production-characterization-potential-uses-3d-tissue-engineered-human

Production, Characterization and Potential Uses of a 3D Tissue-engineered Human Esophageal Mucosal Model

The incidence of both esophageal adenocarcinoma and its precursor, Barrett&#8217;s Metaplasia, are rising rapidly in the western world. Furthermore ...

Sheffield Teaching Hospitals NHS Foundation Trust

There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in the Western world. However, how iron mediates carcinogenesis at the molecular level remains unclear. In this study, we investigated the expression of iron transport proteins involved in cellular iron import, export, and storage in the premalignant lesion Barrett's metaplasia and esophageal adenocarcinoma.

Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma.

Markers of crypt cell proliferation are frequently employed in studies of the impact of genetic and exogenous factors on human colonic physiology. Human studies often rely on the assessment of tissue acquired at endoscopy. Modulation of cell proliferation by bowel preparation with oral laxatives may confound the findings of such studies, but there is little data on the impact of commonly used bowel preparations on markers of cell proliferation.

Commonly used bowel preparations have significant and different effects upon cell proliferation in the colon: a pilot study.

A number of studies, notably EPIC, have shown a descrease in colorectal cancer risk associated with increased fibre consumption. Whilst the underlying mechanisms are likely to be multifactorial, production of the short-chain fatty-acid butyrate fro butyratye is frequently cited as a major potential contributor to the effect. Butyrate inhibits histone deacetylases, which work on a wide range of proteins over and above histones. We therefore hypothesized that alterations in the acetylated proteome may be associated with a cancer risk phenotype in the colorectal mucosa, and that such alterations are candidate biomarkers for effectiveness of fibre interventions in cancer prevention. METHODS AN DESIGN: There are two principal arms to this study: (i) a cross-sectional study (FACT OBS) of 90 subjects recruited from gastroenterology clinics and; (ii) an intervention trial in 40 subjects with an 8 week high fibre intervention. In both studies the principal goal is to investigate a link between fibre intake, SCFA production and global protein acetylation. The primary measure is level of faecal butyrate, which it is hoped will be elevated by moving subjects to a high fibre diet. Fibre intakes will be estimated in the cross-sectional group using the EPIC Food Frequency Questionnaire. Subsidiary measures of the effect of butyrate on colon mucosal function and pre-cancerous phenotype will include measures of apoptosis, apoptotic regulators cell cycle and cell division.

A study protocol to investigate the relationship between dietary fibre intake and fermentation, colon cell turnover, global protein acetylation and early carcinogenesis: the FACT study.

&#x6709;&#x53EF;&#x9760;&#x7EC4;&#x7EC7;&#x5DE5;&#x7A0B;&#x5316;&#x7684;&#x4E09;&#x7EF4;&#x6A21;&#x578B;&#x4F5C;&#x4E3A;&#x4E00;&#x4E2A;&#x5B9E;&#x9A8C;&#x5E73;&#x53F0;&#x7528;&#x4E8E;&#x8C03;&#x67E5;&#x98DF;&#x7BA1;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x751F;&#x7269;&#x5B66;&#x548C;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x7684;&#x98DF;&#x7BA1;&#x80BF;&#x7624;&#x524D;&#x4F53;&#x75C5;&#x53D8;&#x5982;&#x5DF4;&#x96F7;&#x7279;&#x7684;&#x4E0A;&#x76AE;&#x5316;&#x751F;&#x7684;&#x98DF;&#x7BA1;&#x9ECF;&#x819C;&#x7684;&#x9700;&#x6C42;&#x3002;&#x8BF4;&#x660E;&#x4E86;&#x5927;&#x91CF;&#x7684;&#x6A21;&#x578B;&#xFF0C;&#x4F46;&#x4E0D;&#x540C;&#x7684;&#x65B9;&#x6CD5;&#xFF0C;&#x96BE;&#x4EE5;&#x9009;&#x62E9;&#x9996;&#x9009;&#x5E73;&#x53F0;&#x5C0F;&#x7CFB;&#x7EDF;&#x7684;&#x8BC4;&#x4F30;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x8BC4;&#x4F30;&#x5668;&#x5B98;&#x6587;&#x5316;&#x4F7F;&#x7528;&#x56DB;&#x4E2A;&#x4E0D;&#x540C;&#x652F;&#x67B6; &#xFF08;&#x4EBA;&#x7C7B;&#x98DF;&#x7BA1;&#x77E9;&#x9635;&#x3001; &#x732A;&#x98DF;&#x7BA1;&#x3001; &#x4EBA;&#x7C7B;&#x771F;&#x76AE;&#x4EE5;&#x53CA;&#x80F6;&#x539F;&#xFF09; &#x548C;&#x4E24;&#x79CD;&#x4E0D;&#x540C;&#x7684;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x7C7B;&#x578B; &#xFF08;&#x4E3B;&#x4EBA;&#x98DF;&#x7BA1;&#x9CDE;&#x72B6;&#x7EC6;&#x80DE;&#x548C; Het-1A &#x98DF;&#x7BA1;&#x9CDE;&#x72B6;&#x7EC6;&#x80DE;&#x7EBF;&#xFF09; &#x7684;&#x5C5E;&#x6027;&#x3002;&#x4EBA;&#x7C7B;&#x7684;&#x98DF;&#x7BA1;&#x77E9;&#x9635;&#x548C;&#x771F;&#x76AE;&#x6CA1;&#x6709;&#x63D0;&#x4F9B;&#x4E00;&#x81F4;&#x7684;&#x7ED3;&#x679C;&#xFF0C;&#x4F46;&#x732A;&#x98DF;&#x7BA1;&#x77E9;&#x9635;&#x548C;&#x80F6;&#x539F;&#x8BC1;&#x660E;&#x66F4;&#x53EF;&#x9760;&#x548C;&#x66F4;&#x8BE6;&#x7EC6;&#x5730;&#x8FDB;&#x884C;&#x4E86;&#x7814;&#x7A76;&#x3002;&#x8FD9;&#x4E24;&#x4E2A;&#x77E9;&#x9635;&#x652F;&#x6301;&#x7C7B;&#x4F3C;&#x4E8E;&#x6B63;&#x5E38;&#x4EBA;&#x98DF;&#x7BA1;&#x3001; Ki67&#x3001; CK4&#x3001; CK14&#x3001; &#x548C;&#x589E;&#x52A0;&#x67D3;&#x8272;&#x6240;&#x8868;&#x73B0;&#x51FA;&#x7684;&#x6210;&#x719F;&#x5206;&#x5C42;&#x4E0A;&#x76AE;&#x7684;&#x5F62;&#x6210;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x80F6;&#x539F;&#x663E;&#x793A;&#x51CF;&#x5C11;&#x4E0A;&#x76AE;&#x7684;&#x9075;&#x5B88;&#xFF0C;&#x800C;&#x78B1;&#x6027;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x6E17;&#x900F;&#x5230;&#x732A;&#x7684;&#x77E9;&#x9635;&#x5F88;&#x5DEE;&#x3002;&#x4F7F;&#x7528; Het-1A &#x7EC6;&#x80DE;&#x590D;&#x5408;&#x6587;&#x5316;&#x6CA1;&#x6709;&#x8BC1;&#x636E;&#x7684;&#x5206;&#x5316;&#x4E0E;&#x5F62;&#x6210; hyperproliferative &#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x3002;&#x6211;&#x4EEC;&#x5EFA;&#x8BAE;&#x4EBA;&#x98DF;&#x7BA1;&#x9CDE;&#x72B6;&#x7EC6;&#x80DE;&#x690D;&#x5165;&#x5230;&#x732A;&#x98DF;&#x7BA1;&#x57FA;&#x8D28;&#x4E0A;&#x4F5C;&#x4E3A;&#x6B63;&#x5E38;&#x4EBA;&#x98DF;&#x7BA1;&#x7684;&#x9996;&#x9009;&#x6A21;&#x5F0F;&#x3002;

&#x53D1;&#x5C55;&#x548C;&#x5668;&#x5B98;&#x7EC4;&#x7EC7;&#x5DE5;&#x7A0B;&#x5316;&#x4EBA;&#x7C7B;&#x98DF;&#x7BA1;&#x9ECF;&#x819C;&#x6A21;&#x578B;&#x7684;&#x8868;&#x5F81;&#x3002;

There is a demand for a reliable three-dimensional tissue-engineered model of the esophageal mucosa for use as an experimental platform for investigating esophageal epithelial biology and the pathogenesis of esophageal neoplasia and precursor lesions such as Barrett's metaplasia. A number of models have been described, but there has been little systematic assessment of the different approaches, making selection of a preferred platform difficult. This study assesses the properties of organotypic cultures using four different scaffolds (human esophageal matrix, porcine esophageal matrix, human dermal matrix, and collagen) and two different epithelial cell types (primary human esophageal squamous cells and the Het-1A esophageal squamous cell line). Human esophageal matrix and dermis did not give consistent results, but porcine esophageal matrix and collagen proved more reliable and were studied in greater detail. Both matrices supported the formation of a mature stratified epithelium that was similar to that of the normal human esophagus, demonstrated by Ki67, CK4, CK14, and involucrin staining. However, collagen showed reduced epithelial adherence, while fibroblast penetration into the porcine matrix was poor. Composite cultures using Het-1A cells formed a hyperproliferative epithelium with no evidence of differentiation. We propose human esophageal squamous cells seeded onto porcine esophageal matrix as the preferred model of the normal human esophagus.

