a-method-for-generating-pulmonary-neutrophilia-using-aerosolized

A Method for Generating Pulmonary Neutrophilia Using Aerosolized Lipopolysaccharide

Acute lung injury (ALI) is a severe disease characterized by alveolar neutrophilia, with limited treatment options and high mortality. Experimental models ...

Karolinska Institutet

Glucocorticoids have several important roles in the lung and play a key role in lung development and maturation. However, the specific molecular mechanisms of glucocorticoid action in lung are unclear. In this study, we have investigated two glucocorticoid-regulated genes expressed in the lung epithelium, the secretory protein CCSP, and the P450-enzyme CYP2B1. In transient transfections of lung epithelial cells, glucocorticoids increased expression from the CCSP and CYP2B1 promoters and we demonstrated that induction was dependent on the integrity of C/EBP-binding sites in both promoters. Electrophoretic mobility shift assays revealed increased DNA-binding of C/EBPbeta and C/EBPdelta after glucocorticoid treatment, which was not correlated to altered protein levels. The results of this study indicate a previously unknown role for C/EBP transcription factors in glucocorticoid signaling in the lung epithelium.

Glucocorticoids regulate the CCSP and CYP2B1 promoters via C/EBPbeta and delta in lung cells.

The basic region-leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) and the homeodomain transcription factor Nkx2.1/thyroid transcription factor-1 are essential for normal lung morphogenesis. Nkx2.1 is expressed from the onset of lung development, whereas C/EBPalpha expression is turned on at later stages. The expression of C/EBPalpha correlates to the appearance of lung-specific proteins with differentiation-dependent expression patterns, such as the Clara cell secretory protein (secretoglobin 1a1 (Scgb1a1), CCSP). In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene. We show that the synergistic activity of C/EBPalpha and Nkx2.1 originates from cis-acting elements in the proximal promoter of CCSP and that the synergism is dependent on NH(2)-terminal transactivation domains of C/EBPalpha and Nkx2.1. Our results suggest that the cooperation of C/EBPalpha and Nkx2.1 is a major determinant for the high level, lung epithelial-specific expression of CCSP during the later stages of lung development and in the adult lung.

Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding protein alpha and the homeodomain factor Nkx2.1/thyroid transcription factor-1.

Estrogen, mainly estradiol (E2), and progesterone (P) are essential for the growth and differentiation of the breast, but their roles in breast cancer are highly debated. To understand how E2 and P influence cell proliferation and differentiation, it is essential to know how their receptors are regulated. Because of limited tissue availability, little is known about regulation of the two estrogen receptors (ERalpha and ERbeta) and the two progesterone receptor isoforms (PR-A and PR-B) in the normal human breast. What we know comes from rodent studies, which are not always pertinent for the human breast. We report now on regulation of gonadal hormone receptors during the menstrual cycle, pregnancy, and lactation in rhesus monkey mammary gland and on the relationship of these receptors to proliferation. We found that ERalpha but not ERbeta is down-regulated when E2 levels increase and when cells enter the cell cycle. PR-B but not PR-A is expressed in proliferating cells. Thus under normal conditions, the ratio of ERalpha to ERbeta in the breast depends on plasma concentrations of E2. Elevated expression of ERalpha (as occurs in postmenopausal women) is a normal response to loss of E2 and indicates nonproliferating cells. As selective receptor ligands become available, they will be helpful in delineation of the functions of these receptors.

Differential regulation of estrogen receptor (ER)alpha and ERbeta in primate mammary gland.

Glucocorticoids are widely prescribed anti-inflammatory drugs used for the treatment of many inflammatory lung disorders. However, much still remains unknown about their molecular mechanisms of action. We have previously shown that glucocorticoid-induced transcription in the lung epithelial cell line NCI-H441 is mediated via C/EBP sites in the promoters of target genes, and is likely to involve the transcription factors C/EBPbeta and C/EBPdelta. Here, we report that C/EBPbeta is the most active C/EBP-factor in both human and mouse lung epithelium and that glucocorticoids induce DNA binding of C/EBPbeta in cultured primary mouse lung epithelial cells. Mechanistic studies in H441 cells revealed that glucocorticoids, acting via the glucocorticoid receptor, increase C/EBPbeta binding starting 10 min after stimulation. The mechanism is independent of de novo protein synthesis and involves phosphorylation of C/EBPbeta at Thr(235). Together this shows that glucocorticoids increase DNA-binding activity of C/EBPbeta via post-translational mechanism(s) involving phosphorylation.

Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation.

The lung develops from the endoderm through a process of branching morphogenesis. This process is highly active during the pseudoglandular stage of lung development and continues into the canalicular stage, resulting in the formation of terminal sacs. CCAAT/enhancer binding proteins (C/EBPs) are transcription factors regulating central aspects of differentiation and proliferation. We report here the developmental expression of C/EBPalpha, -beta, and -delta in the lung. C/EBPalpha exhibits a dynamic expression pattern and is first detected during the late pseudoglandular stage. At this stage, expression is observed in a subset of epithelial cells in the distal parts of the branching tubules. The expression of C/EBPalpha is confined to nonproliferating cells. To examine the role of C/EBPalpha in lung development, we generated transgenic mice ectopically expressing C/EBPalpha in the lung epithelium using the human surfactant protein C promoter. Lungs from these mice were of normal size but exhibited a phenotype characterized by fewer and larger developing epithelial tubules, indicating that the branching process was affected. No effects on overall proliferation or cellular differentiation were observed. When this phenotype was compared with that of mice carrying a targeted mutation of the Cebpa gene, the Cebpa-/- mice exhibited a similar developmental phenotype. In conclusion, our results show a role for C/EBPalpha in lung development and suggest a function in the later stages of lung branching morphogenesis.

Ectopic expression of C/EBPalpha in the lung epithelium disrupts late lung development.

