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1
IJpma, Gijs. "Airway smooth muscle dynamics." AUT University, 2010. http://hdl.handle.net/10292/941.
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The current study aims to investigate the relative contributions of each of the processes that govern airway smooth muscle mechanical behaviour. Studies have shown that breathing dynamics have a substantial effect on airway constriction in healthy and diseased subjects, yet little is known about the dynamic response of the main instigator of airway constriction, Airway Smooth Muscle (ASM). In this work several models are developed to further the understanding of ASM dynamics, particularly the roles and interactions of the three dominant processes in the muscle: contractile dynamics, length adaptation and passive dynamics. Three individual models have been developed, each describing a distinct process or structure within the muscle. The first is a contractile model which describes the contractile process and the influence of external excitation on contractile behaviour. The second model incorporates the contractile model to describe length adaptation, which includes the reorganisation and polymerisation of contractile elements in response to length changes. The third model describes the passive behaviour of the muscle, which entails the mechanical behaviour of all non-contractile components and processes. As little data on the passive dynamics of the muscle was available in the literature, a number of experiments were conducted to investigate relaxed ASM dynamics. The experimental data and mathematical modelling showed that passive dynamics plays not only a dominant role in relaxed ASM, but contributes considerably to the dynamics of contracted muscle as well. A novel theory of sequential multiplication in passive ASM is proposed and implemented in a mathematical model. Experiments and literature validated the model simulations. Further integration of the models and improved force control modelling of length adaptation is proposed for future study. It is likely that the coupling of the models presented here with models describing other airway wall components will provide a more complete picture of airway dynamics, which will be invaluable for understanding respiratory disease.
2
Du, Youhua. "Airway smooth muscle response to vibrations." AUT University, 2006. http://hdl.handle.net/10292/974.
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The main goal of this research was the in vitro investigation of the stiffness response of contracted airway smooth muscles under different external oscillations. Living animal airway smooth muscle tissues were dissected from pig tracheas and stimulated by a chemical stimulus (acetylcholine). These tissues were then systematically excited with different external vibrations. The force change was recorded to reflect the muscle stiffness change under vibration. The static and dynamic stiffness of contracted airway smooth muscles in isometric contraction were determined before, during and after vibrations. A continuum cross-bridge dynamic model (the fading memory model) was modified to accommodate smooth muscle behaviour and dynamically describes the cross-bridge kinetics. A two-dimensional finite element model (FEM) was developed to simulate longitudinal and transverse vibrations of the tissue. An empirical equation, derived from the experiments, is incorporated into the FEM. The results indicate that the stiffness of active smooth muscles can be physically reduced using external vibrations. This reduction is caused by a certain physical position change between actin and myosin. The dynamic stiffness has the tendency of decreasing as the frequency and/or amplitude of external vibration increases. However, the static stiffness decreases with an increase in the frequency and amplitude of excitation until it reaches a critical value of frequency where no variation in stiffness is observed. It is postulated that the tissue elasticity and mass inertia are the main contributors to the dynamic stiffness while the actin-myosin cross-bridge cycling is the main contributor to the static stiffness.
3
Chin, Leslie Yee Mann. "Airway smooth muscle in health and disease." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/27650.
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This thesis focuses on the structure and function of airway smooth muscle (ASM) in health and disease. By employing the use of structural analysis by electron microscopy, functional analysis by mechanical measurements, and biochemical analysis, this thesis
provides valuable insight into ASM pathophysiology. The first two chapters focus on the
mechanisms by which the contractile apparatus is arranged within the cell. The studies
examined whether the actin filament lattice acts a scaffold to facilitate myosin filament
assembly within contractile units and the contractile response to potassium chloride
(KCl). The muscle was treated with cytochalasin D (CD), a known actin filament
disrupter, but this provided little insight on whether the actin lattice guides myosin
filament assembly, since CD had a limited effect on actin filaments but a significant
effect on force. KCl was found to cause contraction of similar force to acetylcholine
contraction, despite the presence of fewer myosin filaments. KCl likely caused
depolymerization of myosin filaments upon activation and allowed for force generation
by non-filamentous myosin molecules. In the last two studies, human ASM was sourced
from the tracheas of whole lungs donated for medical research. From this tissue source it
was shown that, unlike in previous human ASM studies, human muscle is similar to that
of other mammalian species and capable of significant isotonic shortening. This finding
lends support to the use of animal ASM models as a proxy for human ASM. This also
was the first study to examine human ASM in the paradigm of mechanical plasticity,
using in situ muscle length as a reference length instead of the traditional Lmax, and was
the first to demonstrate length adaptation in human ASM. The mechanical properties of
asthmatic ASM were found to differ from those of non-asthmatic ASM at several key measurements. Asthmatic ASM was found to have an altered length-tension relationship,
increased passive tension, and maintained force better in response to a mechanical
perturbation than non-asthmatic ASM. This last finding provides a possible mechanism
by which asthmatic airways are more resistant to the bronchodilating effects of deep
inspiration. Force generating capacity, shortening extent and velocity were not different.
4
Jia, Yanlin. "Nitric oxide and airway smooth muscle responsiveness." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29052.
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Airway hyperresponsiveness to bronchoconstrictors has been found in asthma and related to the severity of the disease. The factors which result in hyperresponsiveness are not completely understood. A possible mechanism is an imbalance between endogenous bronchoconstrictors and dilators. NO is known to relax tracheal smooth muscle by activating soluble guanylate cyclase and increasing the level of intracellular cyclic guanosine monophosphate (GMP). The first hypothesis tested was that the NO-cyclic GMP-relaxant pathway is involved in the regulation of airway responsiveness. Inhibition of endogenous nitric oxide by N$ sp{ omega}$-nitro-L-arginine (L-NNA) significantly increased airway responsiveness to inhaled methacholine in normoresponsive Lewis rats but less so in hyperresponsiveness Fisher rats. In addition, carbachol increased cyclic GMP levels in tracheal tissues from both strains; this cyclic GMP accumulation in tracheal tissues was also less in Fisher than in Lewis rats and abolished by L-NNA in both strains, indicating that it was mediated by a NO-dependent mechanism. These results suggest that endogenous NO plays a role in regulation of airway responsiveness and contributes to the strain-related difference in airway responsiveness in rats. To investigate the NO-cyclic GMP-relaxant pathway in rat airway, the effect of sodium nitroprusside (SNP, a NO donor) on airway responsiveness to a cholinergic agonist was measured in hyperresponsive Fisher rats and compared with the less responsive Lewis strain. Fisher rats were resistant to SNP as evidenced by less relaxation of carbachol contracted tracheal rings by SNP and less cyclic GMP accumulation induced by SNP in cultured airway smooth muscle cells in Fisher rats compared with Lewis rats, indicating an impaired response to SNP in Fisher airways.NO is known to be synthesized from L-arginine in a reaction catalyzed by NO synthase (NOS). Liver cytochrome P450 also catalyzes the oxidative cleavage of C=N bonds of compounds containing a -C(NH$ sb2$)NOH function, producing NO in vitro. We hypothesized that the biosynthesis of NO in airway smooth muscle cells could result from P450 enzymes acting on appropriate substrates. NO can be synthesized in a number of lung cell types. However, to date, no constitutive form of NOS activity has been found in airway smooth muscle cells. We next examined the possibility that airway smooth muscle itself might be able to synthesize NO. Formamidoxime, a compound containing the -C(NH$ sb2$)NOH function, was found to produce NO in cultured airway smooth muscle cells. As well, formamidoxime relaxed pre-contracted trachealis and cyclic GMP accumulation in airway smooth muscle cells in culture. These effects were inhibited by P450 inhibitors but not by NOS inhibitors. Thus, an L-arginine-independent pathway for production of NO was demonstrable in airway smooth muscle cells. This NO production was catalyzed by P450 but not by NOS.