The development and characterization of an organotypic tissue-engineered human esophageal mucosal model.

Il existe une demande pour un mod&egrave;le fiable de tissulaire en trois dimensions de la muqueuse oesophagienne pour servir une plateforme exp&eacute;rimentale pour &eacute;tudier la biologie &eacute;pith&eacute;lium oesophagienne et la pathogen&egrave;se des l&eacute;sions de n&eacute;oplasie et pr&eacute;curseur oesophagiennes tels que de la m&eacute;taplasie de Barrett. Un certain nombre de mod&egrave;les ont &eacute;t&eacute; d&eacute;crites, mais il y a eu peu &eacute;valuation syst&eacute;matique des approches diff&eacute;rentes, ce qui rend difficile le choix d&#39;une plateforme pr&eacute;f&eacute;r&eacute;e. Cette &eacute;tude &eacute;value les propri&eacute;t&eacute;s de culture organotypique en utilisant quatre &eacute;chafaudages diff&eacute;rents (matrice oesophagien humaine, porcine oesophagien matrice, matrice dermique humaine et collag&egrave;ne) et deux types diff&eacute;rents de cellules &eacute;pith&eacute;liales (cellules humaines primaires de carcinomes oesophagiens et la ligne d&#39;&eacute;pidermo&iuml;de oesophagien Het-1 a). Derme et matrice oesophagien humain n&#39;a pas donn&eacute; des r&eacute;sultats coh&eacute;rents, mais le collag&egrave;ne et matrice oesophagien porcin s&#39;est av&eacute;r&eacute;e plus fiables et ont &eacute;t&eacute; &eacute;tudi&eacute;s plus en d&eacute;tail. Les deux matrices a soutenu la formation d&#39;un &eacute;pith&eacute;lium stratifi&eacute; mature qui &eacute;tait semblable &agrave; celle de l&#39;oesophage humain normal, d&eacute;montr&eacute;e par Ki67, CK4 CK14 et coloration involucrin. Toutefois, le collag&egrave;ne a montr&eacute; adh&eacute;rence &eacute;pith&eacute;liale r&eacute;duite, tandis que la p&eacute;n&eacute;tration de fibroblastes dans la matrice porcine &eacute;tait pauvre. Cultures composites &agrave; l&#39;aide de cellules de Het-1 a forment un &eacute;pith&eacute;lium HYPERPROLIF&Eacute;RATIVES qui ne pr&eacute;sentaient pas de diff&eacute;renciation. Nous vous proposons des cellules malpighiennes oesophagiens humains ensemenc&eacute;s sur une matrice oesophagienne porcine comme le mod&egrave;le pr&eacute;f&eacute;r&eacute; de l&#39;oesophage humain normal.

Le d&eacute;veloppement et la caract&eacute;risation d&#39;un organotypique tissulaire humaine oesophagiens muqueux mod&egrave;le.

Es gibt eine Nachfrage f&uuml;r eine zuverl&auml;ssige dreidimensionale Gewebe-Engineering Modell der Speiser&ouml;hre Schleimhaut zur Verwendung als experimentelle Plattform f&uuml;r die Untersuchung von Speiser&ouml;hre epitheliale Biologie und die Pathogenese der Speiser&ouml;hre Neoplasie und Vorl&auml;ufer L&auml;sionen wie Barrett-Metaplasie. Eine Reihe von Modellen sind beschrieben worden, aber wenig systematische Beurteilung der verschiedenen Ans&auml;tze, erschwert die Auswahl einer bevorzugten Plattform gegeben hat. Diese Studie untersucht die Eigenschaften der organotypische Kulturen mit vier verschiedenen Ger&uuml;sten (menschliche Speiser&ouml;hre Matrix, porcine &ouml;sophageale Matrix, menschlichen dermalen Matrix und Kollagen) und zwei unterschiedliche Epithelzellen-Typen (prim&auml;re Humanzellen &ouml;sophageale Plattenepithelkarzinom und die Het-1A-&ouml;sophageale Plattenepithelkarzinom-Linie). Menschliche Speiser&ouml;hre Matrix und Dermis konsistente Ergebnisse nicht geben, aber Schweine &ouml;sophageale Matrix und Kollagen als zuverl&auml;ssiger erwiesen und wurden genauer untersucht. Beide Matrizen unterst&uuml;tzt die Bildung von einer Reifen geschichtete Epithel, die &auml;hnlich der normalen menschlichen &Ouml;sophagus, Ki67 CK4, CK14 und Involucrin F&auml;rbung nachgewiesen wurde. Kollagen zeigte allerdings reduzierte epitheliale festhalten, w&auml;hrend Fibroblast-Eindringen in die Schweine Matrix schlecht war. Zusammengesetzte Kulturen mit Het-1A Zellen gebildet ein Hyperproliferative Epithel ohne Beweise der Differenzierung. Wir schlagen die Speiser&ouml;hre Plattenepithelkarzinom Humanzellen ausges&auml;t auf Schweine &ouml;sophageale Matrix als das bevorzugte Modell des normalen menschlichen &Ouml;sophagus.

Die Entwicklung und Charakterisierung eines organotypische Gewebe-Engineering menschliche Speiser&ouml;hre Schleimhaut Modells.

C&#39;&egrave; una domanda di un affidabile modello tridimensionale tessutale della mucosa esofagea per l&#39;uso come piattaforma sperimentale per studiare biologia epiteliale dell&#39;esofago e la patogenesi delle lesioni neoplasie e precursore dell&#39;esofago come metaplasia di Barrett. Un certo numero di modelli &egrave; stati descritti, ma c&#39;&egrave; stato poco valutazione sistematica degli approcci differenti, rendendo difficile la scelta di una piattaforma preferita. Questo studio valuta la propriet&agrave; delle colture organotypic utilizzando quattro diversi ponteggi (matrice umana esofagea, porcino esofageo matrix, matrice dermica umana e collagene) e due tipi differenti delle cellule epiteliali (cellule squamose dell&#39;esofago umane primarie e la linea di cellule squamose dell&#39;esofago Het-1A). Derma e matrice umana esofageo non ha dato risultati coerenti, ma collagene e matrice esofageo suina si &egrave; rivelata pi&ugrave; affidabili e sono state studiate in dettaglio. Entrambe matrici sostegno la formazione di un epitelio stratificato maturo che era simile a quello dell&#39;esofago normale umano, ha dimostrato di Ki67, CK4, CK14 e osserva la colorazione. Tuttavia, collagene ha mostrato ridotta aderenza epiteliale, mentre la penetrazione dei fibroblasti nella matrice dei suini &egrave; stata scarsa. Culture Composite utilizzando cellule Het-1A formano un epitelio iperproliferative con nessuna evidenza di differenziazione. Proponiamo umane cellule squamose dell&#39;esofago seminate sulla suina esofageo matrix come il modello preferito dell&#39;esofago normale umano.

Sviluppo e caratterizzazione di un organotypic tessutale esofageo mucosa modello umano.