Fibroblast growth factor (FGF) segnalazione e beta-catenina attivazione hanno dimostrato di essere fondamentale per lo sviluppo di fegato embrionale precoce. Questo studio ha determinato il significato di FGF10-mediata segnalazione in una popolazione di cellule progenitrici fegato embrionale murino, come pure la sua relazione con attivazione beta-catenina. Abbiamo osservato che Fgf10(-/-) e Fgfr2b(-/-) fegati embrionali del mouse sono pi&ugrave; piccoli di fegati wild-type; Fgf10(-/-) fegati esibiscono diminuita proliferazione di hepatoblasts. Un confronto delle attivit&agrave; di beta-galattosidasi come una lettura dell&#39;espressione Fgf10 nei topi Fgf10(+/LacZ) e di attivazione beta-catenina in topi TOPGAL, picco dimostrata Fgf10 espressione da E9 E13.5 in concomitanza con l&#39;attivazione di beta-catenina di picco. Isolamento e marcatore gene espressione analisi citofluorimetriche di cellule LacZ(+) da E13.5 Fgf10(+/LacZ) e TOPGAL fegati, rispettivamente, ha rivelato che Fgf10 espressione e beta-catenina segnalazione si verificano distintamente nelle cellule stellate/myofibroblastic e hepatoblasts, rispettivamente. Inoltre, hepatoblasts express Fgfr2b, che suggerisce fortemente che possono rispondere alle FGF10 ricombinante prodotta da cellule stellate. Fgfr2b(-/-)/TOPGAL(+/+) embrionali fegati visualizzato meno attivit&agrave; di beta-galattosidasi di fegati di Fgfr2b(+/+)/TOPGAL(+/+) littermates. Inoltre, le culture di fegato intero explants in Matrigel o cellule in sospensione da E12.5 TOPGAL(+/+) topi visualizzato un marcato aumento nell&#39;attivit&agrave; della beta-galattosidasi e la sopravvivenza delle cellule dopo trattamento con FGF10 ricombinante, che indica che l&#39;attivazione FGFR (probabilmente FGFR2B) &egrave; a monte della beta-catenina segnalazione e promuovere hepatoblast sopravvivenza. CONCLUSIONE: Le cellule stellate/myofibroblastic embrionali promuovono attivazione beta-catenina e la sopravvivenza di hepatoblasts via FGF10-mediata segnalazione. Consigliamo un ruolo per stellate/myofibroblastic FGF10 entro la nicchia delle cellule staminali del fegato nel sostenere la proliferazione hepatoblast.

Fattore di crescita dei fibroblasti 10 &egrave; fondamentale per la crescita di fegato durante l&#39;embriogenesi e controlla hepatoblast sopravvivenza tramite attivazione beta-catenina.

&#x78B1;&#x6027;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x751F;&#x957F;&#x56E0;&#x5B50; (FGF) &#x4FE1;&#x53F7;&#x548C;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B;&#x5DF2;&#x88AB;&#x8BC1;&#x660E;&#x662F;&#x65E9;&#x671F;&#x80DA;&#x80CE;&#x809D;&#x810F;&#x53D1;&#x80B2;&#x7684;&#x5173;&#x952E;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x5DF2;&#x786E;&#x5B9A; FGF10 &#x4ECB;&#x5BFC;&#x5C0F;&#x9F20;&#x80DA;&#x80CE;&#x809D;&#x810F;&#x7956;&#x7EC6;&#x80DE;&#x4EBA;&#x53E3;&#xFF0C;&#x4EE5;&#x53CA;&#x5176;&#x5173;&#x7CFB;&#x5230;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B;&#x4FE1;&#x53F7;&#x7684;&#x610F;&#x4E49;&#x3002;&#x6211;&#x4EEC;&#x89C2;&#x5BDF;&#x5230; Fgf10(-/-) &#x548C; Fgfr2b(-/-) &#x5C0F;&#x9F20;&#x80DA;&#x80CE;&#x809D;&#x90FD;&#x5C0F;&#x4E8E;&#x91CE;&#x751F;&#x578B;&#x809D;&#x810F; &#xFF1B;Fgf10(-/-) &#x809D;&#x810F;&#x8868;&#x73B0;&#x51FA;&#x51CF;&#x5C11;&#x7684;&#x6269;&#x6563;&#x7684; hepatoblasts&#x3002;&#x4F5C;&#x4E3A;&#x8BFB;&#x51FA; Fgf10 Fgf10(+/LacZ) &#x5C0F;&#x9F20;&#x4E2D;&#x7684;&#x8868;&#x8FBE;&#x548C;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B; TOPGAL &#x5C0F;&#x9F20;&#x3001; &#x8868;&#x73B0;&#x51FA;&#x7684;&#x5CF0;&#x503C; Fgf10 &#x8868;&#x8FBE;&#x5F0F;&#x4ECE; E9 &#x5BF9;&#x8111;&#x795E;&#x7ECF;&#x4E0E;&#x9AD8;&#x5CF0;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B;&#x76F8;&#x543B;&#x5408;&#x7684; &beta;-&#x534A;&#x4E73;&#x7CD6;&#x82F7;&#x9176;&#x6D3B;&#x6027;&#x7684;&#x6BD4;&#x8F83;&#x3002;&#x6D41;&#x6D41;&#x5F0F;&#x7EC6;&#x80DE;&#x4EEA;&#x9694;&#x79BB;&#x548C;&#x6807;&#x8BB0;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x5206;&#x6790; LacZ(+) &#x7EC6;&#x80DE;&#x7684;&#x8111;&#x795E;&#x7ECF; Fgf10(+/LacZ) &#x53CA; TOPGAL &#x7684;&#x809D;&#x810F;&#xFF0C;&#x5206;&#x522B;&#x663E;&#x793A; Fgf10 &#x8868;&#x8FBE;&#x53CA;&#x8FDE;&#x73AF;&#x4FE1;&#x53F7;&#x4E2D;&#x51FA;&#x73B0;&#x7684;&#x660E;&#x663E;&#x661F;&#x72B6;/&#x808C;&#x7EA4;&#x7EF4;&#x6BCD;&#x7EC6;&#x80DE;&#x7EC6;&#x80DE;&#x548C; hepatoblasts&#xFF0C;&#x5206;&#x522B;&#x3002;&#x6B64;&#x5916;&#xFF0C;hepatoblasts &#x8868;&#x793A; Fgfr2b&#xFF0C;&#x8FD9;&#x6709;&#x529B;&#x5730;&#x8868;&#x660E;&#x4ED6;&#x4EEC;&#x53EF;&#x4EE5;&#x54CD;&#x5E94;&#x4EA7;&#x751F;&#x7684;&#x661F;&#x72B6;&#x7EC6;&#x80DE;&#x91CD;&#x7EC4; FGF10&#x3002;Fgfr2b(-/-)/TOPGAL(+/+) &#x80DA;&#x80CE;&#x809D;&#x810F;&#x663E;&#x793A;&#x809D;&#x810F;&#x7684; Fgfr2b(+/+)/TOPGAL(+/+) littermates &#x6BD4;&#x5C11; &beta;-&#x534A;&#x4E73;&#x7CD6;&#x82F7;&#x9176;&#x6D3B;&#x6027;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x6587;&#x5316;&#x7684;&#x6574;&#x4E2A;&#x809D;&#x810F;&#x5916;&#x690D;&#x4F53;&#x5728; Matrigel &#x6216;&#x4E2D;&#x6B62;&#x4ECE; E12.5 TOPGAL(+/+) &#x5C0F;&#x9F20;&#x663E;&#x793A; beta-&#x534A;&#x4E73;&#x7CD6;&#x82F7;&#x9176;&#x6D3B;&#x6027;&#x53CA;&#x91CD;&#x7EC4; FGF10&#xFF0C;&#x5904;&#x7406;&#x540E;&#x7684;&#x7EC6;&#x80DE;&#x5B58;&#x6D3B;&#x663E;&#x8457;&#x7684;&#x589E;&#x52A0;&#x8868;&#x660E; FGFR &#xFF08;&#x6700;&#x6709;&#x53EF;&#x80FD; FGFR2B&#xFF09; &#x6FC0;&#x6D3B;&#x662F;&#x4E0A;&#x6E38;&#x7684;&#x8FDE;&#x73AF;&#x4FE1;&#x4EE4;&#x548C;&#x4FC3;&#x8FDB; hepatoblast &#x751F;&#x5B58;&#x4E2D;&#x7684;&#x5355;&#x5143;&#x683C;&#x3002;&#x7ED3;&#x8BBA;: &#x661F;&#x72B6;/&#x808C;&#x7EA4;&#x7EF4;&#x6BCD;&#x7EC6;&#x80DE;&#x80DA;&#x80CE;&#x7EC6;&#x80DE;&#x4FC3;&#x8FDB;&#x5728;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B;&#x548C;&#x751F;&#x5B58;&#x7684; hepatoblasts &#x901A;&#x8FC7; FGF10 &#x4ECB;&#x5BFC;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x3002;&#x6211;&#x4EEC;&#x5EFA;&#x8BAE;&#x4E3A;&#x661F;&#x72B6;/&#x808C;&#x7EA4;&#x7EF4; FGF10 &#x652F;&#x6301;&#x589E;&#x6B96;&#x7684; hepatoblast &#x809D;&#x810F;&#x5E72;&#x7EC6;&#x80DE;&#x9F9B;&#x5185;&#x7684;&#x4F5C;&#x7528;&#x3002;

