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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Reduced proliferation and increased TSLP expression by lung fibroblasts from COPD patients

Tripathi, Soma 14 January 2014 (has links)
Chronic obstructive pulmonary disease (COPD) is identified with partially reversible airflow limitation, chronic bronchitis, small airway remodelling, and alveolar destruction. COPD is also progressive in nature. TSLP (Thymic stromal lymphopoietin), an Interleukin (IL)-7 like cytokine expressed by structural cells, is a determinant of inflammation. We aimed to characterize human lung fibroblasts (HLF) from human donors with COPD as well as patients without COPD (non-COPD), comparing proliferation and TSLP release. Statins can exert anti-proliferative and anti-inflammatory effects, and their use has been linked to improved lung health, thus we also examined the effect of statins on proliferation and cytokine release by lung fibroblasts from COPD and non-COPD donors. Primary HLF cultures from three COPD diagnosed and non- COPD donors were used. Proliferation was measured using laser scanning cytometry (LSC) counting of H33248-stained cells with 5% fetal bovine along with the addition of simvastatin (0.1µM and 0.5µM). TNFα (tumor necrosis factor α) and/or IL-1β (interleukin 1β) (10ng/mL), and various concentrations of cigarette smoke extract (CSE) were used to stimulate cells. TSLP release, mRNA abundance and transcriptional activity were measured by ELISA, Real Time Polymerase Chain Recation (RT- PCR) and luciferase assay, respectively. RT-PCR was also utilized to profile TNFα and Interleukin 1β receptors. We also ascertained the effect of various stimuli on receptor-mediated signaling pathways using Western blotting. Impact of simvastatin (1-10µM) on TSLP release was determined by ELISA. During exponential growth phase, HLF from COPD donors proliferated 46.7% slower than from non-COPD. Simvastatin (0.5µM) inhibited proliferation, as indicated by 53% (P<0.01) and 48% (P< 0.001) fewer COPD and non-COPD donor HLFs at Day 6 culture. At baseline COPD HLFs make approximately 2-fold (P<0.05) more TSLP/cell compared to non-COPD HLFs. TNFα and/or IL-1β (10ng/ml, 48h) induced approximately 1.8 to 2.3-fold (P<0.05) more TSLP release in COPD HLFs. Interestingly, simvastatin had no impact on basal TSLP release, but in the presence of TNFα (5µM, 72h), TSLP release was actually increased approximately 2.19-fold (COPD) and 1.8-fold (non-COPD). TSLP mRNA levels were maximum at 6h in both COPD and non-COPD HLFs and relative TSLP mRNA was approximately 15-fold higher in COPD HLFs compared to non-COPD HLFs (P<0.01). This correlated with human TSLP promoter luciferase reporter assays that showed baseline transcription in COPD HLFs is markedly (approximately 17-fold) higher than non-COPD HLFs. In TNFα-stimulated cultures, TSLP luciferase activity was approximately 10-fold higher in COPD HLFs compared to HLFs from non-COPD. There was no difference in mRNA abundance of receptor subunits for TNFα or IL-1β between patient groups. Phosphorylation of mitogen activated protein kinases, ERK1/2 and p38MAPK, were also comparatively higher in COPD HLFs when stimulated with TNFα suggesting increased response via TNFα receptors. Additionally, in TNFα-stimulated cultures, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity was approximately 2.6-fold higher in COPD HLFs as compared to HLFs from non-COPD donors. Collectively our data show that proliferation of HLFs from COPD subjects is lower and can be further reduced by simvastatin. COPD HLFs exhibit increased basal and cytokine-stimulated TSLP mRNA expression, transcription and release, suggesting these cells carry stable intrinsic differences in regulatory mechanisms. Differences in TSLP levels are not due to differential abundance of TNFα and IL-1β receptors although the intracellular responses mediated by TNF α receptor is higher in COPD HLFs. Simvastatin augments TNFα-induced TSLP release in COPD and non-COPD HLFs. These data indicate further investigation of the role of TSLP and its response to therapy, in COPD is warranted.
2