In conclusion, my studies have demonstrated an important role for endogenous NO production in determining the airway responsiveness of normal rats to inhaled cholinergic agonists. This mechanism contributes to strain-related differences in airway responsiveness in the rat.
5
Tao, Florence C. Y. "Mechanisms of altered airway smooth muscle calcium signalling in airway hyperresponsiveness." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0022/NQ50267.pdf.
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Tao, Florence C. Y. 1968. "Mechanisms of altered airway smooth muscle calcium signalling in airway hyperresponsiveness." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35949.
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The pathophysiological origins of airway hyperresponsiveness (AHR) in asthma are unknown. The objectives of this thesis were to establish an association between AHR in an animal model of asthma and altered contractility of airway smooth muscle (ASM) and to elucidate changes in contractile signalling that could account for any observed differences in ASM contractility. The Fisher strain of rat is spontaneously hyperresponsive to methacholine inhalation challenge relative to Lewis rats. These inbred rat strains provide a model with which to study genetically-determined variations in airway smooth muscle that may underlie AHR. Fisher rats were found to be also hyperresponsive to serotonin (5-HT) in vivo compared to Lewis rats, indicating that their AHR is not agonist specific the narrowing capacity and velocity of contraction of Fisher intraparenchymal airways in cultured explants were also greater than explanted. Lewis intraparenchymal airways in response to 5-HT. In addition, 5-HT stimulated higher Ca2+ transients in Fisher than Lewis ASM, in parallel with their rank order of intraparenchymal airway responsiveness. These results suggest that ASM contractility may be determined by the extent of Ca2+ mobilization in airway myocytes. To examine the mechanism of enhanced intracellular Ca2+ mobilization in Fisher ASM, the role of the inositol (1,4,5)trisphospbate (Ins (1,4,5)P 3) pathway in determining interstrain differences in ASM Ca2+ was studied. 5-HT produced higher levels of Ins (1,4,5)P3 in Fisher than Lewis ASM. This appeared to be caused by a lower expression and activity in Fisher ASM of the type I and II 5-phosphatases which inactivate Ins (1,4,5)P3. Inhibition of 5-phosphatase activity increased Ins (1,4,5)P3-mediated Ca2+ release in ASM from both strains of rat, equalizing Ca2+ signals between Lewis and Fisher ASM. Since Ins (1,4,5)P3 receptor sensitivity to Ins (1,4,5)P 3 was found to be similar between the two rat strains, the differences in 5-phosphatas
7
Lei, Min. "Airway smooth muscle orientation using en-face dissection." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22759.
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Airway smooth muscle (ASM) shortening is the key event leading to broncho-constriction. The degree of airway narrowing which occurs with ASM shortening is a function both of the mechanical properties of the airway wall as well as the angle of orientation of ASM. If ASM is oriented very obliquely, ASM shortening would in part be transduced to a change in airway length rather than airway narrowing. Previous reports have suggested that the angle of ASM orientation may be as high as 30$ sp circ.$ To measure ASM orientation we have developed a technique based on en-face dissection. The lungs from 4 cats and one human were fixed with 10% buffered formalin at 25 cmH$ sb2$O for 48 hrs. The airway generations 4 to 17 were dissected out from the left lower lobes. Each airway generation was individually embedded in paraffin from which 5$ mu$m thick serial sections were cut parallel to the airway long axis ("en-face") and stained with haematoxylin-phloxine-saffron. Each block yielded 3-5 sections in which the orientation of ASM nuclei relative to the airway long axis ($ theta$) was measured as an index of ASM orientation. $ theta$ was measured clockwise and counterclockwise to the short axis by using a digitizing tablet and a light microscope (X250) equipped with a drawing tube attachment. Inspection of the sections revealed extensive ASM crisscrossing without a homogeneous orientation. Between 29 and 102 nuclei were measured per generation. Although there was considerable variation within airway generations, $ theta$ clustered between $-$20$ sp circ$ and 10$ sp circ$ in all generations and did not vary significantly between generations in any of the subjects. When $ theta$ was converted to an acute angle without regard to sign($ Theta$), the mean angle was 12-13$ sp circ$ both in cat and the human lung. (Abstract shortened by UMI.)
8
Le, Jeune Ivan Robert. "Phosphodiesterase 4D5 in human airway smooth muscle cells." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408054.
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Opazo, Saez Anabelle M. (Anabelle Marjorie). "Airway responsiveness to methacholine and airway smooth muscle in the guinea pig." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60629.
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The purpose of this study was two-fold: (1) to examine the relationship between the amount of airway smooth muscle and the airway responsiveness to inhaled aerosolized methacholine (MCh) in guinea pigs, and (2) to characterize the distribution of airway narrowing following MCh.In summary: (1) the quantity of airway smooth muscle (ASM) does not appear to determine differences in maximal bronchoconstriction among normal guinea pigs; the lack of a correlation between responsiveness and amount of ASM may be explained by the heterogenous distribution of bronchoconstriction among the airways studied or the modality of challenge; (2) the sensitivity to MCh appears to be related to differences in the amount of ASM in intraparenchymal cartilaginous airways; (3) variability in the EC$ sb{50}$ may also reflect differences in airway cross-sectional area; (4) lung resistance appears to be a good measure of constriction since the morphometric measure of airway narrowing correlated well with resistance; (5) the heterogeneity of airway narrowing does not appear to be determined by differences in ASM.
10
Lau, Justine Y. "Novel genes associated with airway smooth muscle proliferation in asthma." Connect to full text, 2008. http://hdl.handle.net/2123/5134.
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Thesis (Ph. D.)--University of Sydney, 2009.Title from title screen (viewed Aug. 11, 2009) Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Pharmacology, Faculty of Medicine. Degree awarded 2009; thesis submitted 2008. Includes bibliographical references. Also available in print form.
11
Stretton, Colin David. "Neuropeptide interactions with autonomic control of airway smooth muscle." Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/46568.
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Halayko, Andrew John. "Characterization of determinants of airway smooth muscle cell heterogeneity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23606.pdf.
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13
Clayton, Robert Alan. "The effect of hypoxia on airway smooth muscle function." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244358.
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14
Gavrila, Adelina. "Modulating steroid insensitive pathways in airway smooth muscle cells." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37616.