&#x98DF;&#x9053;&#x7C98;&#x819C;&#x98DF;&#x9053;&#x4E0A;&#x76AE;&#x751F;&#x7269;&#x5B66;&#x304A;&#x3088;&#x3073;&#x30D0;&#x30EC;&#x30C3;&#x30C8;&#x4E0A;&#x76AE;&#x5316;&#x751F;&#x306A;&#x3069;&#x306E;&#x98DF;&#x9053;&#x816B;&#x760D;&#x304A;&#x3088;&#x3073;&#x524D;&#x99C6;&#x75C5;&#x5909;&#x306E;&#x75C5;&#x56E0;&#x3092;&#x8ABF;&#x67FB;&#x3059;&#x308B;&#x305F;&#x3081;&#x5B9F;&#x9A13;&#x30D7;&#x30E9;&#x30C3;&#x30C8;&#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x3068;&#x3057;&#x3066;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x4FE1;&#x983C;&#x6027;&#x306E;&#x9AD8;&#x3044; 3&#x6B21;&#x5143;&#x7D44;&#x7E54;&#x5DE5;&#x5B66;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x9700;&#x8981;&#x3067;&#x3059;&#x3002;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x6570;&#x304C;&#x8A18;&#x8F09;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3001;&#x3057;&#x304B;&#x3057;&#x3001;&#x6700;&#x5BC4;&#x308A;&#x306E;&#x30D7;&#x30E9;&#x30C3;&#x30C8;&#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x306E;&#x9078;&#x629E;&#x304C;&#x96E3;&#x3057;&#x304F;&#x3001;&#x7570;&#x306A;&#x308B;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x306E;&#x5C11;&#x3057;&#x306E;&#x4F53;&#x7CFB;&#x7684;&#x306A;&#x8A55;&#x4FA1;&#x3092;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x672C;&#x7814;&#x7A76;&#x306F; 4 &#x3064;&#x306E;&#x7570;&#x306A;&#x308B;&#x8DB3;&#x5834; (&#x98DF;&#x9053;&#x884C;&#x5217;&#x306E;&#x4EBA;&#x9593;&#x3001;&#x8C5A;&#x306E;&#x98DF;&#x9053;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x3001;&#x4EBA;&#x9593;&#x306E;&#x771F;&#x76AE;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x3068;&#x30B3;&#x30E9;&#x30FC;&#x30B2;&#x30F3;) &#x3068; 2 &#x3064;&#x306E;&#x7570;&#x306A;&#x308B;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x578B; (&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x3072;&#x3068;&#x98DF;&#x9053;&#x6241;&#x5E73;&#x4E0A;&#x76AE;&#x764C;&#x7D30;&#x80DE;&#x3068; Het 1A &#x98DF;&#x9053;&#x6241;&#x5E73;&#x4E0A;&#x76AE;&#x764C;&#x7D30;&#x80DE;&#x306E;&#x7DDA;) &#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x5207;&#x7247;&#x30AB;&#x30EB;&#x30C1;&#x30E3;&#x306E;&#x30D7;&#x30ED;&#x30D1;&#x30C6;&#x30A3;&#x3092;&#x8A55;&#x4FA1;&#x3057;&#x307E;&#x3059;&#x3002;&#x98DF;&#x9053;&#x884C;&#x5217;&#x306E;&#x4EBA;&#x9593;&#x3068;&#x771F;&#x76AE;&#x4E00;&#x8CAB;&#x6027;&#x306E;&#x3042;&#x308B;&#x7D50;&#x679C;&#x3092;&#x4E0E;&#x3048;&#x3066;&#x3044;&#x306A;&#x3044;&#x304C;&#x3001;&#x8C5A;&#x306E;&#x98DF;&#x9053;&#x884C;&#x5217;&#x3068;&#x30B3;&#x30E9;&#x30FC;&#x30B2;&#x30F3;&#x3088;&#x308A;&#x4FE1;&#x983C;&#x6027;&#x306E;&#x9AD8;&#x3044;&#x8A3C;&#x660E;&#x3057;&#x3088;&#x308A;&#x8A73;&#x7D30;&#x306B;&#x8ABF;&#x3079;&#x305F;&#x3002;&#x4E21;&#x65B9;&#x306E;&#x884C;&#x5217;&#x30AD;67&#x3001;CK4&#x3001;CK14, &#x3068; involucrin &#x67D3;&#x8272;&#x306B;&#x3088;&#x308A;&#x5B9F;&#x8A3C;&#x6B63;&#x5E38;&#x3072;&#x3068;&#x98DF;&#x9053;&#x7C98;&#x819C;&#x306E;&#x305D;&#x308C;&#x306B;&#x4F3C;&#x3066;&#x3044;&#x305F;&#x6210;&#x719F;&#x306E;&#x91CD;&#x5C64;&#x4E0A;&#x76AE;&#x306E;&#x5F62;&#x6210;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x30D6;&#x30BF;&#x306E;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x3078;&#x306E;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x6D78;&#x900F;&#x304C;&#x4E0D;&#x826F;&#x3067;&#x3042;&#x3063;&#x305F;&#x4E00;&#x65B9;&#x30B3;&#x30E9;&#x30FC;&#x30B2;&#x30F3;&#x524A;&#x6E1B;&#x4E0A;&#x76AE;&#x4ED8;&#x7740;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;Het 1 a &#x7D30;&#x80DE;&#x3092;&#x7528;&#x3044;&#x305F;&#x8907;&#x5408;&#x6587;&#x5316;&#x69CB;&#x9020;&#x4E0A;&#x76AE;&#x5206;&#x5316;&#x306E;&#x8A3C;&#x62E0;&#x3092;&#x5F62;&#x6210;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30D6;&#x30BF;&#x306E;&#x98DF;&#x9053;&#x306E;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x4E0A;&#x306B;&#x901A;&#x5E38;&#x306E;&#x4EBA;&#x9593;&#x306E;&#x98DF;&#x9053;&#x306E;&#x6700;&#x5BC4;&#x308A;&#x306E;&#x30E2;&#x30C7;&#x30EB;&#x3068;&#x3057;&#x3066;&#x30B7;&#x30FC;&#x30C9;&#x3072;&#x3068;&#x98DF;&#x9053;&#x6241;&#x5E73;&#x4E0A;&#x76AE;&#x764C;&#x7D30;&#x80DE;&#x3092;&#x63D0;&#x6848;&#x3059;&#x308B;.

&#x958B;&#x767A;&#x3068;&#x5207;&#x7247;&#x7D44;&#x7E54;&#x5DE5;&#x5B66;&#x3072;&#x3068;&#x98DF;&#x9053;&#x7C98;&#x819C;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x7279;&#x6027;&#x5316;

&#xC2DD;&#xB3C4; &#xC0C1;&#xD53C; &#xC0DD;&#xBB3C;&#xD559;&#xACFC; &#xBC14; &#xB81B;&#xC758; metaplasia &#xAC19;&#xC740; &#xC2DD;&#xB3C4; &#xC2E0; &#xC0DD;&#xBB3C; &#xBC0F; &#xC804;&#xC870; &#xBCC0;&#xC758; pathogenesis &#xC870;&#xC0AC;&#xB97C; &#xC704;&#xD55C; &#xC2E4;&#xD5D8; &#xD50C;&#xB7AB;&#xD3FC;&#xC73C;&#xB85C; &#xC0AC;&#xC6A9; &#xD558;&#xAE30; &#xC704;&#xD574; &#xC2DD;&#xB3C4; &#xC810; &#xB9C9;&#xC758; &#xC2E0;&#xB8B0;&#xD560; &#xC218; &#xC788;&#xB294; 3 &#xCC28;&#xC6D0; &#xC870;&#xC9C1; &#xC124;&#xACC4; &#xBAA8;&#xB378;&#xC5D0; &#xB300; &#xD55C; &#xC218;&#xC694;&#xAC00; &#xC788;&#xB2E4;. &#xBAA8;&#xB378; &#xC218;&#xB97C; &#xC124;&#xBA85; &#xD558;&#xC9C0;&#xB9CC; &#xC120;&#xD638; &#xD558;&#xB294; &#xD50C;&#xB7AB;&#xD3FC;&#xC758; &#xC120;&#xD0DD;&#xC744; &#xC5B4;&#xB835;&#xAC8C; &#xD558;&#xB294; &#xB2E4;&#xB978; &#xBC29;&#xC2DD;&#xC758; &#xC791;&#xC740; &#xCCB4;&#xACC4;&#xC801;&#xC778; &#xD3C9;&#xAC00; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xB294; 4 &#xAC1C;&#xC758; &#xB2E4;&#xB978; &#xAC74;&#xC124; &#xAE30;&#xACC4; &#xC784;&#xB300; (&#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;, &#xB3FC;&#xC9C0; &#xC2DD;&#xB3C4; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;, &#xC778;&#xAC04;&#xC758; &#xD53C;&#xBD80; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; &#xBC0F; &#xCF5C;&#xB77C;&#xAC90;)&#xACFC; &#xB450; &#xAC1C;&#xC758; &#xB2E4;&#xB978; &#xC0C1;&#xD53C; &#xC138;&#xD3EC; &#xC720;&#xD615; (&#xAE30;&#xBCF8; &#xC778;&#xAC04; &#xC2DD;&#xB3C4; &#xD3B8;&#xD3C9; &#xC0C1;&#xD53C; &#xC138;&#xD3EC; &#xBC0F; Het 1A &#xC2DD;&#xB3C4; &#xD3B8;&#xD3C9; &#xC138;&#xD3EC; &#xC120;)&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; organotypic &#xBB38;&#xD654;&#xAD8C;&#xC758; &#xC18D;&#xC131; &#xD3C9;&#xAC00; &#xD569;&#xB2C8;&#xB2E4;. &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;&#xC640; &#xC9C4; &#xC77C;&#xAD00; &#xB41C; &#xACB0;&#xACFC;&#xB294; &#xC601;&#xD5A5;&#xC744; &#xC8FC;&#xC9C0; &#xC54A; &#xC558; &#xC5B4; &#xD558;&#xC9C0;&#xB9CC; &#xB3FC;&#xC9C0; &#xC2DD;&#xB3C4; &#xD589;&#xB82C;&#xACFC; &#xCF5C;&#xB77C;&#xAC90; &#xC548;&#xC815;&#xC801; &#xC785;&#xC99D; &#xB354; &#xC790;&#xC138;&#xD558;&#xAC8C;&#xC5D0;&#xC11C; &#xACF5;&#xBD80; &#xD588;&#xB2E4;. &#xB450; &#xD589;&#xB82C; Ki67, CK4, CK14, &#xBC0F; involucrin &#xC5BC;&#xB8E9;&#xC5D0; &#xC758;&#xD574; &#xC99D;&#xBA85; &#xD558;&#xB294; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xBE44;&#xC2B7;&#xD55C;&#xB294; &#xC911; &#xB144; &#xCE35; &#xD654; &#xC0C1;&#xD53C; &#xD615;&#xC131; &#xC9C0;&#xC6D0;. &#xADF8;&#xB7EC;&#xB098;, &#xCF5C;&#xB77C;&#xAC90; &#xB3FC;&#xC9C0; &#xD589;&#xB82C;&#xC73C;&#xB85C; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; &#xCE68;&#xD22C;&#xB294; &#xBD88; &#xC30D; &#xD55C; &#xB3D9;&#xC548; &#xAC10;&#xC18C; &#xC0C1;&#xD53C; &#xC900;&#xC218;&#xB97C; &#xBCF4;&#xC600;&#xB2E4;. Het 1A &#xC140;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xBCF5;&#xD569; &#xBB38;&#xD654; &#xD615;&#xC131; hyperproliferative &#xC0C1;&#xD53C; &#xBD84;&#xD654;&#xC758; &#xC99D;&#xAC70;. &#xC6B0;&#xB9AC;&#xB294; &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xD3B8;&#xD3C9; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xB97C; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4;&#xC758; &#xAE30;&#xBCF8; &#xBAA8;&#xB378;&#xB85C; &#xB3FC;&#xC9C0; &#xC2DD;&#xB3C4; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;&#xC5D0; &#xC2DC;&#xB4DC;&#xB97C; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;.