Staphylococcus aureus and toll-like receptor activity in atopic dermatitis

Tan, Soo Yee January 2012 (has links)
Introduction: Staphylococcus aureus skin infection is an almost ubiquitous feature of patients with atopic dermatitis (AD). TLR1, 2 and 6 are important in immune sensing of these bacteria. The aim of this study was to determine whether defects in TLR1, 2 and/or 6 expression/function may explain the propensity to infection in humans and the NC eczema mouse model. Methods: Fibroblast cell lines from severe AD, nonatopic controls, and mouse embryonic fibroblasts (MEFs) from the NC, MSM/Ms wild-type strain and a 3T3 control strain TLR1, 2 and 6 expression were measured by qPCR and FACS. IL-6, TNF-α, TSLP and IL-33 production was measured by qPCR and ELISA at baseline and after stimulation with LPS, HKSA and a live strain of Staphylococcus aureus that produced only SEB. Results: No differences were found in either TLR expression or function in human fibroblasts derived from patients and controls. The MSM/Ms MEFs expressed significantly more TLR1 and 2, as well as exhibited high inflammatory profile after stimulation comparing with 3T3 and the NC MEFs. Live Staphylococcus aureus, but not HKSA, LPS or SEB, was a potent stimulus for the Th2-inducing cytokines (TSLP and IL-33), and induce cell death. Cytokines levels were found to be similar in AD and NC MEFs when compared to healthy controls. Conclusion: Eczema in both the human and NC mouse is not associated with abnormalities in fibroblasts TLR1, 2, and 6. Live, but not killed Staphylococcus aureus or its enterotoxin, is a potent inducer of TSLP and IL-33 in both species.
3

Molecular regulation and effector functions of the high affinity IgE receptor (FcεRI) in human airway smooth muscle cells

Redhu, Naresh Singh January 2009 (has links)
The prevalence and economic burden of chronic airway disorders such as asthma is on the rise annually. Allergic asthma is characterized by chronic airway inflammation, airway hyper-responsiveness (AHR), and structural airway remodeling due to increased smooth muscle mass. Most allergic asthma occurs due to the overproduction of immunoglobulin E (IgE) antibodies against common allergens. Classically, IgE has been shown to modulate airway smooth muscle (ASM) contraction/relaxation which is believed to be the underlying cause of airway hyperreactivity. However, the molecular mechanisms underlying IgE effects on ASM cell are not established. Recently, the high-affinity Fc receptor for IgE (FcεRI) has been identified in human ASM cells in vitro and in vivo within bronchial biopsies of allergic asthma patients. However, it is unknown whether FcεRI activation on ASM can modulate the immune response within the airways. We hypothesized that the IgE-FcεRI interaction plays a key role in inducing phenotypic and functional changes in ASM cells that eventually contributes to the establishment of airway inflammation, AHR, and remodeling. We sought to investigate the regulation, effector functions, and underlying mechanisms of FcεRI activation in ASM cells. Our work shows that the proinflammatory tumor necrosis factor (TNF) and T helper type 2 (Th2) cytokine interleukin (IL)-4 enhanced the FcεRI abundance and amplified the IgE-induced chemokine (eotaxin-1/CCL11, RANTES/CCL5, IL-8/CXCL8, and IP-10/CXCL10) release in ASM cells via transcriptional mechanisms. Both TNF and IgE induced a novel, Th2-favoring cytokine thymic stromal lymphopoietin (TSLP) through the activation of spleen tyrosine kinase (Syk), and nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). In addition, IgE induced de novo DNA synthesis and ASM cell proliferation via mitogen-activated protein kinases (MAPKs) and signal-transducer and activator of transcription 3 (STAT3) activation. Collectively, our data suggest that the IgE-induced FcεRI activation leads to the expression of multiple chemokines in ASM which may indirectly recruit inflammatory cells and promote allergic airway inflammation; IgE induces TSLP which can promote the Th2 immune responses within the airways; and IgE may potentially induce airway remodeling by directly inducing ASM cell proliferation. Therefore, targeting the IgE-FcεRI network on ASM may offer a novel therapeutic strategy in allergic asthma.
4