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Approximately 5 to 10% of patients with asthma have difficult-to-control or severe disease that is refractory or poorly responsive to glucocorticoids (GC). This group represents a significant unmet clinical need and is responsible for a disproportionate share of health care costs and morbidity associated with the disease. This thesis investigated the underlying molecular mechanisms of steroid insensitivity in airway smooth muscle (ASM) in patients with severe asthma. We used a natural compound isolated from an African plant called Compound A (CpdA) in an in vitro model of steroid insensitivity of ASM cells treated with TNFα and IFNγ. This is the first report to show that CpdA, independently of the GRα, differentially suppressed the expression of GC-insensitive chemokines in ASM cells. We elucidated one mechanism responsible for the inhibition of fluticasone-resistant CXCL10 by CpdA via up-regulation of the MAPK deactivator, MKP-1. This thesis described the modulation of fluticasone-resistant chemokines (CCL5, CX3CL1) via inhibition of the MAPK pathway (p38MAPK, JNK), raising the possibility that targeting these kinases in ASM could be beneficial in treating steroid insensitivity. The potential synergistic effect of using MAPK inhibitors (p38, ERK) in combination with fluticasone showed a beneficial effect in reducing the production of GC-resistant chemokines (CCL5 and CXCL10). Finally, this study identified another potential mechanism involved in CpdA action via inhibition of the transcription factor IRF-1 which we showed was important in driving cytokine-induced CCL5 and CX3CL1 expression. More importantly, IRF-1 was activated within the ASM in biopsies from severe asthmatics and its expression was unaffected by GC treatment. IRF-1 expression within the ASM from severe asthmatic biopsies correlated with serum IgE, sputum eosinophils and ENo levels, with some differences depending on treatment. This thesis provided evidence for the effectiveness of CpdA in the suppression of GC-insensitive genes in our in vitro model. This work supports the involvement of IRF-1 in driving steroid insensitive pathways in ASM cells and suggests that targeting IRF-1 axis could offer an alternative therapy for asthma. Inhibition of MAPK kinases and up-regulation of endogenous MAPK deactivators could also be potential strategies for treatment.
15
Whicker, Susan D. "Pharmacological studies of [beta]-adrenoceptors in airway smooth muscle." Thesis, The University of Sydney, 1990. https://hdl.handle.net/2123/26279.
Full textAbstract:
Airway smooth muscle receptor-mediated responsiveness and receptor characteristics for airway tissue from non-asthmatic and asthmatic patients, and guinea pigs with airway responsiveness, were investigated for airway preparations using drug concentration-response relationships and radiolabelled ligand binding studies.
Between—patient variability was approximately SSO-fold greater than within-patient variability for B-adrenoceptor-mediated responsiveness of human airway tissue.
Alteration in B-adrenoceptor characteristics (Kd and Bmax) could not account for the marked between-patient variability demonstrated for B-adrenoceptor mediated responsiveness.
Exposure of human airway tissue in vivo with preoperative Bz-adrenoceptor agonist medication did not influence B-adrenoceptor-mediated responsiveness, however in vitro exposure of airway tissue to B-adrenoceptor agonist did reduce G-adrenoceptor-mediated responsiveness. This suggests, that in vivo concentrations reached for Bz-adrenoceptor agonist medication were not great enough to induce an alteration in B-adrenoceptor-mediated function.
Chronic administration of B-adrenoceptor antagonist medication of patients and rats reduced B-adrenoceptor-mediated responsiveness of airway tissue in vivo. The B-adrenoceptor-mediated responsiveness of peripheral airway tissue from spontaneously hypertensive rats was similar to that for tissue from normotensive animals. Evidence suggests therefore that the reduced 8--adrenoceptor-mediated responsiveness is not due to the hypertension but to the accumulation of the 13--adrenoceptor antagonist in the peripheral airway tissue.
Airway smooth muscle from asthmatic patients demonstrated similar relaxation responsiveness to tissue from non-asthmatics and reduced responsiveness to contractile agonists. These results suggest that airway hyperresponsiveness in vivo is regulated by factors other than smooth muscle characteristics.
Relaxation responsiveness of airway smooth muscle from asthmatic patients was similar to that in non-asthmatic patients, however contractile responsiveness was reduced. Alteration of muscarinic cholinoceptor responsiveness, suggesting that alteration in muscarinic-mediated responsiveness is distal to the muscarinic cholinoceptors. B-Adrenoceptor characteristics remained unchanged.
It is concluded that airway hyperresponsiveness in vivo is not represented by parallel changes in receptor-mediated tissue responsiveness, suggesting that neural and/or humoral influences may influence airway control.
16
Pascoe, Christopher Daniel. "Mechanical and molecular contribution of airway smooth muscle to airway hyperresponsiveness in asthma." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/51862.
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This thesis focuses on the mechanical and molecular role of airway smooth muscle (ASM) in asthma with the aim to determine the contribution of ASM to both asthma and airway hyperresponsiveness (AHR). The first three chapters involve studies probing the mechanical properties of tracheal ASM strips and how these may contribute to the development of AHR. They will aim to show that ASM can contribute to AHR without fundamental changes to the tissue. Specifically, the first chapter investigated the ASMs response to force oscillations mimicking breathing maneuvers under levels of activation that induce force adaptation, a phenomenon potentially seen in asthmatics. It shows that force adaptation can persist under conditions that mimic breathing maneuvers and therefore could contribute to AHR and ASM hypercontractility. The second chapter investigated the role of tone in limiting the strain imposed on ASM by breathing maneuvers and the subsequent response of ASM to those strains. The stiffening of muscle in response to agonist precedes force development and acts to decrease the strain applied to the ASM. As strain decreased, the effect on the muscle contractility was blunted. Interestingly, a prior history of oscillations induced a bronchoprotective effect in the strip and caused a two times greater decline in force than would normally be expected by the small strains indicating that prior DIs are effective in limiting the responsiveness of the ASM to agonist. The third chapter investigated whether the ASM is intrinsically responsible for the bronchoprotective effect of deep inspirations (DIs). This study showed that simulated prior DIs can increase the compliance of the muscle to subsequent DIs, and although the effect on a single strip of muscle is small, the effect at the whole lung level may be sufficient to explain the bronchoprotective effect of DIs. The final chapter describes the molecular phenotype of ASM in asthma at both the gene and protein level. Proteins involved in contraction were found not to be significantly altered in asthmatics; however a host of proteins involved in cytoskeletal structure were changed and could explain why asthmatic ASM is stiffer and less responsive to DIs.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
17
Wikström, Jonsson Eva. "Functional characterisation of receptors for cysteinyl leukotrienes in smooth muscle /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2897-5.
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Dechert, Melissa A. "Signaling through p21-activated kinase 1 in airway smooth muscle /." abstract and full text PDF (UNR users only), 2002. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3090865.
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Rhoden, Kerry J. "Neural and neuropeptide control of airway smooth muscle in vitro." Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/46524.
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Lau, Justine Yeeman, and jlau@med usyd edu au. "Novel genes associated with airway smooth muscle proliferation in asthma." University of Sydney, 2008. http://hdl.handle.net/2123/5134.
