa. Type B metaplasia (intestinal metaplasia without Paneth cells) was most common and type C (intestinal metaplasia with Paneth cells) was less frequent. No gastric tumor or intestinal metaplasia appeared in non-irradiated control rats. This study shows that local X-irradiation of the gastric region induced both gastric tumor and intestinal metaplasia independently.

Animals↗
PubMed1998

Atrophy of the coeliac mucosa.

Details of 12 patients suffering from atrophy of the coeliac mucosa (ACM) are presented. These patients failed to respond to the elimination of gluten from their diets. Their jejunal biopsies were examined in detail with particular attention given to Paneth cell numbers, crypt length, mitotic rate and mucosal thickness. These biopsies were compared with the biopsies of responsive coeliac patients. The ACM patients were found to have a statistically significant reduction in Paneth cell numbers (P < 0.0005), reduced crypt length (P < 0.0125), reduced mitotic rate (P < 0.0005) and a thinner mucosa (P < 0.0005), when compared with the responsive coeliac group. In addition the ACM group had a lower albumin level compared with the responsive group (P < 0.0005). Most of the ACM patients responded when treated with oral corticosteroids. It is considered that the above features are markers of a non-responsive group of coeliac patients and thus might be useful for identifying those patients who may benefit from early treatment with oral corticosteroids if gluten withdrawal is not rapidly effective.

Aged↗
PubMed2005

Expression and localization of Muc4/sialomucin complex (SMC) in the adult and developing rat intestine: implications for Muc4/SMC function.

Muc4/sialomucin complex (SMC) is a high molecular mass heterodimeric membrane mucin, encoded by a single gene, and originally discovered in a highly metastatic ascites rat mammary adenocarcinoma. Subsequent studies have shown that it is a prominent component of many accessible and vulnerable epithelia, including the gastrointestinal tract. Immunoblot and immunofluorescence analyses demonstrated that Muc4/SMC expression in the rat small intestine increases from proximal to distal regions and is located predominantly in cells at the base of the crypts. These cells were postulated to be Paneth cells, based on their location, morphology, and secretory granule content. Immunohistochemistry indicated the presence of Muc4/SMC in these granules. Muc4/SMC expression was higher in the rat colon than small intestine and was abundantly present in colonic goblet cells, but not in goblet cells in the small intestine. Immunohistochemistry also suggested the presence of MUC4 in human colonic goblet cells. Biochemical analyses indicated that rat colonic Muc4/SMC is primarily the soluble form of the membrane mucin. Analyses of Muc4/SMC during development of the rat gastrointestinal tract showed its appearance at embryonic day 14 of the esophagus and at day 15 at the surface of the undifferentiated stratified epithelium at the gastroduodenal junction, then later at cell surfaces in the more distal regions of the differentiated epithelium of the small intestine, culminating in expression as an intracellular form in the crypts of the small intestine at about day 21. Limited expression in the colon was observed during development before birth at cell surfaces, with expression as an intracellular form in the goblet cells arising during the second week after birth. These results suggest that membrane mucin Muc4/SMC serves different functions during development of the intestine in the rat, but is primarily a secreted product in the adult animal.

Age Factors↗
PubMed1998

Isolation of human intestinal defensins from ileal neobladder urine.

We describe the isolation of naturally occurring human intestinal defensins HD-5 and HD-6 from ileal neobladder urine and ileal mucosa. Using an antibody-based detection assay, we found multiple N-terminally processed forms of HD-5. The predominant HD-5 forms in tissue were longer than those in neobladder urine (amino acid (aa) 23-94 and 29-94 versus aa 36-94, 56-94 and 63-94) suggesting that Paneth cells store prodefensin that is processed to mature defensin during or after degranulation. Search for mature HD-6 yielded aa 69-100 as the predominant form in both sources. The ileal neobladder is a promising model to study human Paneth cell secretion.

Amino Acid Sequence↗
PubMed1985

Late ultrastructural effects of heavy ions and gamma irradiation in the gastrointestinal tract of the mouse.