Molecular regulation and effector functions of the high affinity IgE receptor (FcεRI) in human airway smooth muscle cells

Redhu, Naresh Singh January 2009 (has links)
The prevalence and economic burden of chronic airway disorders such as asthma is on the rise annually. Allergic asthma is characterized by chronic airway inflammation, airway hyper-responsiveness (AHR), and structural airway remodeling due to increased smooth muscle mass. Most allergic asthma occurs due to the overproduction of immunoglobulin E (IgE) antibodies against common allergens. Classically, IgE has been shown to modulate airway smooth muscle (ASM) contraction/relaxation which is believed to be the underlying cause of airway hyperreactivity. However, the molecular mechanisms underlying IgE effects on ASM cell are not established. Recently, the high-affinity Fc receptor for IgE (FcεRI) has been identified in human ASM cells in vitro and in vivo within bronchial biopsies of allergic asthma patients. However, it is unknown whether FcεRI activation on ASM can modulate the immune response within the airways. We hypothesized that the IgE-FcεRI interaction plays a key role in inducing phenotypic and functional changes in ASM cells that eventually contributes to the establishment of airway inflammation, AHR, and remodeling. We sought to investigate the regulation, effector functions, and underlying mechanisms of FcεRI activation in ASM cells. Our work shows that the proinflammatory tumor necrosis factor (TNF) and T helper type 2 (Th2) cytokine interleukin (IL)-4 enhanced the FcεRI abundance and amplified the IgE-induced chemokine (eotaxin-1/CCL11, RANTES/CCL5, IL-8/CXCL8, and IP-10/CXCL10) release in ASM cells via transcriptional mechanisms. Both TNF and IgE induced a novel, Th2-favoring cytokine thymic stromal lymphopoietin (TSLP) through the activation of spleen tyrosine kinase (Syk), and nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). In addition, IgE induced de novo DNA synthesis and ASM cell proliferation via mitogen-activated protein kinases (MAPKs) and signal-transducer and activator of transcription 3 (STAT3) activation. Collectively, our data suggest that the IgE-induced FcεRI activation leads to the expression of multiple chemokines in ASM which may indirectly recruit inflammatory cells and promote allergic airway inflammation; IgE induces TSLP which can promote the Th2 immune responses within the airways; and IgE may potentially induce airway remodeling by directly inducing ASM cell proliferation. Therefore, targeting the IgE-FcεRI network on ASM may offer a novel therapeutic strategy in allergic asthma.
5

Tslp Production by Dendritic Cells Is Modulated by IL-1β and Components of the Endoplasmic Reticulum Stress Response

Elder, Matthew J., Webster, Steven J., Williams, David L., Gaston, J. S.Hill, Goodall, Jane C. 01 February 2016 (has links)
Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of TH2-cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β-glucans requires dectin-1, Syk, NF-κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL-1β, but not TNF-α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol-requiring transmembrane kinase/endonuclease 1 and protein kinase R-like ER kinase, which are activated by dectin-1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin-1, the IL-1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC-controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue.
6

Thymic Stromal Lymphopoietin: Expression and Secretion by Airway Epithelium as a Function of Genotype / Airway Epithelial-Derived Thymic Stromal Lymphopoietin