&#x78B1;&#x6027;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x751F;&#x957F;&#x56E0;&#x5B50; 10 &#x5BF9;&#x4E8E;&#x809D;&#x810F;&#x80DA;&#x80CE;&#x53D1;&#x751F;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x6210;&#x957F;&#x662F;&#x81F3;&#x5173;&#x91CD;&#x8981;&#x7684;&#x5E76;&#x63A7;&#x5236;&#x901A;&#x8FC7;&#x8FDE;&#x73AF;&#x6FC0;&#x6D3B; hepatoblast &#x751F;&#x5B58;&#x3002;

Fibroblast growth factor (FGF) signaling and beta-catenin activation have been shown to be crucial for early embryonic liver development. This study determined the significance of FGF10-mediated signaling in a murine embryonic liver progenitor cell population as well as its relation to beta-catenin activation. We observed that Fgf10(-/-) and Fgfr2b(-/-) mouse embryonic livers are smaller than wild-type livers; Fgf10(-/-) livers exhibit diminished proliferation of hepatoblasts. A comparison of beta-galactosidase activity as a readout of Fgf10 expression in Fgf10(+/LacZ) mice and of beta-catenin activation in TOPGAL mice, demonstrated peak Fgf10 expression from E9 to E13.5 coinciding with peak beta-catenin activation. Flow cytometric isolation and marker gene expression analysis of LacZ(+) cells from E13.5 Fgf10(+/LacZ) and TOPGAL livers, respectively, revealed that Fgf10 expression and beta-catenin signaling occur distinctly in stellate/myofibroblastic cells and hepatoblasts, respectively. Moreover, hepatoblasts express Fgfr2b, which strongly suggests they can respond to recombinant FGF10 produced by stellate cells. Fgfr2b(-/-)/TOPGAL(+/+) embryonic livers displayed less beta-galactosidase activity than livers of Fgfr2b(+/+)/TOPGAL(+/+) littermates. In addition, cultures of whole liver explants in Matrigel or cell in suspension from E12.5 TOPGAL(+/+)mice displayed a marked increase in beta-galactosidase activity and cell survival upon treatment with recombinant FGF10, indicating that FGFR (most likely FGFR2B) activation is upstream of beta-catenin signaling and promote hepatoblast survival. CONCLUSION: Embryonic stellate/myofibroblastic cells promote beta-catenin activation in and survival of hepatoblasts via FGF10-mediated signaling. We suggest a role for stellate/myofibroblastic FGF10 within the liver stem cell niche in supporting the proliferating hepatoblast.

Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta-catenin activation.