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Doctor of Philosophy (PhD)It is well recognised that both genetic and environmental factors determine an individual’s predisposition to asthma. In recent years, the airway smooth muscle (ASM) cell has come to the attention of researchers to, not merely be a contractile cell of the airway, but one that orchestrates events affecting airway remodelling and proliferation. Experiments described in this thesis have, for the first time, examined genes that are associated with various aspects of the pathogenesis of asthma by using the candidate gene approach and a genome wide search. Genes have not only been identified to be differentially expressed in ASM cells derived from asthmatic and non-asthmatic participants, but have also been linked with a functional consequence of asthma. The three genes found to be differentially regulated between ASM cells derived from asthmatic and non-asthmatic participants were Peroxisome Proliferator-Activated Receptor- gamma (PPARγ), mimecan and fibulin-1. Expression of the anti-proliferative transcriptional factor PPARγ, found by the candidate gene approach, was elevated in ASM cells derived from asthmatic participants. Whilst elevated, the anti-proliferative effect of PPARγ was absent in ASM cells derived from asthmatic participants. By microarray analysis, mimecan, an anti-proliferative agent was identified. Mimecan levels, although not different basally in ASM cells, were upregulated by transforming growth factor β (TGFβ) only in asthmatic derived ASM cells. Silencing mimecan, by the use of specific oligonucleotides, increased proliferation of ASM cells. This suggested that by increasing mimecan expression, the proliferation of ASM cells may be halted. Fibulin-1, also found by microarray analysis and the final gene examined in this thesis, was found in elevated levels in BAL fluid, serum and ASM cells obtained from asthmatic participants. In addition, ASM cells derived from asthmatic participants, for the first time were shown to have faster wound healing rates compared with nonasthmatics. The elevated fibulin-1 levels in ASM cells derived from asthmatic participants, in the presence of TGFβ, were demonstrated to contribute to this increased wound healing. Specifically, fibulin-1 was found to affect wound healing by increasing proliferation rather than migration. The current available treatments for asthma, target the contractility and inflammatory conditions in the airway. Through this thesis, novel genes discovered to be associated with proliferation may be potential therapeutic targets to treat asthma. In particular, the fibulin-1 gene is outstandingly promising, as it was shown that silencing fibulin-1 resulted in slower wound healing rates through decreased cell proliferation, to possibly inhibit the airway remodelling observed in asthma, and furthermore, corticosteroid therapy was demonstrated not to affect to this gene.
21
Binnion, Amy Margaret. "Regulation of chemokine expression in human airway smooth muscle cells." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11344/.
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Asthma is an inflammatory disease of the airways characterised by airway remodelling and hyperresponsiveness. New treatments are needed for patients with severe asthma whose disease is not controlled with currently available therapies. Asthma pathophysiology is complex, however, accumulating evidence suggests multiple inflammatory pathways in asthma converge onto a relatively small number of downstream targets that may be of therapeutic interest. These include mitogen activated protein kinases (MAPKs), the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) and transcriptional regulators such as histone acetyl transferases (HATs) and histone deacetylases (HDACs). Chemokines are molecules secreted at sties of inflammation, attracting inflammatory cells and perpetuating the inflammatory response. Here we studied the mechanisms by which the pro-inflammatory mediator endothelin-1 (ET-1) and the cytokine tumour necrosis factor-alpha (TNF-alpha) promoted expression by primary human airway smooth muscle cells (HASMC) of two important chemokines, monocyte chemotactic protein-1 (MCP-1) and eotaxin. Further, we studied the mechanisms by which existing asthma therapies (long acting beta agonists (LABA) and glucocorticoids) modulated TNF-alpha-stimulated eotaxin expression. Endothelin-1 stimulated MCP-1 release through a transcriptional mechanism involving NF-kappaB and AP-1; the upstream signalling pathway involved p38 and p44/p42 MAPKs. Previously, this lab showed that TNF-alpha-induced eotaxin release is also NF-kappaB-dependent, involving histone H4 acetylation at the eotaxin promoter. Here we found that TNF-alpha-induced eotaxin release does not involve histone H3 acetylation, and that TNF-alpha-dependent histone H4 acetylation does not occur through alterations in total histone activity or levels of the key HDACs -1 and -2. Similarly, modulation of TNF-alpha effects on eotaxin expression by glucocorticoids and LABA is independent of total HDAC activity and HDAC-1 and -2 levels. These studies support the body of evidence suggesting that multiple inflammatory pathways in asthma converge onto a small number of downstream targets, and are relevant to the understanding and treatment of asthma.
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Billington, Charlotte K. "Muscarinic M2 receptor signalling in human airway smooth muscle cells." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342489.
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Kong, Kok Choi. "Sphingosine 1-phosphate signalling in guinea pig airway smooth muscle." Thesis, University of Strathclyde, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248742.
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Latourelle, Jeanne C. (Jeanne Catherine) 1976. "Dynamic equilibration of airway smooth muscle length during physiological loading." Thesis, Massachusetts Institute of Technology, 2000. http://hdl.handle.net/1721.1/89295.
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Comer, Brian S. "Cyclooxygenase-2 expression in asthmatic human airway smooth muscle cells." Thesis, University of South Alabama, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3608829.
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Asthmatic human airway smooth muscle cells (hASMCs) exhibit enhanced expression of numerous cytokine-responsive genes but this trend has not been observed for cyclooxygenase-2 (COX-2) expression despite knowledge that conserved regulatory mechanisms exist for cytokine-responsive gene expression. Enhanced expression of cytokine-responsive genes in asthmatic hASMCs has been attributed to differences in histone post-translational modifications and microRNA (miR or miRNA) expression. COX-2 expression is of interest because it serves as a model cytokine-responsive gene and is regulated by epigenetic mechanisms. In other cell types, miR-146a represses COX-2 and Interleukin (IL)-1β expression, directly and indirectly, respectively. Due to sequence homology, miR-146b is predicted to repress the expression of COX-2 and IL-1β. I investigated COX-2 expression in asthmatic and non-asthmatic hASMCS treated with cytomix (IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ). Also, I chose to compare histone acetylation, transcription factor binding, and miR-146a/b expression in asthmatic and non-asthmatic hASMCs to identify any correlations with COX-2 expression. A major goal of this project was to help identify new treatment targets for asthma therapeutics . I hypothesized that asthmatic hASMCs treated with cytomix express more COX-2 and secrete more prostaglandinE2 (PGE2) than non-asthmatic hASMCs due to differences in COX-2 epigenetic regulation. It is reported here that asthmatic hASMCs treated with cytomix expressed more COX-2 (mRNA/protein), and secreted more PGE2 than non-asthmatic hASMCs. Histone H3/H4 pan-acetylation at the COX-2 promoter did not increase with cytomix treatment and was not different in asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased RNA Polymerase II and nuclear factor-κB binding at the COX-2 promoter with no difference between asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased miR-146a and miR-146b expression with greater miR-146a expression in asthmatic. MiR-146a/b expression in asthmatic hASMCs treated with cytomix did not negatively correlate with COX-2 expression. These results led me to investigate whether miR-146a/b were capable of negatively regulating COX-2 and IL-1β expression in hASMCs. MiR-146a and miR-146b mimics reduced COX-2 and IL-1β mRNA/protein, and PGE2 secretion in hASMCs. MiR-146a and miR-146a/b combination inhibition increased COX-2 and pro-IL-1β protein in hASMCs but not miR-146b inhibition alone. In conclusion, elevated miR-146a expression and histone acetylation are not responsible for increased COX-2 expression in asthmatic hASMCs. MiR-146a is a minor negative regulator of COX-2 and IL-1β expression in hASMCs at physiological expression levels but mimics are capable of antagonizing cytokine-responsive gene expression profoundly. These results coupled with other evidence from the literature indicate that miR-146a/b should be investigated in animal models of asthma to determine if they are relevant asthma drug target in patients that do not respond to current anti-inflammatory therapies.