&#xAC1C;&#xBC1C; &#xBC0F; organotypic &#xC870;&#xC9C1; &#xC124;&#xACC4; &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xC810; &#xB9C9; &#xBAA8;&#xB378;&#xC758; &#xD2B9;&#xC131; &#xBD84;&#xC11D;.

Existe una demanda de un modelo tridimensional tejido-dirigida confiable de la mucosa del es&oacute;fago para su uso como una plataforma experimental para la investigaci&oacute;n Biolog&iacute;a epitelial del es&oacute;fago y la patogenesia de lesiones de neoplasia y precursor del es&oacute;fago como metaplasia de Barrett. Se han descrito varios modelos, pero ha habido poca evaluaci&oacute;n sistem&aacute;tica de los diferentes enfoques, dificultando la selecci&oacute;n de una plataforma preferida. Este estudio eval&uacute;a las propiedades de las culturas organotypic con cuatro diferentes andamios (matriz del es&oacute;fago humano, porcino del es&oacute;fago matriz, matriz d&eacute;rmica humana y col&aacute;geno) y dos tipos diferentes de c&eacute;lulas epiteliales (c&eacute;lulas escamosas del es&oacute;fago humanas primarias y la l&iacute;nea de c&eacute;lulas escamosas del es&oacute;fago Het-1A). DermIS y matriz del es&oacute;fago humano no dio resultados consistentes, pero col&aacute;geno y matriz del es&oacute;fago porcina result&oacute; m&aacute;s confiables y estudiaron detalladamente. Ambas matrices apoyaron la formaci&oacute;n de un epitelio estratificado maduro que era similar a la del es&oacute;fago humano normal, demostrado por Ki67, CK4, CK14 y la coloraci&oacute;n de involucrin. Sin embargo, col&aacute;geno demostr&oacute; menor adherencia epitelial, mientras que la penetraci&oacute;n de fibroblastos en la matriz de porcina era pobre. Culturas compuestas utilizando c&eacute;lulas de Het-1A forman un epitelio hyperproliferative sin evidencia de diferenciaci&oacute;n. Proponemos las c&eacute;lulas escamosas del es&oacute;fago humanas sembradas en porcino matriz del es&oacute;fago como el modelo preferido del es&oacute;fago humano normal.

El desarrollo y caracterizaci&oacute;n de un organotypic tejido-dirigida del es&oacute;fago mucosa modelo humano.

Riboflavin (vitamin B2) is an essential dietary component with a known function in oxidative metabolism. Our previous data using a rat model of riboflavin deficiency suggested that riboflavin also functions as a luminal signaling molecule regulating crypt development and cell turnover. Riboflavin deficiency is prevalent in both high- and low-income countries across the globe. This study aims to establish whether riboflavin deficiency has consequences for gastrointestinal (GI) morphology in adults and what the effects and effectors of any such alteration may be.

Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors.

Butyrate has been implicated in the mechanistic basis of the prevention of colorectal cancer by dietary fibre. Numerous in vitro studies have shown that butyrate regulates cell cycle and cell death. More recently we have shown that butyrate also regulates the integrity of the intermediate filament (IF) cytoskeleton in vitro. These and other data suggest a link between the role of diet and the implication of a central role for the keratin 8 (K8) as guardian of the colorectal epithelium.

Keratin 8 expression in colon cancer associates with low faecal butyrate levels.

Previous reports have suggested that the VEGF receptor neuropilin-1 (NRP-1) is expressed in a singly dispersed subpopulation of cells in the normal colonic epithelium, but that expression becomes dysregulated during colorectal carcinogenesis, with higher levels in tumour suggestive of a poor prognosis. We noted that the spatial distribution and morphology if NRP-1 expressing cells resembles that of enteroendocrine cells (EEC) which are altered in response to disease state including cancer and irritable bowel syndrome (IBS). We have shown that NRP-1 is down-regulated by butyrate in colon cancer cell lines in vitro and we hypothesized that butyrate produced in the lumen would have an analogous effect on the colon mucosa in vivo. Therefore we sought to investigate whether NRP-1 is expressed in EEC and how NRP-1 and EEC respond to butyrate and other short-chain fatty acids (SCFA - principally acetate and propionate). Additionally we sought to assess whether there is a field effect around adenomas.

Short-chain fatty acid level and field cancerization show opposing associations with enteroendocrine cell number and neuropilin expression in patients with colorectal adenoma.