Facteur de croissance des fibroblastes (FGF) de signalisation et la b&#xEA;ta-cat&#xE9;nine activation ont &#xE9;t&#xE9; r&#xE9;v&#xE9;l&#xE9;s cruciaux pour le d&#xE9;veloppement du foie embryonnaire pr&#xE9;coce. Cette &#xE9;tude a d&#xE9;termin&#xE9; l&#x26;#39;importance de la signalisation m&#xE9;di&#xE9;e par FGF10 dans une population murine foie embryonnaire de cellules souches ainsi que sa relation avec la b&#xEA;ta-cat&#xE9;nine activation. Nous avons observ&#xE9; que FGF10 (- / -) et FGFR2b (- / -) foies embryonnaires de souris sont plus petites que les foies de type sauvage; FGF10 (- / -) foies pr&#xE9;sentent la prolif&#xE9;ration diminution de h&#xE9;patoblastes. Une comparaison de la b&#xEA;ta-galactosidase comme une lecture de FGF10 expression dans FGF10 (+ / LacZ) chez la souris et de la b&#xEA;ta-cat&#xE9;nine activation chez la souris TOPGAL, d&#xE9;montr&#xE9; pic FGF10 expression de E9 &#xE0; E13.5 co&#xEF;ncidant avec un pic la b&#xEA;ta-cat&#xE9;nine activation. L&#x26;#39;isolement par cytom&#xE9;trie en flux et analyse de l&#x26;#39;expression de g&#xE8;ne marqueur LacZ (+) des cellules de E13.5 FGF10 (+ / LacZ) et les foies TOPGAL, respectivement, a r&#xE9;v&#xE9;l&#xE9; que FGF10 expression et beta-cat&#xE9;nine se distinctement dans stellaire / cellules myofibroblastiques et h&#xE9;patoblastes, respectivement . En outre, h&#xE9;patoblastes expresse FGFR2b, ce qui sugg&#xE8;re fortement qu&#x26;#39;ils puissent r&#xE9;pondre aux recombinant FGF10 produite par les cellules &#xE9;toil&#xE9;es. FGFR2b (- / -) / TOPGAL (+ / +) de foies embryonnaires affich&#xE9; moins activit&#xE9; beta-galactosidase que les foies de FGFR2b (+ / +) / TOPGAL (+ / +) de la m&#xEA;me port&#xE9;e. En outre, des cultures d&#x26;#39;explants de foie entiers dans Matrigel ou d&#x26;#39;une cellule en suspension de E12.5 TOPGAL (+ / +) chez la souris affich&#xE9; une augmentation marqu&#xE9;e de la b&#xEA;ta-galactosidase et la survie cellulaire apr&#xE8;s traitement avec FGF10 recombinant, ce qui indique que FGFR (les plus susceptibles FGFR2b ) d&#x26;#39;activation est en amont de beta-cat&#xE9;nine et promouvoir la survie hepatoblast. CONCLUSION: stellaire embryonnaire / cellules myofibroblastiques promouvoir la b&#xEA;ta-cat&#xE9;nine dans l&#x26;#39;activation et la survie de h&#xE9;patoblastes via FGF10 la signalisation m&#xE9;di&#xE9;e. Nous sugg&#xE9;rons un r&#xF4;le &#xE0; jouer stellaire / myofibroblastique FGF10 dans la niche de cellules souches du foie dans le soutien du hepatoblast prolif&#xE8;rent.

Fibroblast Growth Factor 10 est critique pour la croissance du foie pendant l&#x26;#39;embryogen&#xE8;se et contr&#xF4;le la survie Hepatoblast Via b&#xEA;ta-cat&#xE9;nine activation

Fibroblasten-Wachstumsfaktor (FGF)-Signalisierung und Beta-Catenin-Aktivierung sind entscheidend f&uuml;r fr&uuml;he Embryonalentwicklung Leber gezeigt worden. Diese Studie bestimmt die Bedeutung von FGF10-vermittelte signalisieren in einer Zellpopulation murinen embryonalen Vorl&auml;uferzellen Leber sowie ihre Beziehung zur Beta-Catenin-Aktivierung. Wir beobachteten, dass Fgf10(-/-) und Fgfr2b(-/-) Maus embryonalen Leber kleiner als Wildtyp Lebern sind; Fgf10(-/-) Leber weisen geringere Verbreitung von Hepatoblasts. Ein Vergleich der &beta;-Galactosidase-Aktivit&auml;t als ein Auslesen von Fgf10 Ausdruck bei Fgf10(+/LacZ) M&auml;usen und Beta-Catenin-Aktivierung bei TOPGAL M&auml;usen, demonstrierte Spitze Fgf10 Ausdruck von E9 bis E13.5 zeitgleich mit Spitze-Beta-Catenin-Aktivierung. Flie&szlig;en Cytometric Isolierung und Marker Genexpressionsanalyse von LacZ(+) Zellen aus E13.5 Fgf10(+/LacZ) und TOPGAL Leber ergeben bzw., dass Fgf10 Ausdruck und Beta-Catenin signalisieren deutlich in stellate/myofibroblastischer Zellen und Hepatoblasts, bzw. auftreten. Dar&uuml;ber hinaus schnelles Hepatoblasts Fgfr2b, was stark darauf hindeutet, dass sie auf rekombinante FGF10 produziert von stellate Zellen reagieren k&ouml;nnen. Fgfr2b(-/-)/TOPGAL(+/+) embryonalen Leber angezeigt weniger &beta;-Galactosidase-Aktivit&auml;t als Leber von Fgfr2b(+/+)/TOPGAL(+/+) Wurfgeschwister. Dar&uuml;ber hinaus Kulturen der ganzen Leber explants in Matrigel oder Zelle Aufhebung von E12.5 TOPGAL(+/+) M&auml;use angezeigt eine deutliche Zunahme der &beta;-Galactosidase-Aktivit&auml;t und Zelle &Uuml;berleben nach Behandlung mit rekombinantem FGF10, darauf hinweist, dass FGFR-bedingten (wahrscheinlich FGFR2B) Aktivierung ist Beta-Catenin signalisieren upstream und f&ouml;rdern Hepatoblast &uuml;berleben. Fazit: Beta-Catenin-Aktivierung in und &Uuml;berleben der Hepatoblasts &uuml;ber FGF10-vermittelte Signalisierung embryonale stellate/myofibroblastischer Zellen f&ouml;rdern. Wir empfehlen eine Rolle f&uuml;r stellate/myofibroblastischer FGF10 innerhalb der Leber Stammzelle Nische der ausufernden Hepatoblast zu unterst&uuml;tzen.