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Norris, Brandon Anthony. "Development and maintenance of force and stiffness in airway smooth muscle." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54875.
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The primary function of airway smooth muscle (ASM) is to contract upon stimulation. Mechanical manifestation of contraction includes development and maintenance of force and stiffness, and when the developed force is greater than the load on the muscle, shortening occurs. Dysfunction of ASM could lead to excessively stiff or narrowed airways. This thesis research is aimed at advancing our understanding of the basic mechanisms involved in the development and maintenance of force and stiffness in ASM and how these mechanical properties are regulated by enzymes and their associated signalling pathways. The research is also aimed at identifying new targets for asthma therapy with specific interventions that reduce airway stiffness and narrowing. Recently, stiffness of the passive components of ASM –unrelated to that stemming from attached myosin crossbridges - has been shown to be actively regulated by intracellular enzymes. Chapter 2 of this thesis shows that the passive components of the ASM can be activated to generate force and augment stiffness. This activation is cross-bridge independent, as the calcium within the ASM cells was removed and the phosphorylation of the regulatory myosin light chain was abolished. The activation could be prevented when Rho-kinase was inhibited. Rho-kinase is known to be actively involved in the cytoskeletal dynamics of ASM; therefore, it is reasonable to assume that the cytoskeletal network is at least partly responsible for the activation of the passive components in ASM. Chapter 3 of the thesis aimed to explain the biphasic response that occurs when a ramp stretch is applied to an activated ASM strip. By performing ramp stretches in different conditions, the two phases of the biphasic force response revealed an intricate relationship between the two contributors to muscle stiffness – the attached actomyosin crossbridges and the cytoskeleton. Results presented in both chapters of the thesis suggest that signalling pathways involving Rho-kinase is crucial for regulating the calcium dependent and independent ASM force and stiffness. This has provided a focus for future studies in identifying enzyme or structural protein targets for modulating ASM mechanical properties down stream of the Rho-kinase.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Pasternyk, Stephanie Marika 1983. "Effect of extracellular matrix and mechanical strain on airway smooth muscle." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111560.
Full textAbstract:
Airway remodeling in asthma includes alterations in extracellular matrix and airway smooth muscle (ASM) mass. For this study, ASM cells were obtained from rats that were challenged with ovalbumin (OVA) or saline (SAL) as control. OVA and SAL cells were seeded on plastic control (PC) or on plates coated with decorin or biglycan. OVA cell number was significantly increased versus SAL cells, for cells seeded on PC (48 h). A significant decrease in cell number was observed for both OVA and SAL cells seeded on decorin compared to PC cells (48 h). OVA cells, however, showed a more modest reduction in cell number. Furthermore, biglycan decreased SAL cell number only. Compared to no strain (NS), mechanical strain (S) reduced cell number for OVA and SAL cells on all matrices. In addition, S up-regulated expression of beta 1-integrin relative to NS controls. Results suggest an ability of ASM cells to be modulated by matrix and mechanical stimulation.
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Styhler, Angela. "Proliferative response of airway smooth muscle cells to macrophage-derived products." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22812.
Full textAbstract:
Brown Norway rats show increased airway smooth muscle content following repeated allergen challenges. Macrophages synthesize many growth factors in vitro which potentially stimulate proliferation of airway smooth muscle cells. Leukotriene C$ sb4$, an important mediator of allergic airway responses, can stimulate macrophages to release platelet-derived growth factor (PDGF) which is a potent stimulator of proliferation. The purpose of this study was to investigate the role of the macrophage in the proliferative response of airway smooth muscle cells leading to airway remodelling. Macrophages were harvested from 7- to 9-week-old male Brown Norway rats, allowed to adhere to plastic 25cm$ sp2$ culture flasks for 25 minutes, rinsed with sterile PBS at 37$ sp circ$C to wash off cells other than macrophages and maintained in short-term culture in serum-free medium. Airway smooth muscle cells were also harvested and cultured. Supernatant from macrophages significantly stimulated airway smooth muscle cell proliferation 5-fold as compared to controls (p $<$ 0.05). This stimulation was affected neither by the addition of the cyclooxygenase inhibitor ASA, nor by the addition of the LTD$ sb4$ inhibitor MK-571. However, stimulation was decreased by the addition of the PDGF inhibitor suramin, as well as by an anti-PDGF polyclonal antibody. Maximal inhibition observed with antibody was 34% (p $<$ 0.01). We conclude that macrophages have the ability to stimulate airway smooth muscle cell proliferation by releasing growth factors, that one of these growth factors is PDGF, and that PDGF contributes 34% of the total airway smooth muscle cell proliferation. Therefore, it is likely that macrophages play an important role in airway remodelling and that this airway remodelling may be an important component in the pathology of asthma. (Abstract shortened by UMI.)
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Joubert, Philippe. "Expression and function of chemokine receptors on airway smooth muscle cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103385.
Full textAbstract:
Asthma is a respiratory disease that affects 2.5-3 million Canadians. This condition is characterized by a Th2-driven immune response that implicates the infiltration of eosinophils and remodelling of the airways. In the last decade, airway smooth muscle cells (ASMC) have became the subject of intense research in the field of inflammatory lung diseases including asthma. It is known that ASMC respond to a wide variety of inflammatory mediators such as cytokines and chemokines. Function of ASMC in the context of asthma has extended beyond its traditional role of a structural cell. Indeed, it is believed that they can participate in the initiation and the perpetuation of the inflammatory response that takes place in the airway of asthmatic subjects. The general aim of this work was to investigate the role of ASMC in the pathogenesis of asthma. More specifically, we studied the expression of two C-C chemokine receptors, CCR3 and CCR1 in the context of asthma.For the first time, this work describes the expression of chemokine receptors by ASMC. We have shown that eotaxin, an important chemokine in asthma, induces migration of ASMC through the activation of CCR3. Although CCR3 expression is not regulated by Th2 cytokines in vitro, ASMC isolated from asthmatic patients expressed intrinsically higher levels of the surface receptor when compared to controls. We also describe the expression of CCR1 by ASMC, a receptor involved in airway remodelling in an animal model of asthma. We reported the expression of CCR1 mRNA in biopsies obtained from mild, moderate and severe asthmatics and showed that mild group express the highest level of CCR1. We also confirmed that ASMC express the receptor in vivo and showed that stimulation of this receptor with its ligands induces intra-cellular calcium mobilization, which confirms its functionality. Regulation of CCR1 on ASMC was also assessed using proinflammatory, Th1 and Th2 cytokines. We found that TNF-alpha and to a lesser extent, IFN-gamma, upregulated CCR1 mRNA and protein expression, while Th2 cytokines had no effect. The effect of these two cytokines was totally suppressed by either dexamethasone or mithramycin.
Collectively, our results demonstrate the expression of functional C-C chemokine receptors by ASMC. Interestingly, we have shown that CCR3 activation mediates ASMC migration and provides a new possible mechanism for the increased smooth muscle mass observed in asthmatic patients. Although the exact function of the CCR1 expressed by ASMC is unknown, our results suggest an involvement in asthma pathogenesis, possibly through airway remodelling.