Hui, Claudia C.K. 11 1900 (has links)
Thymic stromal lymphopoietin (TSLP) is a pleotropic cytokine highly implicated in the pathophysiology of asthma and allergic diseases. Although there are robust data regarding the associations of TSLP polymorphisms with the development of allergy and asthma, there is very little information on how these TSLP variants functionally affect downstream effector pathways and disease phenotype. The overall objective of this thesis was to investigate how TSLP polymorphisms are linked to alterations in TSLP secretion and subsequent downstream cellular events. Initially, we investigated the influence of innate and adaptive stimuli on epithelial-derived TSLP expression and secretion, including effects on dendritic cells (DC). We show that polyinosinic:polycytidylic acid (polyI:C) and allergen-specific T cells induced enhanced TSLP secretion from asthmatic bronchial epithelial cells (BEC) compared to non-asthmatic BEC. Furthermore, activated-BEC culture supernatants induced TSLP-dependent CCL17 production from monocyte-derived DC in relation to clinical asthmatic status (Chapter 2). Next, we examined effects of TSLP on hemopoietic progenitor eosinophil-basophil (Eo/B) differentiation, demonstrating enhanced TSLP-mediated hemopoiesis ex vivo in relation to clinical atopic status. We further demonstrated p38MAPK-dependent autocrine signaling by TNFα in TSLP-mediated human Eo/B differentiation ex vivo (Chapter 3). Lastly, to explore the potential functional consequences of a key variant of the TSLP gene, we investigated associations between the rs1837253 TSLP variant and ex vivo production of TSLP in nasal epithelial cells (NEC). We showed that NEC derived from individuals with the “protective” minor allele have diminished TSLP secretion, which suggests that this rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion (Chapter 4). The novel work presented herein provides further evidence for TSLP regulation of distinct immunological pathways in allergic immune inflammatory airway responses initiated at the epithelial surface, and thus (by implication) of allergic disease. These observations support the concept that TSLP is potentially an important biomarker and therapeutic target for allergic diseases characterized by increased Th2 and/or eosinophilic-basophilic inflammation. Continued investigations into the functional mechanisms linking TSLP variants to allergic disease phenotype are of critical importance. / Dissertation / Doctor of Science (PhD)
7

Tezepelumab : En ny effektiv behandling för patienter med svår, okontrollerad astma?