Fibroblasten-Wachstumsfaktor 10 ist kritisch f&uuml;r die Leber Wachstum w&auml;hrend der Embryogenese und steuert Hepatoblast &Uuml;berleben &uuml;ber Beta-Catenin-Aktivierung.

&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x5897;&#x6B96;&#x56E0;&#x5B50;&#xFF08;FGF&#xFF09;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x304A;&#x3088;&#x3073;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x521D;&#x671F;&#x80DA;&#x809D;&#x81D3;&#x958B;&#x767A;&#x306E;&#x305F;&#x3081;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x304C;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x30DE;&#x30A6;&#x30B9;&#x80DA;&#x6027;&#x809D;&#x524D;&#x99C6;&#x7D30;&#x80DE;&#x96C6;&#x56E3;&#x3068;&#x540C;&#x69D8;&#x306B;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;&#x306E;&#x95A2;&#x4FC2;&#x306B;&#x304A;&#x3051;&#x308B;FGF10&#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306E;&#x91CD;&#x8981;&#x6027;&#x3092;&#x6C7A;&#x5B9A;&#x3057;&#x305F;&#x3002;&#x809D;&#x81D3;&#x306F;&#x3001;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x6E1B;&#x5C11;&#x5897;&#x6B96;&#x3092;&#x793A;&#x3059;FGF10&#xFF08; -  /  - &#xFF09;&#xFF08; -  /  - &#xFF09;&#x3068;Fgfr2b&#xFF08; -  /  - &#xFF09;&#x30DE;&#x30A6;&#x30B9;&#x80DA;&#x6027;&#x809D;&#x91CE;&#x751F;&#x578B;&#x809D;&#x81D3;&#x3088;&#x308A;&#x3082;&#x5C0F;&#x3055;&#x3044;&#x6211;&#x3005;&#x306F;&#x3001;FGF10&#x3053;&#x3068;&#x3092;&#x89B3;&#x5BDF;&#x3057;&#x305F;&#x3002; FGF10 FGF10&#x306E;&#x767A;&#x73FE;&#xFF08;+ / LacZ&#xFF09;&#x3092;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x3068;TOPGAL&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x8AAD;&#x307F;&#x51FA;&#x3057;&#x306A;&#x3069;&#x306E;&#x3B2;-&#x30AC;&#x30E9;&#x30AF;&#x30C8;&#x30B7;&#x30C0;&#x30FC;&#x30BC;&#x6D3B;&#x6027;&#x306E;&#x6BD4;&#x8F03;&#x3067;&#x306F;&#x3001;&#x30D4;&#x30FC;&#x30AF;&#x6642;&#x306E;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;&#x4E00;&#x81F4;E9&#x304B;&#x3089;E13.5&#x306B;&#x30D4;&#x30FC;&#x30AF;FGF10&#x306E;&#x767A;&#x73FE;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x30D5;&#x30ED;&#x30FC;&#x30B5;&#x30A4;&#x30C8;&#x30E1;&#x30C8;&#x30EA;&#x30FC;&#x5206;&#x96E2;&#x304A;&#x3088;&#x3073;LacZ&#x306E;&#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x89E3;&#x6790;&#xFF08;+&#xFF09;&#x306F;&#x3001;&#x305D;&#x308C;&#x305E;&#x308C;E13.5 FGF10&#x306E;&#x7D30;&#x80DE;&#xFF08;+ / LacZ&#xFF09;&#x3068;TOPGAL&#x809D;&#x81D3;&#x306F;&#x3001;FGF10&#x306E;&#x767A;&#x73FE;&#x3068;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306F;&#x305D;&#x308C;&#x305E;&#x308C;&#x3001;&#x661F;&#x72B6;/&#x7B4B;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x3068;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x3067;&#x660E;&#x3089;&#x304B;&#x306B;&#x8D77;&#x3053;&#x308B;&#x3053;&#x3068;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;&#x307E;&#x305F;&#x3001;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306B;&#x5F37;&#x304F;&#x3001;&#x5F7C;&#x3089;&#x304C;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308A;&#x7523;&#x751F;&#x3055;&#x308C;&#x308B;&#x7D44;&#x63DB;&#x3048;FGF10&#x306B;&#x5BFE;&#x5FDC;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x6025;&#x884C;Fgfr2b&#x3001;&#x3002; Fgfr2b&#xFF08; -  /  - &#xFF09;/ TOPGAL&#xFF08;+ / +&#xFF09;&#x80CE;&#x5150;&#x306E;&#x809D;&#x81D3;&#x306F;Fgfr2b&#xFF08;+ / +&#xFF09;/ TOPGAL&#xFF08;+ / +&#xFF09;&#x540C;&#x8179;&#x5B50;&#x306E;&#x809D;&#x81D3;&#x672A;&#x6E80;&#x306E;&#x3B2;-&#x30AC;&#x30E9;&#x30AF;&#x30C8;&#x30B7;&#x30C0;&#x30FC;&#x30BC;&#x6D3B;&#x6027;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;E12.5&#x304B;&#x3089;&#x30DE;&#x30C8;&#x30EA;&#x30B2;&#x30EB;&#x307E;&#x305F;&#x306F;&#x61F8;&#x6FC1;&#x6DB2;&#x4E2D;&#x306E;&#x7D30;&#x80DE;&#x5185;&#x306E;&#x5168;&#x809D;&#x79FB;&#x690D;&#x7247;&#x306E;&#x57F9;&#x990A;TOPGAL&#xFF08;+ / +&#xFF09;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x305D;&#x306E;FGFR&#xFF08;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x5834;&#x5408;FGFR2B&#x3092;&#x793A;&#x3059;&#x7D44;&#x63DB;&#x3048;FGF10&#x306B;&#x3088;&#x308B;&#x6CBB;&#x7642;&#x6642;&#x306B;&#x3B2;-&#x30AC;&#x30E9;&#x30AF;&#x30C8;&#x30B7;&#x30C0;&#x30FC;&#x30BC;&#x6D3B;&#x6027;&#x3068;&#x7D30;&#x80DE;&#x751F;&#x5B58;&#x7387;&#x306E;&#x8457;&#x3057;&#x3044;&#x5897;&#x52A0;&#x3092;&#x793A;&#x3057;&#x305F;&#xFF09;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306E;&#x4E0A;&#x6D41;&#x306B;&#x3042;&#x308B;&#x3068;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x751F;&#x5B58;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x3002;&#x7D50;&#x8AD6;&#xFF1A;&#x80CE;&#x5150;&#x661F;&#x72B6;/&#x7B4B;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306F;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;FGF10&#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x3092;&#x4ECB;&#x3057;&#x305F;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x751F;&#x5B58;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x5897;&#x6B96;&#x3092;&#x652F;&#x63F4;&#x3059;&#x308B;&#x4E0A;&#x3067;&#x306E;&#x809D;&#x5E79;&#x7D30;&#x80DE;&#x306E;&#x30CB;&#x30C3;&#x30C1;&#x5185;&#x306E;&#x7B4B;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;/&#x661F;&#x72B6;FGF10&#x306E;&#x5F79;&#x5272;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x5897;&#x6B96;&#x56E0;&#x5B50;10&#x306F;&#x3001;&#x80DA;&#x767A;&#x751F;&#x6642;&#x306E;&#x809D;&#x81D3;&#x306E;&#x6210;&#x9577;&#x306E;&#x305F;&#x3081;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308A;&#x3001;&#x3B2;-&#x30AB;&#x30C6;&#x30CB;&#x30F3;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x809D;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x751F;&#x5B58;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;