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Woodman, Lucy. "Cellular interactions of airway smooth muscle and human lung mast cells." Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/7382.
Full textAbstract:
Asthma is characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), inflammation and remodeling. Mast cells (MC) co-localise to airway structures such as epithelium and airway smooth muscle (ASM) - the latter is a key determinant of AHR. Our group has reported that the CXCL10/CXCR3 axis is important in MC migration towards ASM, MCs adhere to ASM predominately via CADM-1 and this interaction promotes MC survival and proliferation. Whether there are other important mechanisms driving MC localization, ASM migration, and how MCs affect ASM differentiation is uncertain. We sought to examine i) chemokine concentrations in airway secretions in eosinophilic bronchitis (EB), and asthma, and their effects on MC migration ii) CCR3 mediated ASM migration, iii) effects of MC–ASM co-culture on ASM differentiation. Bronchoalveolar lavage (BAL) CXCL10 and CXCL8 concentrations were increased in subjects with EB compared to asthmatics and controls; were chemotactic for MCs and was attenuated by CXCR1 or CXCR3 inhibition. CCL11 mediated ASM migration and wound healing, but had no effect on proliferation or survival. Co-culture with β-tryptase or MCs degraded CCL11, and inhibited CCL11-mediated ASM migration. In vitro co-culture of ASM cells with β-tryptase or MCs increased ASM-derived TGF-β1 secretion, α-smooth muscle actin (α-SMA) expression and agonist-provoked contraction. Promotion to a more contractile phenotype was inhibited by leupeptin and TGF-β1 neutralization, suggesting ASM differentiation was driven by the autocrine release of TGF-β1 in response to β-tryptase. Importantly, in vivo, in asthmatic bronchial biopsies, intensity of α-SMA expression was strongly related to the number of MCs within or adjacent to ASM bundles. In conclusion, CXCL8 and CXCL10 are important in MC migration to the epithelium, but CCL11 is unlikely to be important in ASM migration. MCs drive ASM differentiation to a more contractile phenotype via autocrine release of TGF-β1, which may contribute to the disordered airway physiology in asthma.
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Sweeney, David. "Human airway smooth muscle cell Ca2+ dynamics in asthma and health." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10130.
Full textAbstract:
The funding for this research project was kindly provided by the Medical Research Council (MRC) and the British Thoracic Society (BTS)Intracellular Ca2+ homeostasis and handling were investigated in passaged human airway smooth muscle, hASM, cells from asthma and normal donors. Temporal changes in fluorescence of Ca2+-sensitive indicator fura-2 loaded into quiescent sub-confluent hASM cells were monitored using epifluorescence video microscopy. Spontaneous amplitude changes in basal fluorescence of temporal waveforms, or Ca2+ oscillations, were measured. Also, spectral analysis using the FFT transform generated a Ca2+ oscillation dominant frequency (CODF) variable. Neither amplitude nor CODF were significantly different in asthma compared to normal hASM cell donors. However, there was a significant difference (P<0.0001) between CODF in airflow obstruction (AFO), defined as FEV1/FVC<70% and FEV1< 80%, and non-AFO donors, making CODF a strong phenotypic predictor of AFO. hASM cell Ca2+ handling was investigated by Ca2+ uncaging using confocal microscopy and by bradykinin stimulation using epifluorescence microscopy. Basal Ca2+ level, Ca2+ handling exponential decay rate constants (K), SERCA activity and expression, and SOCE after a SR Ca2+-store depletion event, all demonstrated that Ca2+ handling was not significantly different between hASM cells from asthma or normal donors. There was no correlation between FEV1 and K, however there was an emerging correlation between FEV1/FVC and K for bradykinin. The postulate that Ca2+ homeostasis and handling are intrinsically dysfunctional in hASM cells from asthma compared to normal donors is ergo not supported by these data. Caffeine was found to decrease basal Ca2+ and inhibit Ca2+ oscillations in hASM cells. Future work using freshly dispersed hASM cells is required to understand in vivo Ca2+ dynamics using the methods described in this thesis. Since CODF correlates with FEV1, pattern recognition of Ca2+ oscillation frequency spectra has the potential to help define clinical asthma phenotypes. Inevitably, a post-genomic approach to comparative protein expression in asthma and normal hASM cell donors will accelerate understanding of Ca2+ dynamics.
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Stocks, Joanne. "The production of soluble angiogenic factors by human airway smooth muscle." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430617.
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Nguyen, Trang Thi Bao. "Modulation of human airway smooth muscle proliferation by the extracellular matrix." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406267.
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Darby, Peter James. "Isolation and characterization of caveolae from canine airway and intestinal smooth muscle." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ66199.pdf.
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Robins, Stephanie. "The p38 MAPK pathway in human airway smooth muscle: roles in asthma." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97233.
Full textAbstract:
The mitogen activated protein kinase (MAPK) signaling pathways play key roles in mediating inflammatory responses. Asthma is a disease characterized by excessive inflammation and the mainstay of treatment is the use of glucocorticoids which, among other effects, control the activity of p38 MAPK. Human airway smooth muscle (HASM) cells contribute to the pathology of asthma as they regulate bronchomotor tone, proliferate, migrate and secrete inflammatory cytokines. I investigated these processes in HASM using MAPK inhibitors and the glucocorticoid dexamethasone. Following TNFα stimulation, HASM cell production of GM-CSF, IL-1β, IL-33 and CXCL8 were ERK1/ERK2 dependent; all but CXCL8 were diminished by dexamethasone. Neutrophil migration in response to conditioned media from HASM cells was also ERK1/ERK2 dependent. CXCL12 displayed chemotactic activity for HASM which was shown to express the CXCR4 receptor. HASM migration was partially p38 MAPK dependent. These results highlight the potential for important and divergent roles for the MAPKs in HASM in refractory asthma.L'asthme est une maladie inflammatoire dont les glucocorticoïdes constituent le principal traitement via le contrôle de la voie p38 MAPK. Les cellules musculaires lisses bronchiques (CLM) jouent un rôle clé dans la physiopathologie de l'asthme notamment dans le remodelage des voies aériennes via leur capacité à proliférer, migrer et sécréter des médiateurs inflammatoires. La stimulation des CLM avec du TNFα entraine une activation des voies MAPK ERK et p38, induisant l'expression des gènes GM-CSF, IL-1β, IL-33 et CXCL8. L'activation de la voie MAPK ERK est importante dans la migration des neutrophiles exposée à du milieu conditionné provenant de CLM stimulées par TNFα via son rôle sur l'expression de CXCL8. En contrepartie, la voie p38 MAPK joue un rôle important dans la migration des CLM en réponse à CXCL12, un chimiokine élevée dans les bronches de patients asthmatiques. Ces résultats ont mis en évidence un rôle important et divergeant des MAPKs dans les CLM dans la pathophysiologie de l'asthme sevère.
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Freyer, Anette M. S. "The effect of extracellular matrix on human airway smooth muscle cell phenotype." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415554.
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Corteling, Randolph Lee. "The role of TRPC channels in human airway smooth muscle cell homeostasis." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403290.