Khouly, Rama January 2023 (has links)
Bakgrund Astma är en kronisk sjukdom som försvårar lungfunktion och påverkar individer hela livet. Orsakerna för astma är olika mellan olika individer, men sjukdomen har liknande symtom. Nyligen visades Thymic Stromal Lymphopoietin ”TSLP” ha viktig roll vid initiering av inflammationen i lungorna som leder till astmaattack hos patienterna. Biologiska läkemedel, som tezepelumab, avbryter specifikt i initieringen av inflammation som påbörjas vid en exponering hos astmatiker. Tezepelumab är en monoklonal antikropp för behandling vid svår astma. Syfte Syfte med studien var att undersöka om det nya läkemedlet på marknaden var en effektiv behandling för astmapatienter som har lidit av svår och okontrollerad astma. Metod En litteraturstudie genomfördes genom en sökning i databasen PubMed. Det används några nyckelord som tex Astma, Tezepelumab, TSLP och monoklonal antikropp, Det genomfördes ett urval och analysering av studier från PubMed. Resultat De fem studierna visade positiva behandlingseffekt av tezepelumab av okontrollerad astma trots behandlingen med Långverkande beta-2 stimulerare ”LABAs” och Inhaled Corticosteroids”CISs”. Studierna visade att anti TSLP behandling med tezepelumab förbättrade symtomen och livskvalitet hos patienterna.Andelen av astmaanfall reducerades under behandlingens period med tezepelumab. Nivåer av inflammationsmarkörer minskade och patienternas livskvalitet förbättrades. Tezepelumab har lång halveringstid vilket möjliggör dosering endast en gång var fjärde vecka.Tezepelumab visade inga oväntade negativa eller allvarliga livshotande biverkningar, den visade inte ens reaktioner på huden vid injektionsstället eller urtikaria. Slutsats Tezepelumab är en effektiv och säker behandling för svår, okontrollerad astma hos vuxna. / Asthma is one of the most common and chronic diseases in the world. Asthma patients suffer from symptoms related to the respiratory system or the lungs. Symptoms include coughing, increased sputum secretion, shortness of breath, and inflammation in the airways, which may lead to an asthmatic crisis that leads to an emergency admission to the hospital. Asthma treatment was for many years limited to reducing symptoms by means of long-acting beta-agonists, “LABA” or corticosteroid inhalers, “CSI” or both. Still, this treatment was not sufficient for many patients with uncontrolled asthma. With the research development and increased knowledge about  the immune system, the role of the cytokine thymic stromal lymphopoietin (TSLP) in activating TH-cells and other cytokines that cause inflammation has been defined. This increased knowledge has resulted in the development of a new drug which is an antibody against TSLP intended to inactivate TSLP, thereby reducing the symptoms of inflammation in asthma patients.  This study is based on a selection of randomized controlled trials designed to study the effectiveness of the medicine in asthma patients in reducing the frequency of exacerbations of asthma and reducing the vital signs that cause inflammation. Asthma patients in studies Ⅰ- Ⅳ were selected and randomly distributed in groups to take three doses of tezepelumab or a placebo. The results were effective in favor of tezepelumab because it reduced the average of asthma attacks during a year compared to placebo patients, reduced IL-7, IL-5, and reduced eosinophil and FeNO, which usually cause inflammation. Tezepelumab also improved lung function. These results led to an improved quality of patients’ life. When studying the pharmacokinetics, the results indicated that tezepelumab was influential in the body, as it was associated with its target (TSLP) and performed its expected function. The serum half-life t1/2 is four weeks. The studies were similar in terms of several factors, and the results were also similar, which means that the newly developed medicine could bind successfully to TSLP and exert a relatively long-term effect, which reduces the inflammation caused by asthma exacerbation. In conclusion, the chosen studies demonstrate that Tezepelumab has positive results on severe and uncontrolled asthma with no serious side effects.
8

Analysis of Chromatin Accessibility in Human Epidermis Identifies Putative Barrier Dysfunction-sensing Enhancers

Lander, Julie M. January 2017 (has links)
No description available.
9

Etude du rôle de la cytokine thymic stromal lymphopoietin (TSLP) produite par les keratinocytes dans la marche atopique / Study of the role of the thymic stromal lymphopoietin (TSLP) in the atopic march

