1,721,167 research outputs found
The influence of the environment on cell-cell communication in the epithelial-mesenchymal trophic unit
No full textRationale: A key factor involved with the progressive decline in lung function in severeasthma is airway remodelling. This involves collagen deposition within the lamina reticularis, matrix deposition in the submucosa, smooth muscle hyperplasia, and microvascular and neuronal proliferation.Aims: The main aim of this thesis was to test the hypothesis that epithelial susceptibility to environmental injury and a prolonged tissue repair response result in activation of the epithelial mesenchymal trophic unit (EMTU) that in turn promotes airway wall remodelling.Methods: Investigation of epithelial mesenchymal signalling involved use of cells derived from normal or asthmatic volunteers and cultured in vitro. These were tested in simple monocultures and then a „tissue engineered‟ construct was developed to enable assessment of responses in a complex cell model that closely mimics the human bronchial mucosa.Results: Infection of asthmatic bronchial epithelial cells (AS PBEC) with RV-16 caused significantly less apoptosis when compared to infection of bronchial epithelial cells obtained from healthy controls (HC PBEC). As a consequence of this RV replicated more in AS PBEC; this defect may explain the higher susceptibility of the lower airways to RV infection in asthmatic subjects.Using primary bronchial fibroblast cultures, collagen type I and fibronectin significantly increased adhesion rates, while laminin reduced differentiation of fibroblasts into myofibroblasts. None of the ECM components that were evaluated affected fibroblast survival. Although asthmatic fibroblasts expressed more αSMA than normal fibroblasts, no significant difference in terms of fibroblast differentiation was found when different ECM components, of relevance to asthma pathogenesis, were studied. When bronchial fibroblasts were exposed to conditioned media obtained from PBEC infected with RV16, there was no effect on markers of remodelling but there was a marked amplification of the epithelial inflammatory response, mainly due to increased release of IL8, IL6, RANTES and IP-10, suggesting that during a virus-induced exacerbation the fibroblasts promote inflammation. To investigate susceptibility to oxidant stress, PBEC were treated with 20% cigarette smoke extract (CSE). AS PBECs were more susceptible to CSE with a significant increase of early apoptotic (EA) cells compared to HS PBEC. Reduced glutathione protected both HS and AS PBEC from CSE- induced cell death causing a significant increase in cell viability, with a concomitant decrease in apoptosis. Oxidative stress-induced apoptosis in PBECs did not follow the canonical caspase pathways, but rather depended on a more direct mitochondrial damage pathway. The ECM also appeared to play a role in oxidative stress-induced cell death, with collagen IV being most effective in reducing H2O2-induced apoptosis. Finally, we developed and characterised a novel 3D in vitro model of human bronchial mucosa that proved to be very similar to the normal in vivo counterpart with a well differentiated epithelial layer composed of ciliated and goblet cells producing mucus and supported by a functional basement membrane which separated the epithelium from a mesenchymal layer containing fibroblasts dispersed in a well organised ECM. This model allowed investigation of the long term effects of CSE exposure which showed that CSE caused many characteristic signs of remodelling such as thickening of the basement membrane, disarray of the ECM, loss of ciliated cells and hyperproduction of mucus. These effects occurred in the absence of inflammatory or immune cells.Conclusions:The finding that epithelial cells from asthmatic donors have increased susceptibility to viral and oxidative stress emphasises the importance of tissue susceptibility in asthma. These findings, together with the observations that there is substantial cross talk between epithelial cells and fibroblasts supports the concept that abnormal function of the EMTU is animportant contributory factor for asthma pathogenesis.<br/
Asthmatic epithelial cells are more sensitive to smoke-induced apoptosis: differential role of antioxidants.
No full textExposure of bronchial epithelial cells to Cigarette Smoke Extracts (CSE) induces caspase-independent apoptosis.
No full textDoes Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost” Layer of the Bowel
Full text linkIn this brief Opinion paper, the term “muco-microbiotic layer” is introduced to describe the innermost layer of the intestinal wall. This layer may contribute not only to the overall health of the bowel, but also to that of extraintestinal organs. Its constituents, in terms of soluble molecules and nanovesicles, need to be studied further. Moreover, one can hypothesize the existence of an analogous layer in other organs, such as the airways or some parts of the genital tracts. Further studies on it are needed
Observations on midgut of Apis mellifera workers (Hymenoptera: Apoidea) under controlled acute exposures to a Bacillus thuringiensis-based biopesticide
Full text linkInternational audienceAbstractMorphostructural investigations have been carried out on Apis mellifera workers treated with single controlled acute exposures to a biopesticide containing Bacillus thuringiensis (Bt), to detect midgut changes until 96 h. Our findings show concentration-dependence of these changes, reflecting in different degrees on both mortality and behaviour. In particular, some midgut changes are also found 96 h after treatment. Our results show that the tested product does not affect survival at presumable environmental concentrations, so confirming the lesser toxicity of Bt-based biopesticides compared to other pesticides. However, in the light of the discovered long-term changes, we discuss the opportunity of taking into account possible chronic exposures to Bt-based products on A. mellifera
Inflammatory mediators release from asthmatic & non-asthmatic bronchial epithelial cells following infection with rhinovirus (RV)
No full textDifferential effects of IL-13 on morphogenesis and MUC5AC expression in human embryonic lung explants – a role for IL-13Rα2?
No full textToxic Tau Oligomers Modulated by Novel Curcumin Derivatives
Full text linkThe pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers
Effect of IL-13Ralpha2 Receptor levels on the biological activity of IL-13 variant R110Q.
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