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Morris, Gavin Edward. "Mechanisms of airway smooth muscle activation by agonists of toll-like receptors." Thesis, University of Sheffield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425196.
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McVicker, Clare Geldard. "Calcium influx mechanisms during mediator-induced responses in human airway smooth muscle." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404814.
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Chang, Po-Jui. "Investigation of corticosteroid responsiveness in airway smooth muscle cells of severe asthma." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11590.
Full textAbstract:
Asthma is characterised by airway inflammation, hyper-responsiveness and airway remodelling. Features of airway remodelling include hypertrophy/hyperplasia of airway smooth muscle cells (ASMC), which possess an important synthetic capacity in addition to their contractile function. Patients with severe asthma respond poor to even high-dose corticosteroids and consume enormous healthcare resources. Corticosteroid insensitivity in peripheral blood mononuclear cells and alveolar macrophages of severe asthma has been reported. It is still unclear whether ASMC display a similar phenotype. I hypothesised that corticosteroid insensitivity exists in ASMC of severe asthma, and the underlying mechanisms were investigated. ASMC were obtained from endobronchial biopsy and were experimented with at passage 4-5. TNF-α induced CCL11, CXCL8 and CXCL10 expression in ASMC. IFN-γ suppressed TNFα-induced CCL11 and CXCL8, through attenuation of NF-κB (p65) recruitment to the gene promoters, but potentiated induced CXCL10. CX3CL1 was induced synergistically only by combined both cytokines. Baseline and TNFα-induced CCL11 expression in non-severe asthma were greater than the healthy and severe asthma, while IFNγ-induced CXCL10 was increased in severe asthma. Whereas TNFα-induced p65 expression was increased in severe asthma, there was no difference in nuclear translocation or recruitment to the gene promoters between groups. The effect of dexamethasone was reduced in terms of suppressing induced CCL11 and CXCL8 expression in severe asthma, while the potentiating effect on CX3CL1 was not different between groups. Of the mitogen-activated protein kinases (MAPK), p38 activation was heightened in severe asthma, and p38 inhibition restored the corticosteroid sensitivity. Expression of glucocorticoid receptor (GR) was decreased in asthma, while nuclear translocation of GR was impaired only in severe asthma. In conclusion, there is differential expression of inflammatory chemokines in ASMC of asthma. Corticosteroid insensitivity exists in ASMC of severe asthma in terms of suppressing induced chemokines, partially attributed to heightened p38 MAPK activity and impaired nuclear translocation of GR.
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Inouye, David Shoichi. "Perturbed equilibria of myosin binding in airway smooth muscle and its implications in airway hyperresponsiveness and asthma." Thesis, Massachusetts Institute of Technology, 2000. http://hdl.handle.net/1721.1/9372.
Full textAbstract:
Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000."September 1999."
Includes bibliographical references (leaves 139-145).
In asthma, the key effector driving acute airway narrowing is thought to be airway smooth muscle (ASM); as the muscle surrounding the airways shortens, the airway lumen narrows. Airway hyperresponsiveness (AHR) - the excessive narrowing of the airways - is one of the cardinal features of asthma. Yet, the mechanism(s) regulating the airway lumenal radius, and perhaps the failure of these mechanisms to prevent excessive airway constriction, remains largely unexplained. This thesis shows that the regulation of ASM length corresponds to a dynamically equilibrated steady-state, not the static mechanical equilibrium that had been previously assumed. This dynamic steady state requires as an essential feature a continuous supply of external mechanical energy (derived from tidal lung inflations) that act to perturb the interactions of myosin with actin, drive the molecular state of the system far away from thermodynamic equilibrium, and bias the muscle toward lengthening. This mechanism leads naturally to the suggestion that excessive airway narrowing in asthma may be associated with the destabilization of that dynamic process and its resulting collapse back to static equilibrium. With this collapse the muscle undergoes a phase transition and virtually freezes at its static equilibrium length. This mechanism may help to elucidate several unexplained phenomena including the multi-factorial origins of AHR, how allergen sensitization leads to AHR, and the inability in asthma of deep inspiration to relax ASM.
by David Shoichi Inouye.
Ph.D.
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Anaparti, Vidyanand. "Role of N-methyl-D-aspartate receptors in the regulation of human airway smooth muscle function and airway responsiveness." American Physiological Society, 2015. http://hdl.handle.net/1993/30657.
Full textAbstract:
Increased airway smooth muscle (ASM) mass contributes to airway hyperresponsiveness (AHR) in asthma and is orchestrated by growth factors, cytokines and chemokines. Airway contractile responses are influenced by neuromediators, such as acetylcholine, and glutamate released by parasympathetic and sympathetic airway nerves. Hyperactivity of these neural elements, termed neurogenic inflammation, is linked with hypercontractility and AHR. Glutamate is a non-essential amino acid derivative, and its physiological role is traditionally considered with respect to its being the primary excitatory neurotransmitter in brain, and regulation of neuronal development and memory. In allergic inflammation, immune cells including dendritic cells, neutrophils and eosinophils, constitutively synthesize and release glutamate, which signals through activation of glutamate receptors, most important among which are ionotrophic N-methyl D-aspartate receptors (NMDA-R). We hypothesized that glutamatergic signaling mediated through NMDA-Rs plays an important role in inducing functional Ca2+ responses in human (H) ASM cells that can underpin airway hypercontractility. We investigated the expression and function of NMDA-Rs in HASM cells, and assessed the effects of pro-inflammatory cytokines on NMDA-R expression and functional responses. Moreover, we measured airway responses to NMDA in mice, murine thin cut lung slice preparations, and floating collagen gels seeded with HASMs. Our data reveal that airway myocytes express multi-subunit NMDA-R complexes that function as receptor-operated calcium channels (ROCCs), mobilizing intracellular Ca2+ in ASM in vitro and airway contraction ex vivo. Individual airway myocytes treated with NMDA-R agonist exhibit disparate temporal patterns of intercellular Ca2+ flux that can be partitioned into four discrete function sub-groups. Further we show that tumor necrosis factor (TNF) exposure modulates NMDA-R subunit expression, and these changes are associated with a shift in the distribution of myocytes in individual Ca2+-mobilization sub-groups in vitro. Further, post-TNF exposure, NMDA-R agonists’ treatment induced Ca2+-dependent airway dilation in murine lung slice preparations, an effect that was prevented by co-treatment with inhibitors of nitric oxide synthase (NOS) or cyclooxygenase (COX). Taken together, we conclude that NMDA-R regulate HASM-mediated airway contraction and their role can be affected upon exposure to asthma-associated inflammatory mediators. Thus, NMDA-Rs are of relevance to mechanisms that determine airway narrowing and AHR associated with chronic respiratory diseases.October 2015
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Hallsworth, Matthew Pearce. "GM-CSF and eosinophil survival in asthma." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341883.
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Svensson, Holm Ann-Charlotte B. "Platelets and airway remodeling : Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro." Doctoral thesis, Linköpings universitet, Farmakologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-61623.
