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Mechanisms of Asthma and Implications for Its Prevention and Treatment: A Personal Journey
Stephen T Holgate 대한천식알레르기학회 2013 Allergy, Asthma & Immunology Research Vol.5 No.6
My research career has focused on the causes of asthma and its treatment. After establishing the key role that mast cells play in the inflammatory response in asthma, attention was turned towards understanding disease chronicity and variability across the lifecourse. Through a combination of studies on airway biopsies and primary cell cultures we have established that asthma is primarily an epithelial disease driven by increased environmental susceptibility to injury and an altered repair response as depicted by sustained activation of the epithelial mesenchymal trophic unit (EMTU) that is invoked in foetal branching morphogenesis. Varied activation of the EMTU connects the origins of asthma to its progression over time with involvement of epithelial susceptibility through impaired barrier and innate immune functions and altered mesenchymal susceptibility as exemplified by polymorphisms of the metalloprotease gene, ADAM33. Taken together these observations have led to a fundamental re-evaluation of asthma pathogenesis. Rather than placing allergic inflammation as the prime abnormality, it is proposed that the airway epithelium lies at the center of asthma pathogenesis, and that in conjunction with the underlying mesenchyme, it is the principle orchestrator of both the induction of asthma and its evolution over the lifecourse. This concept has provided 'the basis for a new preventative and therapeutic approach focused more on increasing the airways resistance to environmental insults rather than suppressing downstream inflammation once it is established.
A Brief History of Asthma and Its Mechanisms to Modern Concepts of Disease Pathogenesis
Stephen T Holgate 대한천식알레르기학회 2010 Allergy, Asthma & Immunology Research Vol.2 No.3
The original concept of asthma being primarily a disease of airways smooth muscle drove the development of bronchodilator drugs. However when it was realised that airway inflammation underpinned the disordered airway function, this gave way to the development of controller therapies such as inhaled cromones and corticosteroids. More recently the discovery of complex interconnecting cytokine and chemokine networks has stimulated the development of biologics with varying success. With the recognition that airway wall “remodelling” is present early in asthma inception and is in part driven by aberrant epithelial-mesenchymal communication both genetic and environmental factors beyond allergen exposure such as virus infection and air pollution are being seen as being increasingly important not only in asthma exacerbations but in the origins of asthma and its evolution into different sub-phenotypes. This brings us round full circle to once again considering that the origins of asthma lie in defects in the formed elements of the airway; the epithelium, smooth muscle, and vasculature. Over the last 25 years Professor You Young Kim has engaged in the exciting discovery science of allergy and asthma and has made an enormous contribution in bringing Korea to the forefront of disease management and research, a position that both he and his colleagues can justly be proud of.
Phan, Cu,Holgate, Daniel L.,Griffin, Gregory J. 한국화학공학회 2003 Korean Journal of Chemical Engineering Vol.20 No.6
Metallic catalytic converters are composed of monoliths through which pass hundreds or thousands of parallel channels. Their mode of manufacture is such that each channel has the cross-section of a sinusoidal curve closed off by a nearly straight edge. During the operation of such converters, heat generated at the channel walls is transferred to the gases flowing through the channels. To understand the overall heat transfer characteristics of the monolith, it is necessary to understand the heat transfer rate between the channel walls and the fluid contained within them. With the use of the computational fluid dynamics package FIDAP, a three-dimensional model of a single channel was used to determine the local Nusselt number (Nu) versus Graetz number (Gz) correlation for heat transfer between the fluid and the walls of the channel. Flow through the channel was laminar and developing from a flat velocity profile at the channel inlet to the fully developed flow towards the outlet. Three different models were developed which corresponded to sinusoid height to width aspect ratios of 5:2, 3:2, and 1:1, respectively. The Nu vs. Gz correlations for the straight edge, curved sinusoidal edge and entire perimeter were calculated and are reported.
Cho, Sang-Heon,Stanciu, Luminita A.,Holgate, Stephen T.,Johnston, Sebastian L. American Thoracic Society 2005 American journal of respiratory and critical care Vol.171 No.3
<P>Increased Th2 cytokine production in asthma is widely accepted, but excess production by asthmatic human airway CD4(+) T cells has not been demonstrated, nor has a relationship with disease severity. The importance of airway CD8(+) T cell type 1 and type 2 cytokine production in asthma is unknown. We investigated frequencies of IFN-gamma, interleukin (IL)-4 and IL-5 producing CD4(+) and CD8(+) blood and sputum T cells from normal subjects and subjects with asthma and compared between cell subsets, subject groups, and body compartments with and without in vitro stimulation and investigated relationships between cytokine production and asthma severity. Production of IL-4, IL-5, and IFN-gamma by unstimulated sputum CD4(+) and CD8(+) T cells was increased in subjects with asthma and related to disease severity, more for CD8(+) than for CD4(+) T cells. Frequencies of sputum CD8(+) T cells producing type 1 and type 2 cytokines were similar to those of CD4(+) T cells. In vitro stimulation polarized peripheral blood cytokine production toward IFN-gamma production, significantly more in subjects with asthma than in normal subjects. These data demonstrate increased type 1 and 2 cytokine production in CD4(+) and CD8(+) T cells in sputum and relate production to disease severity. Findings in blood did not reflect those in airways.</P>
Stanciu, Luminita A,Roberts, Kevan,Papadopoulos, Nikolaos G,Cho, Sang-Heon,Holgate, Stephen T,Coyle, Anthony J,Johnston, Sebastian L BioMed Central 2005 Respiratory research Vol.6 No.-
<P><B>Background</B></P><P>Virus infections are the major cause of asthma exacerbations. CD8<SUP>+ </SUP>T cells have an important role in antiviral immune responses and animal studies suggest a role for CD8<SUP>+ </SUP>T cells in the pathogenesis of virus-induced asthma exacerbations. We have previously shown that the presence of IL-4 during stimulation increases the frequency of IL-5-positive cells and CD30 surface staining in CD8<SUP>+ </SUP>T cells from healthy, normal subjects. In this study, we investigated whether excess IL-4 during repeated TCR/CD3 stimulation of CD8<SUP>+ </SUP>T cells from atopic asthmatic subjects alters the balance of type 1/type 2 cytokine production in favour of the latter.</P><P><B>Methods</B></P><P>Peripheral blood CD8<SUP>+ </SUP>T cells from mild atopic asthmatic subjects were stimulated <I>in vitro </I>with anti-CD3 and IL-2 ± excess IL-4 and the expression of activation and adhesion molecules and type 1 and type 2 cytokine production were assessed.</P><P><B>Results</B></P><P>Surface expression of very late antigen-4 [VLA-4] and LFA-1 was decreased and the production of the type 2 cytokines IL-5 and IL-13 was augmented by the presence of IL-4 during stimulation of CD8<SUP>+ </SUP>T cells from mild atopic asthmatics.</P><P><B>Conclusion</B></P><P>These data suggest that during a respiratory virus infection activated CD8<SUP>+ </SUP>T cells from asthmatic subjects may produce excess type 2 cytokines and may contribute to asthma exacerbation by augmenting allergic inflammation.</P>