&#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; &#xC131;&#xC7A5; &#xC778;&#xC790; (FGF) &#xC2E0;&#xD638; &#xBC0F; &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654; &#xAC04; &#xAC1C;&#xBC1C; &#xCD08;&#xAE30; &#xBC30;&#xC544;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xB300; &#xD55C; &#xAD00;&#xAC74;&#xC774; &#xB420; &#xD45C;&#xC2DC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xB294; &#xAC04; &#xC870;&#xC0C1; murine &#xBC30;&#xC544; &#xC138;&#xD3EC; &#xC778;&#xAD6C; &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654;&#xC758; &#xAD00;&#xACC4;&#xC5D0;&#xC11C; &#xC2E0;&#xD638; FGF10 &#xC911;&#xC7AC;&#xC758; &#xC911;&#xC694;&#xC131;&#xC744; &#xACB0;&#xC815;. Fgf10(-/-) &#xBC0F; Fgfr2b(-/-) &#xB9C8;&#xC6B0;&#xC2A4; &#xBC30;&#xC544; &#xAC04;&#xC5D0; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xAC04;; &#xBCF4;&#xB2E4; &#xC791;&#xC740; &#xAD00;&#xCC30; Fgf10(-/-) &#xAC04;&#xC740; hepatoblasts&#xC758; &#xC800;&#xD558; &#xD655;&#xC0B0; &#xC804;&#xC2DC;. Fgf10(+/LacZ) &#xC950;&#xC5D0; Fgf10 &#xC2DD;&#xC758; &#xBC0F; TOPGAL &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654;, E9 E13.5 &#xD53C;&#xD06C; &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654;&#xC640; &#xB3D9;&#xC2DC;&#xC5D0; &#xAC80;&#xC99D; &#xB41C; &#xD53C;&#xD06C; Fgf10 &#xC2DD;&#xC758; &#xD310;&#xB3C5;&#xC73C;&#xB85C; &#xBCA0;&#xD0C0;-galactosidase &#xD65C;&#xB3D9;&#xC758; &#xBE44;&#xAD50;. &#xD750;&#xB984; cytometric &#xACE0;&#xB9BD;&#xACFC; &#xB9C8;&#xCEE4; &#xC720;&#xC804;&#xC790; &#xC2DD; &#xBD84;&#xC11D; E13.5 fgf10(+/lacz)&#xC640; TOPGAL &#xAC04;&#xC740;&#xC5D0;&#xC11C; LacZ(+) &#xC140;&#xC758; &#xAC01;&#xAC01; &#xADF8; Fgf10 &#xC2DD;&#xACFC; &#xBCA0;&#xD0C0;-catenin &#xC2E0;&#xD638; &#xBC1C;&#xC0DD; &#xBD84;&#xBA85;&#xD788; &#xC8FC;&#xBB38;&#xACFC;/myofibroblastic &#xC138;&#xD3EC;&#xC640; hepatoblasts, &#xAC01;&#xAC01; &#xBC1D;&#xD614;&#xB2E4;. &#xB610;&#xD55C;, hepatoblasts &#xC775;&#xC2A4;&#xD504;&#xB808;&#xC2A4; Fgfr2b, &#xAC15;&#xB825; &#xD558; &#xAC8C; &#xC81C;&#xC548; &#xC8FC;&#xBB38;&#xACFC; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xC0DD;&#xC0B0; &#xB41C; &#xC7AC;&#xC870;&#xD569; fgf10&#xC5D0; &#xB300;&#xCC98;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. Fgfr2b(-/-)/TOPGAL(+/+) &#xBC30;&#xC544; &#xAC04;&#xC744; &#xD45C;&#xC2DC; Fgfr2b(+/+)/TOPGAL(+/+) littermates &#xAC04; &#xBCF4;&#xB2E4; &#xC801;&#xC740; &#xBCA0;&#xD0C0;-galactosidase &#xD65C;&#xB3D9;. &#xB610;&#xD55C;, &#xC804;&#xCCB4; &#xAC04; &#xBB38;&#xD654; Matrigel &#xB610;&#xB294; &#xC140; E12.5 TOPGAL(+/+) &#xB9C8;&#xC6B0;&#xC2A4; &#xD45C;&#xC2DC; &#xBCA0;&#xD0C0;-galactosidase &#xD65C;&#xB3D9; &#xBC0F; &#xC7AC;&#xC870;&#xD569; FGF10 &#xCE58;&#xB8CC; &#xC2DC; &#xC138;&#xD3EC; &#xC0DD;&#xC874;&#xC5D0; &#xD45C;&#xC2DC; &#xB41C; &#xC99D;&#xAC00; FGFR (&#xC8FC;&#xB85C; FGFR2B) &#xD65C;&#xC131;&#xD654; &#xBCA0;&#xD0C0;-catenin &#xC2E0;&#xD638;&#xC758; &#xC5C5;&#xC2A4;&#xD2B8;&#xB9BC;, hepatoblast &#xC0DD;&#xC874; &#xD64D;&#xBCF4; &#xB098;&#xD0C0;&#xB0B4;&#xB294;&#xC5D0;&#xC11C; &#xC11C; &#xC2A4; &#xD39C; &#xC158;&#xC5D0; explants. &#xACB0;&#xB860;: &#xBC30;&#xC544; &#xC8FC;&#xBB38;&#xACFC;/myofibroblastic &#xC138;&#xD3EC;&#xC5D0; &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654; &#xBC0F; &#xC0DD;&#xC874; &#xC2E0;&#xD638; FGF10 &#xC911;&#xC7AC;&#xB97C; &#xD1B5;&#xD574; hepatoblasts&#xC758; &#xD64D;&#xBCF4;. &#xC8FC;&#xBB38;&#xACFC; myofibroblastic/FGF10 &#xBC29;&#xC9C0;&#xD560; hepatoblast &#xC9C0;&#xC6D0; &#xAC04; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xD2C8;&#xC0C8; &#xC2DC;&#xAC04;&#xC5D0; &#xB300; &#xD55C; &#xC5ED;&#xD560;&#xC744; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; &#xC131;&#xC7A5; &#xC778;&#xC790; 10 embryogenesis &#xC911; &#xAC04; &#xC131;&#xC7A5;&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC774;&#xBA70;, &#xBCA0;&#xD0C0;-catenin &#xD65C;&#xC131;&#xD654;&#xB97C; &#xD1B5;&#xD574; hepatoblast &#xC0DD;&#xC874;&#xC744; &#xC81C;&#xC5B4; &#xD569;&#xB2C8;&#xB2E4;.