The irradiated gastrointestinal tract of LAF1 mice was examined one year following a single dose (1000 rad) of either 12C heavy ions or 60Co gamma rays. Qualitative ultrastructural analysis of the gastrointestinal tract of mice exposed to heavy ions or gamma irradiation did not show any discernible differences. In the stomach of irradiated mice, parietal cells contained numerous lysosomes; the gastric chief cells occasionally contained myelin figures. The epithelial cells of the small intestine, especially jejunum and ileum, showed several changes: (1) increased vacuolation was seen both inter- and intra-cellularly, (2) epithelial cell projections penetrated the basal lamina and were in contact with underlying mesenchymal cells, (3) occasional Paneth cells contained intracellular vacuoles consisting of fibrillar and granular material. In the large intestine occasional signs of degeneration were observed. Qualitative analysis of stromal elements of the gut in irradiated mice indicated the presence of damage to capillary endothelial cells, smooth muscle cells and some nerve processes. The amount of basement membrane (BM) around capillaries and small vessels was increased; the same phenomenon was observed to affect the nerve processes, but with less severity. Quantitative analysis of the basement membrane thickness around capillaries in irradiated vs. control mice showed significant differences. Basement membrane thickness around capillaries in the gastric mucosa and duodenum did not differ significantly in any of the treatment groups. In jejunum, the gamma treated animals exhibited significantly higher BM thickness when compared to unirradiated controls. In ileum, only 12C-heavy ion treated animals showed thicker BM when compared to their respective controls. In colon, both 12C- and 60Co-treated animals showed increased BM thickness when compared to controls.

Animals↗
PubMed1987

Mucinous cystadenocarcinoma of the pancreas. Morphologic and immunocytochemical observations.

Twenty mucinous cystadenocarcinomas of the pancreas, most of which occurred in the tail of the pancreas in middle-aged women, were examined histologically and by immunohistochemical stains. Thirteen tumors displayed a marked histological heterogeneity and expressed intestinal differentiation as shown by the colonic appearance of the glands both at the light- and electron-microscopic levels. Other intestinal features included varying numbers of goblet cells, argyrophil and argentaffin cells, and even Paneth cells. By immunohistochemistry, endocrine cells were present in 13 of the 20 tumors (65%) and were more numerous in the poorly differentiated than in the well-differentiated epithelial component of the tumors. Serotonin-containing cells were the most common endocrine cells, followed by somatostatin-containing cells and cells that showed immunoreactivity for pancreatic polypeptide and gastrin. However, none of the patients had clinical manifestations of carcinoid, somatostatinoma, or the Zollinger-Ellison syndrome. The findings support the hypothesis that mucinous cystadenocarcinomas of the pancreas arise from an "endodermal stem cell" that differentiates into cells with intestinal phenotypes.

Adult↗
PubMed1986

Intestinal cell proliferation. I. A comprehensive model of steady-state proliferation in the crypt.

Cell replacement in the crypt of the murine small intestine has been studied and modelled mathematically under steady-state conditions. A great deal of information is available for this system, e.g. cell cycle times, S phase durations, the rate of daily cell production, the Paneth cell distribution etc. The purpose of the present work was to consider simultaneously as much of these data as possible and to formulate a model based upon the behaviour of individual cells which adequately accounted for them. A simple mathematical representation of the crypt has been developed. This consists of sixteen stem cells per crypt (TC = 16 hr, TS = 9 hr), and four subsequent transit cell divisions (TC = 11 to 12 hr, TS = 8 hr) before maturation. Experimental data considered to test the modelling were LI and data on the number of vertical runs of similarly labelled cells. All data were obtained from the ileum after 25 microCi [3H]TdR given at 09:00 hours. A number of alternative assumptions have been considered and either accepted or rejected. Two alternative model concepts of cell displacement explain the data equally well. One is dependent upon strong local cell generation age determinance while the other could accommodate any weak local cell displacement process in conjunction with an environmental cut-off determinant at the middle of the crypt. Both models provide new interpretations of the data, e.g. certain rates of lateral cell exchange between neighbouring columns (250 to 350 per crypt per day out of a total of 420 cell divisions per day) can be concluded from run data, while LI data provide information about the mechanisms involved in maintaining a position-related age order in the crypt.

Animals↗
PubMed1991

The decay of autoradiographic grain number over crypt base columnar cells in murine ileum as a measure of their generation time.

The decay in the number of grains over [3H]-thymidine labelled crypt base columnar cells (BCC) in autoradiographs of the ileum of BDF1 mice has been studied. The results revealed that using the conventional grain count halving (GCH) method it is possible to obtain an estimation of the generation time (Tc) of the proliferative BCC cells in the Paneth cell zone (PC-zone) of 18.8 +/- 0.74 h. This lies within the range obtained by the percent labelled mitoses (PLM) method, but is shorter than most values obtained by stathmokinetic methods. The present data show no evidence for a shortening of the cell cycle 3 days after irradiation (8 Gy) which is contrary to some earlier observations. Some reasons for this discrepancy are discussed. The comparatively high labelling index of the BCC allows a larger amount of data to be easily collected, compared with the PLM technique, and correction factors which take into account the complicated shape of the bottom of the crypt are not required.

Animals↗