Duodenogastro &#x98DF;&#x7BA1; refluxate &#x98DF;&#x7BA1;&#x63A5;&#x89E6;&#x6F5C;&#x5728;&#x987E;&#x5BA2;&#xFF0C;&#x4EE5;&#x53CD;&#x6D41;&#x98DF;&#x9053;&#x708E;&#x548C;&#x88AB;&#x5377;&#x5165;&#x4E86;&#x5DF4;&#x96F7;&#x7279;&#x7684;&#x4E0A;&#x76AE;&#x5316;&#x751F; (BM) &#x7684;&#x53D1;&#x5C55;&#x3002;&#x76F8;&#x5173;&#x4E0E;&#x76F8;&#x4FE1;&#x4E3A; BM &#x53D1;&#x5C55;&#x7684;&#x6838;&#x5FC3;&#xFF0C;&#x867D;&#x7136; NF-&kappa; B &#x6D3B;&#x5316;&#x7684;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x57FA;&#x8D28;&#x91CD;&#x5851;&#x4E2D;&#x7684;&#x91CD;&#x8981;&#x4F5C;&#x7528;&#x7684;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x7684;&#x6FC0;&#x6D3B; NF-&kappa; B &#x4FE1;&#x53F7;&#x5728;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x76EE;&#x6807;&#x662F;&#x7814;&#x7A76;&#x5BF9; NF-&kappa; B &#x6D3B;&#x5316;&#x6210;&#x4E3B;&#x98DF;&#x7BA1;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE; (HOFs) &#x5728;&#x9178;&#x66B4;&#x9732;&#x7684;&#x5F71;&#x54CD;&#x548C;&#x5C0F;&#x5B66;&#x548C;&#x6C38;&#x751F;&#x5316;&#x98DF;&#x7BA1; squames &#x5E76;&#x8C03;&#x67E5;&#x8FD9;&#x4E9B;&#x7EC6;&#x80DE;&#x5BF9;&#x9178;&#x5728;&#x54CD;&#x5E94;&#x4E2D;&#x7684;&#x4EFB;&#x4F55;&#x4E0A;&#x76AE;/&#x57FA;&#x8D28;&#x4EA4;&#x4E92;&#x3002;&#x4E3B; HOFs &#x548C;&#x5C0F;&#x5B66;&#x548C;&#x6C38;&#x751F;&#x5316;&#x98DF;&#x7BA1;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x63A5;&#x89E6;&#x9178; (ph &#x503C; 7-pH 4 &le; 120 &#x5206;&#x949F;&#xFF09; &#x5355;&#x4E2A;&#x6216;&#x8109;&#x51B2;&#x6CBB;&#x7597;&#x3002;&#x4ECE;&#x4EE5;&#x4E0B;&#x7684;&#x9178;&#x66B4;&#x9732;&#x4E5F;&#x9002;&#x7528;&#x4E8E;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x7684;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x7684;&#x57F9;&#x517B;&#x6DB2;&#x3002;&#x7EC6;&#x80DE;&#x6D3B;&#x6027;&#x7684; MTT ESTA &#x786E;&#x5B9A;&#x3002;NF-&kappa; B &#x6D3B;&#x5316;&#x7684; NF-&kappa; B/p65 &#x53EF;&#x89C6;&#x5316;&#x514D;&#x75AB;&#x8367;&#x5149;&#x7EC6;&#x80DE;&#x5B9A;&#x4F4D;&#x7684;&#x786E;&#x5B9A;&#x3002;&#x4ECE;&#x98DF;&#x7BA1;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x7684;&#x57F9;&#x517B;&#x6DB2;&#xFF0C;&#x906D;&#x53D7; pH 5 &#x640F;&#x52A8;&#x6027;&#x66B4;&#x9732;&#xFF0C;&#x6FC0;&#x6D3B; NF-&kappa; B &#x7684;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#xFF0C;&#x4E0E;&#x4E00;&#x4E9B;&#x5185;&#x7684;&#x53D8;&#x5316;&#xFF0C;&#x4F46;&#x8FD9;&#x4E9B;&#x6761;&#x4EF6;&#x4E0D;&#x4F1A;&#x76F4;&#x63A5;&#x6FC0;&#x6D3B; NF-&kappa; B &#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x672C;&#x8EAB;&#x3002;&#x91CD;&#x5927;&#x7684; NF-&kappa; B &#x6FC0;&#x6D3B;&#x6709;&#x4EBA;&#x770B;&#x89C1;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#xFF0C;&#x4F46;&#x53EA;&#x4E0E;&#x66F4;&#x5927;&#x7684;&#x9178;&#x5EA6;&#x548C;&#x66B4;&#x9732;&#x65F6;&#x95F4; &#xFF08;ph &#x503C; 4&#x3001; 60-120 &#x5206;&#x949F;&#xFF09;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x663E;&#x793A;&#x9178;&#x66B4;&#x9732;&#x5BFC;&#x81F4;&#x95F4;&#x63A5;&#x6FC0;&#x6D3B;&#x57FA;&#x8D28;&#x7EC6;&#x80DE;&#x4E0A;&#x76AE;&#x95F4;&#x8D28;&#x7684;&#x4EA4;&#x4E92;&#x3002;&#x8FD9;&#x53EF;&#x80FD;&#x4F1A;&#x5BFC;&#x81F4;&#x98DF;&#x7BA1;&#x75BE;&#x75C5;&#x7684;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x548C;&#x5185;&#x7684;&#x53D8;&#x5F02;&#x53EF;&#x80FD;&#x5728;&#x67D0;&#x79CD;&#x7A0B;&#x5EA6;&#x4E0A;&#x89E3;&#x91CA;&#x4E3A;&#x4EC0;&#x4E48;&#x4E00;&#x4E9B;&#x60A3;&#x8005;&#x98DF;&#x9053;&#x53D1;&#x5C55; BM&#xFF0C;&#x6709;&#x4E9B;&#x5219;&#x6CA1;&#x6709;&#x3002;

&#x6FC0;&#x6D3B; NF-&kappa; B &#x5219;&#x5728;&#x98DF;&#x7BA1;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x4E2D;&#x4EA7;&#x751F;&#x7684;&#x9178;&#x66B4;&#x9732;&#x539F;&#x53D1;&#x6027;&#x98DF;&#x7BA1;&#x9CDE;&#x72B6;&#x7EC6;&#x80DE;&#x65C1;&#x5206;&#x6CCC;&#x4FE1;&#x53F7;&#x7684;&#x54CD;&#x5E94;&#x3002;

Oesophageal exposure to duodenogastro-oesophageal refluxate leads to reflux oesophagitis and is implicated in the development of Barrett's metaplasia (BM). NF-ÎºB signalling in epithelial cells is associated with the activation of transcription factors believed to be central to BM development, whilst NF-ÎºB activation in fibroblasts plays a critical role in matrix remodelling. Our aim was to study the effects of acid exposure on NF-ÎºB activation in primary human oesophageal fibroblasts (HOFs) and primary and immortalized oesophageal squames and to investigate any epithelial/stromal interactions in the response of these cells to acid. Primary HOFs and primary and immortalized oesophageal epithelial cells were exposed to acid (pH 7 - pH 4 â‰¤ 120 min) in single or pulsed treatments. Conditioned medium from epithelial cells following acid exposure was also applied to fibroblasts. Cell viability was determined by MTT-ESTA. NF-ÎºB activation was determined by cellular localization of NF-ÎºB/p65 visualized by immunofluorescence. Conditioned medium from oesophageal epithelial cells, subjected to pH 5 pulsatile exposure, activated NF-ÎºB in fibroblasts, with some inter-patient variability, but these conditions did not directly activate NF-ÎºB in the epithelial cells themselves. Significant NF-ÎºB activation was seen in the epithelial cells but only with greater acidity and exposure times (pH 4, 60-120 min). Our findings show that acid exposure can cause indirect activation of stromal cells by epithelial-stromal interactions. This may contribute to the pathogenesis of oesophageal diseases, and the inter-patient variability may go some way to explain why some patients with reflux oesophagitis develop BM and others do not.

NF-ÎºB is activated in oesophageal fibroblasts in response to a paracrine signal generated by acid-exposed primary oesophageal squamous cells.

Oesophage exposition &agrave; duodenogastro-&oelig;sophageal &oelig;sophagienne permet une &oelig;sophagite de reflux et est impliqu&eacute;e dans le d&eacute;veloppement de la m&eacute;taplasie de Barrett (BM). Dans les cellules &eacute;pith&eacute;liales de NF-&kappa;B est associ&eacute;e &agrave; l&#39;activation de facteurs de transcription, cens&eacute; &ecirc;tre au centre de d&eacute;veloppement de la BM, tandis que l&#39;activation de NF-&kappa;B dans les fibroblastes joue un r&ocirc;le essentiel dans le remodelage de la matrice. Notre objectif &eacute;tait d&#39;&eacute;tudier les effets de l&#39;exposition &agrave; l&#39;acide sur l&#39;activation de NF-&kappa;B dans les fibroblastes humains oesophagiennes primaires (HOFs) et squames oesophagien primaire et immortalis&eacute;es et d&#39;enqu&ecirc;ter sur toutes les interactions &eacute;pith&eacute;liales/stroma dans la r&eacute;ponse de ces cellules &agrave; l&#39;acide. HOFs primaires et primaires et immortalis&eacute;s les cellules &eacute;pith&eacute;liales &oelig;sophagiennes ont &eacute;t&eacute; expos&eacute;s &agrave; l&#39;acide (pH 7 - pH 4 &le; 120 min) dans les traitements simples ou puls&eacute;s. Milieu conditionn&eacute; par les cellules &eacute;pith&eacute;liales apr&egrave;s exposition acide a &eacute;galement &eacute;t&eacute; appliqu&eacute;e &agrave; des fibroblastes. La viabilit&eacute; cellulaire a &eacute;t&eacute; d&eacute;termin&eacute;e par MTT-ESTA. Activation de NF-&kappa;B a &eacute;t&eacute; d&eacute;termin&eacute;e par la localisation cellulaire de NF-&kappa;B/p65 visualis&eacute;e par immunofluorescence. Conditionn&eacute; milieu &agrave; partir de cellules &eacute;pith&eacute;liales &oelig;sophagiennes, soumis &agrave; pH 5 pulsatile exposition, activ&eacute; NF-&kappa;B dans les fibroblastes, avec une certaine variabilit&eacute; inter-patient, mais ces conditions n&#39;activent pas directement de NF-&kappa;B dans les cellules &eacute;pith&eacute;liales eux-m&ecirc;mes. Activation de NF-&kappa;B significative a &eacute;t&eacute; observ&eacute;e dans les cellules &eacute;pith&eacute;liales, mais seulement avec grandes fois d&#39;acidit&eacute; et de l&#39;exposition (pH 4, 60-120 mn). Nos r&eacute;sultats montrent qu&#39;exposition &agrave; l&#39;acide peut causer une activation indirecte des cellules stromales par des interactions &eacute;pith&eacute;liales stromales. Cela peut contribuer &agrave; la pathogen&egrave;se des maladies &oelig;sophagiennes, et la variabilit&eacute; inter-patient peut aller de quelque fa&ccedil;on d&#39;expliquer pourquoi certains patients atteints de &oelig;sophagite de reflux d&eacute;veloppent BM et d&#39;autres pas.