Factor de crecimiento fibrobl&#xE1;stico (FGF) y la activaci&#xF3;n de se&#xF1;alizaci&#xF3;n beta-catenina se han demostrado ser esencial para el desarrollo temprano del h&#xED;gado embrionario. Este estudio determin&#xF3; la importancia de FGF10 se&#xF1;alizaci&#xF3;n mediada por una poblaci&#xF3;n de c&#xE9;lulas embrionarias de rat&#xF3;n h&#xED;gado progenitoras, as&#xED; como su relaci&#xF3;n con la activaci&#xF3;n de la beta-catenina. Hemos observado que FGF10 (- / -) y Fgfr2b (- / -) los h&#xED;gados de embriones de rat&#xF3;n son m&#xE1;s peque&#xF1;os que los de tipo salvaje h&#xED;gados; FGF10 (- / -) h&#xED;gados presentan disminuci&#xF3;n de la proliferaci&#xF3;n hepatoblasts. Una comparaci&#xF3;n de la actividad beta-galactosidasa, como una lectura de FGF10 expresi&#xF3;n en FGF10 (+ / LacZ) en ratones y de la activaci&#xF3;n de la beta-catenina en ratones TOPGAL, demostr&#xF3; m&#xE1;xima expresi&#xF3;n de FGF10 E9 a E13.5 coincidiendo con el pico de la activaci&#xF3;n de la beta-catenina. El aislamiento de citometr&#xED;a de flujo y an&#xE1;lisis del gen marcador de expresi&#xF3;n de LacZ (+) las c&#xE9;lulas de E13.5 FGF10 (+ / LacZ) y los h&#xED;gados TOPGAL, respectivamente, revel&#xF3; que el FGF10 expresi&#xF3;n y de se&#xF1;alizaci&#xF3;n beta-catenina ocurre claramente en el estrellado / c&#xE9;lulas miofibrobl&#xE1;stico y hepatoblasts, respectivamente . Por otra parte, expresa hepatoblasts Fgfr2b, lo cual sugiere que pueden responder a FGF10 recombinante producida por las c&#xE9;lulas estrelladas. Fgfr2b (- / -) / TOPGAL (+ / +) h&#xED;gados de embriones muestran menos actividad de la beta-galactosidasa que los h&#xED;gados de Fgfr2b (+ / +) / TOPGAL (+ / +) de camada. Adem&#xE1;s, los cultivos de explantes de h&#xED;gado entero en Matrigel o c&#xE9;lulas en suspensi&#xF3;n de E12.5 TOPGAL (+ / +) ratones muestran un marcado aumento de la actividad beta-galactosidasa y supervivencia de las c&#xE9;lulas tras el tratamiento con FGF10 recombinante, lo que indica que FGFR (m&#xE1;s probable FGFR2B ) la activaci&#xF3;n est&#xE1; aguas arriba de la beta-catenina de se&#xF1;alizaci&#xF3;n y promover la supervivencia hepatoblast. CONCLUSI&#xD3;N: estrellado embrionario / c&#xE9;lulas myofibroblastic promover la beta-catenina en la activaci&#xF3;n y la supervivencia de hepatoblasts a trav&#xE9;s de la se&#xF1;alizaci&#xF3;n mediada por FGF10. Se sugiere un papel para estrellado / miofibrobl&#xE1;stico FGF10 en el nicho de c&#xE9;lulas madre del h&#xED;gado en el apoyo a la proliferaci&#xF3;n de hepatoblast.

Factor de crecimiento de fibroblastos 10 es fundamental para el crecimiento del h&#xED;gado durante la embriog&#xE9;nesis y Controles de supervivencia Hepatoblast trav&#xE9;s de Beta-catenina activaci&#xF3;n

Understanding the pathways regulating mesenchymal progenitor cell fate during hepatogenesis may provide insight into postnatal liver injury or liver bioengineering. While β-Catenin has been implicated in the proliferation of fetal hepatic epithelial progenitor cells, its role in mesenchymal precursors during hepatogenesis has not been established.