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Airway remodeling is a contributing cause to the pathological structural changes, such as increased cell proliferation, observed in asthma. Platelets have been found in autopsy lungmaterial obtained from asthmatic patients and are well known to induce proliferation in vitro of a variety of cells. However, the role of platelets in airway remodeling is far from understood. This thesis aims to clarify the involvement of platelets in fibroblast and airway smooth muscle cell (ASMC) proliferation in vitro and to elucidate the importance of HA, FAK, eicosanoid and ROS dependent signaling. The results demonstrate that platelets induce ASMC proliferation through NADPH-oxidase and 5-LOX dependent mechanisms. In addition, platelets also induce a 5-LOX dependent fibroblast proliferation. Furthermore, morphological analysis demonstrates that platelets bind to the extracellular matrix component HA through its receptor CD44 and thereby induce a FAK dependent ASMC proliferation. Taken together, the results obtained in this thesis suggest that platelet/HA interaction mediated through CD44 is of importance for platelets ability to induce cell proliferation. Moreover, the results propose that platelet-induced fibroblast proliferation is 5-LOX dependent and that platelets induce a HA, CD44, FAK, 5-LOX, and ROSdependent ASMC proliferation. This action of platelets represents a potential important and novel mechanism that may have an impact on the remodeling process and in the development of new pharmacological strategies in the treatment of inflammatory respiratory disease such as asthma.
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Swyngedouw, Nicholas Eric. "The influence of interleukin-13 on force generation in airway smooth muscle tissue." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58763.
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Airway smooth muscle (ASM) has been implicated in the pathophysiology of asthma by contributing to excessive airway narrowing and Airway Hyperresponsiveness (AHR). Inflammation has also been suggested as a mechanism contributing to AHR. Levels of Interleukin-13 (IL-13), an inflammatory mediator, are increased in asthmatic sera and can alter the expression of specific contractile genes/proteins in cultured ASM cells. In cultured cells, IL-13 can cause increased ASM contractility and force generation in response to different contractile agonists such as acetylcholine (ACh), KCl, or histamine. However, there remains a lack of consensus regarding whether IL-13 can induce changes in mechanical properties of ASM tissue in response to all, or only some, contractile agonists. Our objective was to investigate the influence of IL-13 on the force generation of isolated ASM tissue in response to a variety of agonists. Ovine tracheal smooth muscle was isolated, bathed in Krebs solution, and then equilibrated using electrical field stimulation. To obtain baseline mechanical measurements, tissues were either contracted with a range of ACh concentrations, pre-stimulated with ACh then relaxed with progressively increasing doses of isoproterenol (ISO), or contracted with single a single concentration of KCl or histamine (n=5 per condition). Paired samples from each tissue were pinned at in situ length and incubated for 24h or 72h with or without IL-13 in serum-free DMEM. Responses were compared to their baseline measurements after incubation to determine the influence of IL-13. Compared to non-exposed tissues, IL-13 did not increase maximal force or sensitivity to a range of ACh concentrations after 24 or 72h (n=5 each), nor did it impede the relaxation of ASM induced by ISO after 24h (n=5). Likewise, response to KCl was not changed by IL-13 after 72h (n=5). Response to histamine was ~120% higher compared to control (t=72h) after treatment (% of baseline maximal force, n=5, p=0.03). These findings contrast with previous literature in ASM cell culture experiments. In tissue strips, IL-13 did not induce significant changes to ASM mechanics in response to ACh, ISO, or KCl. However, IL-13 did influence histamine-induced contractile response suggesting a potential avenue by which airway inflammation influences ASM contraction.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Cavers, Andrew. "Mechanical strain bioreactor design and assessment for culture of human airway smooth muscle." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59236.
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Bioreactors capable of subjecting cells and tissues to time-varying mechanical strain are one aspect of simulating in vivo conditions. A bioreactor to impart arbitrary strain waveforms on cells or tissue scaffolds for loading conditions found in the airway was designed and developed and, in the process, it was determined that there are sources of experimental error which could invalidate bioreactor experiments if not properly mitigated. Without effective design and validation, bioreactors can impart significantly different stimuli than the assumed experimental conditions. Cyclic strain is thought to play a role in airway remodeling by mediating cytoskeletal contraction of the airway smooth muscle. In vitro experiments have demonstrated varying changes to the cytoskeleton depending on experimental conditions. Based on literature review, the strain waveform, magnitude, mechanical properties of the substrate, and anisotropy of the strain stimulus may all affect airway smooth muscle (ASM) differentiation. A bioreactor capable of imparting a broad range of strain stimulus was developed using stepper motors as actuators to allow open-loop control. Any changes in the cells subjected to cyclic strain in these bioreactors would be assumed to correlate with cyclic strain, but a poorly designed bioreactor could introduce confounding experimental stimuli which could easily invalidate the experiment. Heat generated by the actuators can overheat the cell cultures. Vibration might alter the cytoskeletal response. Strain response across the substrate can drastically vary from modeling predictions depending on the loading conditions and how the substrate has been constrained. Methods of mitigating heat generation and transfer were developed. The vibrations emitted by the two stepper motor options were evaluated. A method of mapping the substrate was developed such that nonplanar strains across the substrate surface could be characterized to validate the experimental conditions prior to testing. Finally, ASM cells were subjected to cyclic and static strain on PDMS substrates and cell realignment evaluated. Cells were noted to realign in the cyclic strain tests, as has been reported in several earlier publications, but also realigned under static strain conditions. The bioreactor design objectives were met.Applied Science, Faculty of
Graduate
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Wilson, Louise Elizabeth. "Ontogenic changes in porcine pulmonary vascular and airway smooth muscle responsiveness in vitro." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/27700.
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The goals of these studies were to determine if maturational changes occurred in the responsiveness of airway and vascular porcine smooth muscle in vitro. Pulmonary arteries from immature pigs were less responsive than those from adult pigs to adrenoreceptor mediated vasoconstriction. An alpha-2 adrenoreceptor mediated release of endothelium-derived relaxing factor was demonstrated in pulmonary arteries from adult pigs but not in those from immature pigs. Arteries from immature pigs were less responsive to relaxation induced by nitric oxide and hypoxia but not by sodium nitroprusside. Bronchial rings from immature pigs produced greater force (normalised to wet weight) in response to acetylcholine or potassium chloride than did rings from adult pigs, although the concentration of acetycholine required to produced half-maximal response (EC50) was similar. Rings from newborn pigs were more sensitive to the bronchodilator ketamine than those from adult pigs, as manifested by a shift in EC50. The relaxant action of ketamine on tracheal smooth muscle was shown to be due to an inhibitory effect on excitation of the postsynaptic nicotinic receptors of the intramural parasympathetic ganglion and a direct effect on the smooth muscle cell. Nonadrenergic noncholinergic innervation was shown to be present from birth. Hypoxic bronchodilation was seen in bronchial rings from all ages. In conclusion, this study demonstrates age-related changes in the in vitro responsiveness of both pulmonary vascular and airway smooth muscle to contractile and relaxant agonists, responses depending not only upon the agonist used to elicit contraction or relaxation, but also upon the age of the animal studied.
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Wang, Ying. "Phenotypic modulations of cultured canine airway smooth muscle cells and growth-arrested cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ32279.pdf.
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Ma, Xuefei. "Heterogeneity of airway smooth muscle cells and its implications in pathogenesis of asthma." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ32004.pdf.
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Ghaffar, Omar. "Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0024/MQ50776.pdf.
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