NF-&kappa;B est activ&eacute; dans les fibroblastes &oelig;sophagiennes en r&eacute;ponse &agrave; un signal de paracrine g&eacute;n&eacute;r&eacute; par les cellules squameuses &oelig;sophagiennes primaires expos&eacute;s.

&Ouml;sophageale Exposition gegen&uuml;ber Duodenogastro-&ouml;sophageale Refluxate f&uuml;hrt um zu reflux-&Ouml;sophagitis und ist beteiligt an der Entwicklung der Barrett-Metaplasie (BM). NF-&kappa;B Signalisierung in Epithelzellen ist die Aktivierung von Transkriptionsfaktoren, die vermutet, dass zentrale BM Entwicklung, w&auml;hrend NF-&kappa;B Aktivierung in Fibroblasten eine entscheidende Rolle bei der Umgestaltung der Matrix spielt zugeordnet. Unser Ziel war es, die Auswirkungen einer S&auml;ure auf NF-&kappa;B Aktivierung im prim&auml;ren menschlichen &ouml;sophageale Fibroblasten (HOFs) und Prim&auml;r- und verewigt &ouml;sophageale Squames zu studieren und epitheliale und Stromale Wechselwirkungen in der Antwort dieser Zellen zur S&auml;ure zu untersuchen. Prim&auml;re HOFs und &ouml;sophageale Epithelzellen von Prim&auml;r- und verewigt wurden ausgesetzt S&auml;ure (pH 7 - pH 4 &le; 120 min) in Einzel- oder gepulste Behandlungen. Konditionierten Medium aus Epithelzellen, die folgenden sauren Exposition auch Fibroblasten angewendet wurde. Zellviabilit&auml;t wurde von MTT-ESTA bestimmt. NF-&kappa;B Aktivierung wurde durch zellul&auml;re Lokalisierung von NF-&kappa;B/p65 visualisiert durch Immunfluoreszenz bestimmt. Konditioniert Medium aus &ouml;sophageale Epithelzellen, Belichtung, NF-&kappa;B in Fibroblasten, aktiviert, mit einigen inter-patient Variabilit&auml;t pH-Wert 5 pulsierender ausgesetzt, aber diese Bedingungen die NF-&kappa;B in den Epithelzellen selbst nicht direkt aktiviert haben. Bedeutende NF-&kappa;B Aktivierung galt in den Epithelzellen sondern nur mit mehr S&auml;ure und Belichtung Zeiten (pH 4, 60-120 min). Unsere Ergebnisse zeigen, dass die sauren Exposition indirekte Aktivierung stromal Zellen von Epithel-Stroma-Interaktionen f&uuml;hren kann. Dies kann dazu beitragen, die Pathogenese der &ouml;sophageale Krankheiten kann, und die inter-patient Variabilit&auml;t irgendwie zu erkl&auml;ren, warum einige Patienten mit Reflux-&Ouml;sophagitis entwickeln BM und andere nicht.

NF-&kappa;B wird in &ouml;sophageale Fibroblasten als Reaktion auf eine parakrine-Signal generiert durch S&auml;ure-gemachten prim&auml;re &ouml;sophagealen Plattenepithel Zellen aktiviert.

Esposizione esofagea al refluxate duodenogastro-esofagea conduce al reflusso esofagite ed &egrave; implicato nello sviluppo di metaplasia di Barrett (BM). Segnalazione delle cellule epiteliali NF-&kappa;B &egrave; associato con l&#39;attivazione di fattori di trascrizione ritiene che sia fondamentale per lo sviluppo di BM, mentre l&#39;attivazione di NF-&kappa;B in fibroblasti gioca un ruolo fondamentale nel rimodellamento della matrice. Il nostro obiettivo era di studiare gli effetti dell&#39;esposizione acida su attivazione di NF-&kappa;B in fibroblasti umani esofagei primari (HOFs) e squames esofageo primario e immortalata e per indagare su eventuali interazioni epitelio/stromale nella risposta di queste cellule all&#39;acido. HOFs primaria e primarie e immortalate nelle cellule epiteliali esofagei sono stati esposti ad acido (pH 7 - pH 4 &le; 120 min) nel singoli o pulsate trattamenti. Mezzo condizionato dalle cellule epiteliali seguente esposizione acida &egrave; stato applicato anche ai fibroblasti. Vitalit&agrave; cellulare &egrave; stata determinata da MTT-ESTA. Attivazione di NF-&kappa;B &egrave; stato determinato dalla localizzazione cellulare di NF-&kappa;B/p65 visualizzati mediante immunofluorescenza. Condizionata medio da cellule epiteliali esofagei, sottoposti a pH 5 pulsatile esposizione, attivato NF-&kappa;B in fibroblasti, con qualche variabilit&agrave; inter-patient, ma queste condizioni non ha fatto direttamente attivare NF-&kappa;B nelle cellule epiteliali stessi. Significativa attivazione di NF-&kappa;B &egrave; stato visto nelle cellule epiteliali ma solo con una maggiore acidit&agrave; ed esposizione volte (pH 4, 60-120 min). I nostri risultati mostrano che l&#39;esposizione acida pu&ograve; causare indiretti attivazione di cellule stromali da interazioni epiteliali-stromale. Ci&ograve; pu&ograve; contribuire alla patogenesi delle malattie dell&#39;esofago, e la variabilit&agrave; inter-patient pu&ograve; andare qualche modo per spiegare perch&eacute; alcuni pazienti con esofagite da reflusso sviluppano BM e gli altri non lo fanno.

NF-&kappa;B &egrave; attivato in esofagei fibroblasti in risposta ad un segnale paracrina generato da acido-esposti primarie esofagea cellule squamose.