Leyva Castillo, Juan Manuel 24 September 2012 (has links)
La marche atopique désigne la progression séquentielle des maladies atopiques, en particulier l’apparition d’asthme chez les enfants précédée par celle d’une dermatite atopique (DA) sévère chez les nourrissons. De plus, l’asthme est influencé par le degré de sévérité de la DA, qui pourrait ainsi être considérée comme la porte d’entrée pour le développement ultérieur d’une inflammation allergique des voies aériennes.Mon travail de thèse a consisté à déterminer l’implication de la cytokine TSLP produite par les kératinocytes pendant la marche atopique et implication de la cytokine TSLP pendant le développement de la DA. Pour atteindre ces objectifs, j’ai utilisé des modèles murins de maladies atopiques, en combinaison avec plusieurs lignées de souris génétiquement modifiées.Dans la première partie de mon travail de thèse, nous avons montré que la production de la cytokine TSLP dans les kératinocytes est un facteur nécessaire, non seulement pour l’inflammation cutanée, mais aussi pour générer une réponse immunitaire systémique à l’allergène.Dans la deuxième partie de mon travail de thèse, nous avons montré que la cytokine TSLP induise un recrutement de basophiles d’une façon innée, suite d’une augmentation de ce recrutement induit par l'immunité adaptative. De plus, nous avons montré que la réponse de type “Th2” induit par la cytokine TSLP ce le résultat de une coopération coordonnée de cellules dendritiques, de cellules T CD4+ et de basophiles. Des études cliniques sont nécessaires pour déterminer si l’inhibition de l’expression de la cytokine TSLP et/ou son activité pendant une DA peut réduire l’inflammation cutanée et prévenir la sensibilisation aux allergènes. / Atopic march refers to the natural history of allergic diseases, which is characterized by a typical sequence of sensitization and manifestation of symptoms in different tissues. Commonly, the clinical manifestation of atopic dermatitis (AD) appears in the early life and precedes the development of airway allergic diseases. AD has been proposed as an entry point for subsequent atopic diseases.The objective of my thesis was to better understand the role of TSLP in the atopic march and the cascade events initiated by TSLP in vivo in the development of AD. To reach my thesis objectives we used mouse models of atopic diseases in combination with various deficient-mouse lines.In the first part of this work, using a atopic march mouse model developed during my PhD work, we demonstrated that keratinocytic TSLP is essentially required not only for the development of allergic skin inflammation, but also for the generation of the allergen-specific immune response. In the second part of this work, using a cytokine TSLP-induced AD mouse model (topical MC903 treatment), we demonstrated that skin TSLP induces an early innate recruitment of basophils in the skin, followed by a late recruitment involving adaptive immunity. In addition, we demonstrate that TSLP-induced Th2 response requires an orchestrated cooperation of dendritic cells, CD4+ T cells and basophils.This work provide new knowledge in the cellular and molecular mechanisms implicated in atopic diseases involving TSLP and should provide new insight for the development of therapeutic options of these diseases.
10

Étude de la réponse inflammatoire cutanée dans le mélanome et la marche atopique / Skin inflammatory responses in cutaneous melanoma and in the atopic march

Yao, Wenjin 25 September 2018 (has links)
Dans la première partie de ma thèse, nous avons étudié le rôle de la TSLP, une cytokine produite par les kératinocytes, dans la mélanogenèse. Nous avons montré que l'expression de TSLP était induite dans l'épiderme de la peau atteinte de mélanome chez la souris et l'humain. Notre resulats indiquent que la TSLP murine joue un rôle dans la croissance de la tumeur et que ce rôle s'exerçait via les cellules immunitaires. Nos résultats suggèrent l'existence d'un dialogue entre les cellules du mélanome, les kératinocytes et les cellules immunitaires jouant un rôle important dans la croissance et la métastase du mélanome. Dans la seconde partie, nous avons exploré les cytokines produites dans le contexte de la dermatite atopique et leur rôle dans l'initiation de l'asthme. Nous avons trouvé que TSLP est différemment impliquée dans la sensibilisation allergique épicutanée et dermocutanée, et nous avons identifiée l'IL-1β comme un acteur majeur dans la marche atopique. Cette étude expose de nouvelles approches pour le développement de stratégies pour prévenir ou stopper la marche atopique. / My PhD thesis aimed at studying skin inflammatory responses under two pathogenic contexts, melanoma and atopic march. In the first part, we studied the role of keratinocyte-produced cytokine TSLP in melanomagenesis. We showed that TSLP expression was induced in skin epidermis of both mouse and human melanoma. We further provided evidence that TSLP played a tumor-promoting role by ablating or overexpressing TSLP in mouse melanoma, and that such role of TSLP was mediated through immune cells. Our results suggest that a crosstalk between melanoma cells, epidermal keratinocytes and immune cells plays an important role for melanoma growth and metastasis. In the second part, we explored the cytokine factors derived from atopic dermatitis (AD) in driving the asthma. By using an innovative laser-assistant microporation system, we established novel atopic march mouse models. We found that TSLP was differentially implicated in allergen epicutaneous or dermacutaneous sensitization, and further identified IL-1β as an important player in atopic march. This study adds new insight into the development of potential strategies for preventing or stopping the atopic march.

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