β-catenin regulates mesenchymal progenitor cell differentiation during hepatogenesis.

Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.

Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways.

Cigarette smoke is the major cause of chronic obstructive pulmonary disease and lung cancer. The mechanisms by which smoking induces pulmonary dysfunction are complex, involving stress from toxic components and inflammatory responses. Although CCCAAT/enhancer-binding protein (C/EBP)-β is known as a key intracellular regulator of inflammatory signaling, its role in pulmonary inflammation has not been established.

Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke.

CCAAT/enhancer-binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ-deficient mice, although C/EBPβ trans-activate pulmonary genes by binding to virtually identical DNA-sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial-specific (SFTPC-Cre-mediated) deletion of C/EBPα (Cebpa(ΔLE) ), C/EBPβ (Cebpb(ΔLE) ), or both genes (Cebpa(ΔLE) ; Cebpb(ΔLE) ).

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ.

The inflammatory processes associated with pulmonary disorders remains incompletely understood. CCAAT/enhancer-binding protein (C/EBP)β is implicated in inflammatory lung disorders as well as in β(2)-adrenoceptor signaling. We hypothesized that C/EBPβ in the lung epithelium contributes to lipopolysaccharide (LPS)-induced airway neutrophilia and expression of neutrophil chemoattractant chemokine (C-X-C) motif ligand (CXCL)1, as well as the suppressive effects of long-acting β(2)-agonists (LABAs) and glucocorticoids (GCs). To investigate this, mice with a lung epithelial-specific deletion of C/EBPβ (Cebpb(ΔLE)) and control littermates (Cebpb(fl/fl)) were pre-treated with a LABA, formoterol and/or a GC, budesonide, and challenged with LPS. Inflammatory cell recruitment in bronchoalveolar lavage (BAL) fluid and pulmonary expression of inflammatory mediators were investigated. In addition, the ability of formoterol to increase C/EBP transactivation was assessed in vitro. LPS-challenged Cebpb(ΔLE) mice exhibited fewer BAL neutrophils and lower pulmonary expression of CXCL1 versus Cebpb(fl/fl) mice. Suppression of LPS-induced neutrophilia by formoterol was impaired in Cebpb(ΔLE) mice and Cxcl1 expression was increased. However, suppression of the neutrophilia by budesonide with/without formoterol was preserved. Further studies indicated that C/EBP transactivation was increased by the cAMP elevating agent forskolin and formoterol in a β(2)-adrenoceptor dependent manner. Thus, C/EBPβ in the lung epithelium contributes to LPS-induced CXCL1 expression and airway neutrophilia as well as to the suppressive effects of formoterol. Reduced C/EBPβ activity, observed in smokers with chronic obstructive pulmonary disease, may impair the responsiveness to LABAs when used without GCs.

Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol.

Premature infants frequently develop bronchopulmonary dysplasia (BPD). Lung immaturity and impaired epithelial differentiation contribute together with invasive oxygen treatment to BPD onset and disease progression. Substantial evidence suggests that prematurity is associated with long term pulmonary consequences. Moreover, there is increasing concern that lung immaturity at birth may increase the risk of developing chronic obstructive pulmonary disease (COPD). The mechanisms contributing to this phenomenon remains unknown, largely as a consequence of inadequate experimental models and clinical follow-up studies. Recent evidence suggests that defective transcriptional regulation of epithelial differentiation and maturation may contribute to BPD pathogenesis as well as early onset of COPD. The transcriptional regulators CCAAT/enhancer-binding protein (C/EBP)α and C/EBPβ, SMAD family member (Smad)3, GATA binding protein (GATA)6, and NK2 homeobox (NKX)2-1 are reported to be involved in processes contributing to pathogenesis of both BPD and COPD. Increased knowledge of the mechanisms contributing to early onset COPD among BPD survivors could translate into improved treatment strategies and reduced frequency of respiratory disorders among adult survivors of BPD. In this paper, we introduce critical transcriptional regulators in epithelial differentiation and summarize the current knowledge on the contribution of impaired epithelial maturation to the pathogenesis of inflammatory lung disorders.

A Relationship between Epithelial Maturation, Bronchopulmonary Dysplasia, and Chronic Obstructive Pulmonary Disease.

Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

Article	Year
Glucocorticoids regulate the CCSP and CYP2B1 promoters via C/EBPbeta and delta in lung cells. Biochemical and biophysical research communications\| PubMed ID: 12051744	2002
Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding prote... The Journal of biological chemistry\| PubMed ID: 12161423	2002
Differential regulation of estrogen receptor (ER)alpha and ERbeta in primate mammary gland. The Journal of clinical endocrinology and metabolism\| PubMed ID: 15507513	2005
Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochemical and biophysical research communications\| PubMed ID: 16009338	2005
Ectopic expression of C/EBPalpha in the lung epithelium disrupts late lung development. American journal of physiology. Lung cellular and molecular physiology\| PubMed ID: 16698852	2006
Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta-catenin activation. Hepatology (Baltimore, Md.)\| PubMed ID: 17668871	2007
β-catenin regulates mesenchymal progenitor cell differentiation during hepatogenesis. The Journal of surgical research\| PubMed ID: 20381814	2010
Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. PloS one\| PubMed ID: 21283768	2011
Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke. American journal of respiratory and critical care medicine\| PubMed ID: 21562127	2011
Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ. Developmental dynamics : an official publication of the American Association of Anatomists\| PubMed ID: 22411169	2012
Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol. Biochemical and biophysical research communications\| PubMed ID: 22634316	2012
A Relationship between Epithelial Maturation, Bronchopulmonary Dysplasia, and Chronic Obstructive Pulmonary Disease. Pulmonary medicine\| PubMed ID: 23320163	2012
Human enterovirus species B in ileocecal Crohn's disease. Clinical and translational gastroenterology\| PubMed ID: 23804031	2013
[The marginal with Huntington's disease]. Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række\| PubMed ID: 24172632	2013

Tove Berg

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