Duodenogastro &#x98DF;&#x9053; refluxate &#x98DF;&#x9053;&#x66DD;&#x9732;&#x306F;&#x98DF;&#x9053;&#x708E;&#x9006;&#x6D41;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x3057;&#x3001;&#x30D0;&#x30EC;&#x30C3;&#x30C8;&#x4E0A;&#x76AE;&#x5316;&#x751F; (BM) &#x306E;&#x958B;&#x767A;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;NF-&kappa; &#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306F;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B; NF-&kappa; &#x6D3B;&#x6027;&#x5316;&#x884C;&#x5217;&#x3092;&#x6539;&#x9020;&#x3067;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B;&#x3057;&#x306A;&#x304C;&#x3089; BM &#x306E;&#x958B;&#x767A;&#x306B;&#x4E2D;&#x592E;&#x3067;&#x3042;&#x308B;&#x3068;&#x8003;&#x3048;&#x3089;&#x308C;&#x3066;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x79C1;&#x305F;&#x3061;&#x306E;&#x76EE;&#x7684;&#x306F;&#x3001;&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x3072;&#x3068;&#x98DF;&#x9053;&#x7D30;&#x80DE; (HOFs) &#x306B;&#x304A;&#x3051;&#x308B; NF-&kappa; &#x6D3B;&#x6027;&#x5316;&#x306B;&#x53CA;&#x307C;&#x3059;&#x9178;&#x66DD;&#x9732;&#x3068;&#x98DF;&#x9053;&#x76AE;&#x6027;&#x6241;&#x5E73;&#x7D30;&#x80DE;&#x306E;&#x4E00;&#x6B21;&#x4E0D;&#x6B7B;&#x5316;&#x7814;&#x7A76;&#x3057;&#x3001;&#x4EFB;&#x610F;&#x9178;&#x306B;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D30;&#x80DE;&#x306E;&#x5FDC;&#x7B54;&#x3067;&#x4E0A;&#x76AE;&#x9593;&#x8CEA;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x3092;&#x8ABF;&#x67FB;&#x3059;&#x308B;&#x3060;&#x3063;&#x305F;&#x3002;&#x4E3B;&#x306A; HOFs &#x3068;&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x304A;&#x3088;&#x3073;&#x4E0D;&#x6B7B;&#x5316;&#x98DF;&#x9053;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x306F;&#x9178;&#x306B;&#x3055;&#x3089;&#x3055;&#x308C;&#x305F; (pH 7 - pH 4 &le; 120 min) &#x5358;&#x4E00;&#x307E;&#x305F;&#x306F;&#x30D1;&#x30EB;&#x30B9;&#x6CBB;&#x7642;&#x306E;&#x3002;&#x6B21;&#x306E;&#x9178;&#x66B4;&#x9732;&#x306F;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306B;&#x3082;&#x9069;&#x7528;&#x3055;&#x308C;&#x305F;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x99B4;&#x5316;&#x57F9;&#x5730;&#x3002;&#x7D30;&#x80DE;&#x751F;&#x5B58;&#x7387;&#x306F; MTT-ESTA &#x306B;&#x3088;&#x3063;&#x3066;&#x6C7A;&#x5B9A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;NF-&kappa; &#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;NF-&kappa;B/p65 &#x87A2;&#x5149;&#x6297;&#x4F53;&#x6CD5;&#x306B;&#x3088;&#x308B;&#x53EF;&#x8996;&#x5316;&#x306E;&#x7D30;&#x80DE;&#x5C40;&#x5728;&#x306B;&#x3088;&#x3063;&#x3066;&#x6C7A;&#x5B9A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x98DF;&#x9053;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x304B;&#x3089;&#x306E;&#x5A92;&#x4F53;&#x3092;&#x5B8C;&#x5099;&#x3001;&#x9732;&#x51FA;&#x3001;&#x3044;&#x304F;&#x3064;&#x304B; inter-patient &#x306E;&#x5909;&#x52D5;&#x3068;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B; NF-&kappa; &#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6; pH 5 &#x62CD;&#x52D5;&#x3092;&#x53D7;&#x3051;&#x308B;&#x304C;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x6761;&#x4EF6;&#x304C;&#x76F4;&#x63A5; NF-&kappa; &#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x81EA;&#x4F53;&#x3092;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x5316;&#x3057;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x91CD;&#x8981;&#x306A; NF-&kappa; &#x6D3B;&#x6027;&#x5316;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x3067;&#x3059;&#x304C;&#x5927;&#x304D;&#x3044;&#x9178;&#x5473;&#x3068;&#x9732;&#x51FA;&#x6642;&#x9593;&#x3067;&#x306E;&#x307F;&#x898B;&#x3089;&#x308C;&#x305F; &#xFF08;pH 4&#x3001;60-120 &#x5206;&#x3060;)&#x3002;&#x6211;&#x3005; &#x306E;&#x8ABF;&#x67FB;&#x7D50;&#x679C;&#x306F;&#x9178;&#x66DD;&#x9732;&#x304C;&#x4E0A;&#x76AE;&#x30FB;&#x9593;&#x8CEA;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306B;&#x3088;&#x308B;&#x9593;&#x8CEA;&#x7D30;&#x80DE;&#x306E;&#x9593;&#x63A5;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x306F;&#x98DF;&#x9053;&#x75BE;&#x60A3;&#x306E;&#x767A;&#x75C7;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3057;&#x3001;inter-patient &#x306E;&#x53EF;&#x5909;&#x6027;&#x306A;&#x305C; BM &#x8853;&#x306F;&#x9006;&#x6D41;&#x30E9;&#x30C3;&#x30C8;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x958B;&#x767A;&#x3057;&#x3001;&#x4ED6;&#x306F;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x8AAC;&#x660E;&#x3059;&#x308B;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x65B9;&#x6CD5;&#x3092;&#x884C;&#x304F;&#x3053;&#x3068;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

NF-&kappa; &#x9178;&#x3055;&#x3089;&#x3055;&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x98DF;&#x9053;&#x6241;&#x5E73;&#x4E0A;&#x76AE;&#x764C;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x3063;&#x3066;&#x751F;&#x6210;&#x3055;&#x308C;&#x308B;&#x508D;&#x5206;&#x6CCC;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306B;&#x5FDC;&#x7B54;&#x3059;&#x308B;&#x98DF;&#x9053;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x3067;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306B;&#x306A;&#x308A;&#x307E;&#x3059;&#x3002;

Duodenogastro &#xC2DD;&#xB3C4; refluxate &#xC2DD;&#xB3C4; &#xB178;&#xCD9C; &#xB9AC;&#xB4DC; &#xC2DD;&#xB3C4; &#xC5ED;&#xB958; &#xC131; &#xC2DD;&#xB3C4; &#xC5FC;&#xACFC; &#xBC14; &#xB81B;&#xC758; metaplasia (BM) &#xAC1C;&#xBC1C;&#xC5D0; &#xC5F0;&#xB8E8;. NF &kappa;B &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0; &#xC2E0;&#xD638; &#xC5F0;&#xACB0; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; NF &kappa;B &#xD65C;&#xC131;&#xD654; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; &#xAC1C;&#xC7A5;&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC744; &#xC7AC;&#xC0DD; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC911;&#xC559; BM &#xAC1C;&#xBC1C; &#xB420; &#xAC83;&#xC73C;&#xB85C; &#xCD94;&#xC815; &#xD558;&#xB294; &#xC804;&#xC0AC; &#xC778;&#xC790;&#xB97C; &#xD65C;&#xC131;&#xD654;&#xAC00; &#xB429;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xBAA9;&#xD45C;&#xB294; &#xAE30;&#xBCF8; &#xC778;&#xAC04;&#xC758; &#xC2DD;&#xB3C4; &#xAC8C;&#xC7AC; (HOFs)&#xC5D0; &#xC788;&#xB294; NF-&kappa;B &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xC0B0; &#xB178;&#xCD9C; &#xD6A8;&#xACFC; &#xBD88;&#xBA78; &#xD558; &#xAC8C; &#xC2DD;&#xB3C4; squames &#xACF5;&#xBD80; &#xD558; &#xACE0; &#xADF8;&#xB9AC;&#xACE0; &#xC0B0;&#xC774; &#xC138;&#xD3EC;&#xC758; &#xC751;&#xB2F5;&#xC5D0; &#xC5B4;&#xB5A4; &#xC0C1;&#xD53C; stromal &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC744; &#xC870;&#xC0AC;. &#xAE30;&#xBCF8; HOFs &#xBC0F; &#xC2DD;&#xB3C4; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xB97C; &#xBD88;&#xBA78; &#xD558; &#xAC8C; &#xD558; &#xACE0; &#xC8FC; &#xC0B0;&#xC5D0; &#xB178;&#xCD9C; &#xB41C; (pH 7-pH 4 &le; 120 &#xBD84;) &#xB2E8;&#xC77C; &#xB610;&#xB294; &#xD384;&#xC2A4; &#xCE58;&#xB8CC;&#xC5D0;. &#xB2E4;&#xC74C; &#xC0B0; &#xB178;&#xCD9C; &#xB610;&#xD55C; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC;&#xC5D0; &#xC801;&#xC6A9; &#xB41C; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xBC14;&#xB978;&#xB41C; &#xB9E4;&#xCCB4;. &#xC138;&#xD3EC; &#xC0DD;&#xC874; &#xB2A5;&#xB825; MTT ESTA&#xC5D0; &#xC758;&#xD574; &#xACB0;&#xC815; &#xB418;&#xC5C8;&#xB2E4;. NF &kappa;B &#xD65C;&#xC131;&#xD654; NF-&kappa;B/p65 &#xBA74;&#xC5ED; &#xD615;&#xAD11; &#xAC80;&#xC0AC;&#xC5D0;&#xC11C; &#xC2DC;&#xAC01;&#xC758; &#xC140;&#xB8F0;&#xB7EC; &#xC9C0;&#xC5ED;&#xD654;&#xC5D0; &#xC758;&#xD574; &#xACB0;&#xC815; &#xB418;&#xC5C8;&#xB2E4;. &#xC2DD;&#xB3C4; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xB9E4;&#xCCB4;&#xB97C; &#xC870;&#xC808;, &#xB178;&#xCD9C;, &#xC77C;&#xBD80; inter-patient &#xB2E4;&#xC591;&#xC131;&#xC73C;&#xB85C; &#xAC8C;&#xC7AC;, NF-&kappa;B &#xD65C;&#xC131;&#xD654; pH 5 &#xD0C0;&#xC545;&#xAE30;&#xB97C; &#xBCF5;&#xC885; &#xD558;&#xC9C0;&#xB9CC; &#xC774;&#xB7EC;&#xD55C; &#xC870;&#xAC74;&#xC744; &#xC9C1;&#xC811; &#xC2A4;&#xC2A4;&#xB85C; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; NF-&Kappa;b&#xC744; &#xD65C;&#xC131;&#xD654; &#xD558;&#xC9C0; &#xC54A;&#xC740;. &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0;&#xB9CC; &#xD070; &#xC0B0;&#xB3C4; &#xBC0F; &#xB178;&#xCD9C; &#xC2DC;&#xAC04; &#xB9CC;&#xC73C;&#xB85C; &#xC0C1;&#xB2F9;&#xD55C; NF &kappa;B &#xD65C;&#xC131;&#xD654; &#xBCF4;&#xC600;&#xB2E4; (pH 4, 60-120 &#xBD84;). &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xBCF4;&#xC5EC; &#xC0B0; &#xB178;&#xCD9C; &#xC0C1;&#xD53C; stromal &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xC758;&#xD574; stromal &#xC138;&#xD3EC;&#xC758; &#xAC04;&#xC811;&#xC801;&#xC778; &#xD65C;&#xC131;&#xD654;&#xB97C; &#xC77C;&#xC73C;&#xD0AC; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC2DD;&#xB3C4; &#xC9C8;&#xD658;&#xC758; pathogenesis&#xC758; &#xC6D0;&#xC778;&#xC774; &#xB420; &#xC218;&#xC774; &#xACE0; inter-patient &#xB2E4;&#xC591;&#xC131; &#xC65C; &#xC5ED;&#xB958; &#xC131; &#xC2DD;&#xB3C4; &#xC5FC; &#xC2DD;&#xB3C4; &#xC77C;&#xBD80; &#xD658;&#xC790; BM &#xAC1C;&#xBC1C; &#xD558; &#xACE0; &#xB2E4;&#xB978; &#xC0AC;&#xB78C;&#xC740; &#xC124;&#xBA85; &#xD558;&#xB294; &#xBA87; &#xAC00;&#xC9C0; &#xBC29;&#xBC95;&#xC774; &#xAC08; &#xC218;&#xB3C4; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

