Wnt signaling regulates trans-differentiation of stem cell like type 2 alveolar epithelial cells to type 1 epithelial cells.

Background: Type 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s). In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process.

Methods: AT2 cells can be isolated from human lungs and cultured in vitro where they undergo TD into AT1s.

Lipoxin A promotes lung epithelial repair whilst inhibiting fibroblast proliferation.

Therapy that promotes epithelial repair whilst protecting against fibroproliferation is critical for restoring lung function in acute and chronic respiratory diseases. Primary human alveolar type II cells were used to model the effects of lipoxin A upon wound repair, proliferation, apoptosis and transdifferention. Effects of lipoxin A upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also assessed.

Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis.

Background: CD248 or Endosialin is a transmembrane molecule expressed in stromal cells binding to extracellular matrix (ECM) components. It has been previously implicated in kidney fibrosis, rheumatoid arthritis as well as in tumour-stromal interactions. This study investigates the role of CD248 in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis (IPF).

Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence.

In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator-activated receptor gamma (PPARγ)-dependent special cell type of the pulmonary tissue.

Epithelial-mesenchymal transition in lung development and disease: does it exist and is it important?

Epithelial-mesenchymal transition (EMT) is a process when epithelial cells gradually transform into mesenchymal-like cells losing their epithelial functionality and characteristics. EMT is thought to be involved in the pathogenesis of numerous lung diseases ranging from developmental disorders, fibrotic tissue remodelling to lung cancer. The most important question--namely what is the importance and contribution of EMT in the pathogenesis of several chronic lung conditions (asthma, COPD, bronchiolitis obliterans syndrome and lung fibrosis)--is currently intensely debated.

Down-regulation of canonical and up-regulation of non-canonical Wnt signalling in the carcinogenic process of squamous cell lung carcinoma.

The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood.

Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence.

Members of the Wnt family of secreted glyco-lipo-proteins affect intrathymic T-cell development and are abundantly secreted by thymic epithelial cells (TECs) that create the specific microenvironment for thymocytes to develop into mature T-cells. During ageing, Wnt expression declines allowing adipoid involution of the thymic epithelium leading to reduced naïve T-cell output. The protein kinase C (PKC) family of serine-threonine kinases is involved in numerous intracellular biochemical processes, including Wnt signal transduction.

Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence.

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear.

Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells.

In the last decade new glucocorticoid (GC)-signalling mechanisms have emerged. The evolving field of non-genomic GC actions was precipitated from two major directions: (i) some rapid/acute clinical GC applications could not be explained based on the relatively slowly appearing genomic GC action and (ii) accumulating evidence came to light about the discrepancy in the apoptosis sensitivity and GR expression of thymocytes and other lymphoid cell types. Herein, we attempt to sample the latest information in the field of non-genomic GC signalling in T cells, and correlate it with results from our laboratory.

Mitochondrial translocation of the glucocorticoid receptor in double-positive thymocytes correlates with their sensitivity to glucocorticoid-induced apoptosis.

Glucocorticoid receptor (GR) signaling plays an important role in the selection and apoptosis of thymocytes. Besides nuclear translocation, mitochondrial translocation of the ligand-bound GR in lymphoid cells was also shown, which might determine glucocorticoid (GC)-induced apoptosis sensitivity. In the present work, we followed the ligand-induced GR trafficking in CD4+CD8+ double-positive (DP) thymocytes.

Developmental shift in TcR-mediated rescue of thymocytes from glucocorticoid-induced apoptosis.

Glucocorticoid hormone (GC) production by thymic epithelial cells influences TcR signalling in DP thymocytes and modifies their survival. In the present work, we focused on exploring details of GC effects on DP thymocyte apoptosis with or without parallel TcR activation in AND transgenic mice, carrying TcR specific for pigeon cytochrome C, in vivo. Here we show that the glucocorticoid receptor (GR) protein level was the lowest in DP thymocytes, and it was slightly down-regulated by GC analogue, anti-CD3, PCC and combined treatments as well.

Intermolecular relations between the glucocorticoid receptor, ZAP-70 kinase, and Hsp-90.

The glucocorticoid receptor (GR) participates in both genomic and non-genomic glucocorticoid hormone (GC) actions by interacting with other cytoplasmic signalling proteins. Previously, we have shown that high dose Dexamethasone (DX) treatment of Jurkat cells causes tyrosine phosphorylation of ZAP-70 within 5 min in a GR-dependent manner. By using co-immunoprecipitation and confocal microscopy, here we demonstrate that the liganded GR physically associates with ZAP-70, in addition to its phosphorylation changes.

Low glucocorticoid receptor (GR), high Dig2 and low Bcl-2 expression in double positive thymocytes of BALB/c mice indicates their endogenous glucocorticoid hormone exposure.

Several studies have shown that of the four major thymocyte subsets, the CD4/CD8 double positive (DP) thymocytes are the most sensitive to in vivo glucocorticoid hormone (GC)-induced apoptosis. Our aim was to analyse fine molecular differences among thymocyte subgroups that could underlie this phenomenon. Therefore, we characterised the glucocorticoid hormone receptor (GR) expression of thymocyte subgroups both at the mRNA and protein levels by real-time PCR and flow cytometry, and correlated these features to their apoptotic sensitivity.

Dexamethasone induces rapid tyrosine-phosphorylation of ZAP-70 in Jurkat cells.

Steroid hormones are known to mediate rapid non-genomic effects occurring within minutes, besides the classical genomic actions mediated by the nuclear translocation of the cytoplasmic glucocorticoid receptor (GR). The glucocorticoid hormone (GC) has significant role in the regulation of T-cell activation; however, the cross-talk between the GC and T-cell receptor (TcR) signal transducing pathways are still to be elucidated. We examined the rapid effects of GC exposure on in vitro cultured human T-cells.

Antigen and glucocorticoid hormone (GC) induce positive selection of DP thymocytes in a TcR transgenic mouse model.

Thymocyte maturation in the thymus is controlled by stromal and humoral components. Among the humoral regulators locally produced glucocorticoids (GCs) seem to have a key role in the positive selection of thymocytes. Our previous studies have shown that the administration of GCs or the stimulation through the CD3 complex can induce apoptosis of double positive (DP) cells, but the combined presence of these stimuli induces positive selection.