NF &kappa;B &#xC2DD;&#xB3C4; &#xAC8C;&#xC7AC; paracrine &#xC2E0;&#xD638; &#xC0B0; &#xB178;&#xCD9C; &#xAE30;&#xBCF8; &#xC2DD;&#xB3C4; &#xD3B8;&#xD3C9; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xC0DD;&#xC131; &#xB41C;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C; &#xD65C;&#xC131;&#xD654; &#xB429;&#xB2C8;&#xB2E4;.

Exposici&oacute;n esof&aacute;gica al refluxate duodenogastro-esof&aacute;gica conduce a esofagitis de reflujo y est&aacute; implicada en el desarrollo de la metaplasia de Barrett (BM). NF-&kappa;B se&ntilde;alizaci&oacute;n en las c&eacute;lulas epiteliales se asocia con la activaci&oacute;n de factores de transcripci&oacute;n que cree que es fundamental para el desarrollo del BM, mientras que la activaci&oacute;n de NF-&kappa;B en fibroblastos desempe&ntilde;a un papel cr&iacute;tico en la remodelaci&oacute;n de la matriz. Nuestro objetivo fue estudiar los efectos de la exposici&oacute;n de &aacute;cido en la activaci&oacute;n de NF-&kappa;B en fibroblastos esof&aacute;gicos humanos primarios (HOFs) y escamas esof&aacute;gica primaria e inmortalizado y cualquier interacci&oacute;n epitelial/stromal en la respuesta de estas c&eacute;lulas al &aacute;cido. HOFs primarios y las c&eacute;lulas epiteliales esof&aacute;gicas primarias e inmortalizadas fueron expuestas al &aacute;cido (pH 7 - pH 4 &le; 120 min) en tratamientos individuales o pulsados. Medio condicionado de c&eacute;lulas epiteliales siguiente exposici&oacute;n &aacute;cida tambi&eacute;n se aplic&oacute; a los fibroblastos. Viabilidad celular se determin&oacute; por MTT-ESTA. Activaci&oacute;n de NF-&kappa;B determin&oacute; la localizaci&oacute;n celular de NF-&kappa;B/p65 visualizado por inmunofluorescencia. Acondicionado en medio de las c&eacute;lulas epiteliales esof&aacute;gicas, sometidos a pH 5 puls&aacute;til exposici&oacute;n, activan NF-&kappa;B en fibroblastos, con cierta variabilidad entre, pero estas condiciones no activar directamente NF-&kappa;B en las propias c&eacute;lulas epiteliales. Activaci&oacute;n de NF-&kappa;B significativa se observ&oacute; en las c&eacute;lulas epiteliales, pero s&oacute;lo con una mayor acidez y exposici&oacute;n veces (pH 4, 60-120 min). Nuestros resultados demuestran que la exposici&oacute;n de &aacute;cido puede causar activaci&oacute;n indirecta de las c&eacute;lulas estromales por interacciones epiteliales-stromal. Esto puede contribuir a la patogenesia de enfermedades esof&aacute;gicas, y la variabilidad entre puede ir de alguna manera para explicar por qu&eacute; algunos pacientes con esofagitis de reflujo desarrollan BM y otros no.

NF-&kappa;B interviene en fibroblastos esof&aacute;gicos en respuesta a una se&ntilde;al paracrina generada por c&eacute;lulas escamosas esof&aacute;gicas primarias expuestos al &aacute;cido.

 Oesophageal cancer is an increasingly common human malignancy, with its incidence in the West rapidly rising. It is associated with a very poor prognosis, and its exact pathogenesis is uncertain. Dystroglycan and E-cadherin are cell adhesion molecules, the loss of which is often related to tumour differentiation, aggressiveness and invasiveness. The aim was therefore to evaluate their roles in oesophageal carcinogenesis.

Loss of dystroglycan function in oesophageal cancer.

Oesophageal exposure to duodenogastroesophageal refluxate is implicated in the development of Barrett's metaplasia (BM), with increased risk of progression to oesophageal adenocarcinoma. The literature proposes that reflux exposure activates NF-κB, driving the aberrant expression of intestine-specific caudal-related homeobox (CDX) genes. However, early events in the pathogenesis of BM from normal epithelium are poorly understood. To investigate this, our study subjected a 3D model of the normal human oesophageal mucosa to repeated, pulsatile exposure to specific bile components and examined changes in gene expression. Initial 2D experiments with a range of bile salts observed that taurochenodeoxycholate (TCDC) impacted upon NF-κB activation without causing cell death. Informed by this, the 3D oesophageal model was repeatedly exposed to TCDC in the presence and absence of acid, and the epithelial cells underwent gene expression profiling. We identified ~300 differentially expressed genes following each treatment, with a large and significant overlap between treatments. Enrichment analysis (Broad GSEA, DAVID and Metacore™; GeneGo Inc) identified multiple gene sets related to cell signalling, inflammation, proliferation, differentiation and cell adhesion. Specifically NF-κB activation, Wnt signalling, cell adhesion and targets for the transcription factors PTF1A and HNF4α were highlighted. Our data suggest that HNF4α isoform switching may be an early event in Barrett's pathogenesis. CDX1/2 targets were, however, not enriched, suggesting that although CDX1/2 activation reportedly plays a role in BM development, it may not be an initial event. Our findings highlight new areas for investigation in the earliest stages of BM pathogenesis of oesophageal diseases and new potential therapeutic targets.

Article	Year
Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 18223212	2008
Commonly used bowel preparations have significant and different effects upon cell proliferation in the colon: a pilot study. BMC gastroenterology\| PubMed ID: 19014572	2008
A study protocol to investigate the relationship between dietary fibre intake and fermentation, colon cell turnover, global protein acetylation and early carcinogenesis: the FACT study. BMC cancer\| PubMed ID: 19765278	2009
The development and characterization of an organotypic tissue-engineered human esophageal mucosal model. Tissue engineering. Part A\| PubMed ID: 19845463	2010
Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors. Digestive diseases and sciences\| PubMed ID: 20848206	2011
Keratin 8 expression in colon cancer associates with low faecal butyrate levels. BMC gastroenterology\| PubMed ID: 21219647	2011
Short-chain fatty acid level and field cancerization show opposing associations with enteroendocrine cell number and neuropilin expression in patients with colorectal adenoma. Molecular cancer\| PubMed ID: 21401950	2011
NF-ÎºB is activated in oesophageal fibroblasts in response to a paracrine signal generated by acid-exposed primary oesophageal squamous cells. International journal of experimental pathology\| PubMed ID: 21668534	2011
Loss of dystroglycan function in oesophageal cancer. Histopathology\| PubMed ID: 21884196	2011
Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa. International journal of experimental pathology\| PubMed ID: 24713057	2014

Jonathan P. Bury

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