Human Airway Smooth Muscle Cells Express Eotaxin in Response to Signaling following Mast Cell Contact
Wuhan University, Wu-han-shih, Hubei, China Respiration
(Impact Factor: 2.59).
02/2006; 73(2):227-35. DOI: 10.1159/000089923
Asthma is a chronic inflammatory disease of the airways. Mast-cell (MC)-derived cytokines may mediate both airway inflammation and remodeling. It has also been shown that airway smooth muscle cells (ASMC) can be a source of proinflammatory cytokines. In the human airways, MC-ASMC cell interactions may have pivotal effects on modulating inflammation.
We wanted to know whether the production of eotaxin, an important proinflammatory cytokine, through a cell-to-cell contact mechanism of human ASMC activation by MC was mediated by p38 MAPK.
We cocultured normal humanASMC with a human MC line (HMC-1) and assayed for the production of eotaxin.
When cultured together, human ASMC and HMC-1 contact induced eotaxin secretion. Separation of HMC-1 and human ASMC by a porous membrane inhibited this induction. Coculturing of human ASMC with HMC-1 induced increased expression of eotaxin gene mRNA. HMC-1-derived cellular membranes caused an increase in eotaxin production in human ASMC. Activation of p38 MAPK was also seen in cocultures by Western blot, whereas eotaxin production in cocultures was significantly inhibited by the p38 inhibitor SB203580.
These novel studies reveal the importance of cell-to-cell interactions in the complex milieu of airway inflammation.
Available from: Abdelilah Soussi Gounni
Available from: ai.jsaweb.jp
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ABSTRACT: One of the factors that may contribute to the exaggerated airway narrowing in asthma is an abnormality of the airway smooth muscle. This abnormality could take the form of an increase in the amount of muscle or an alteration in its pharmacological reactivity. The former could be due to either hypertrophy (an increase in individual muscle cell size) or hyperplasia (an increase in cell number). Changes in pharmacological reactivity that could be relevant to altered airway calibre could result from an increase in contraction or alternatively, a decrease in relaxation. Based on available evidence, the increase in smooth muscle bulk is probably the consequence of both hyperplasia and hypertrophy and several growth factors, inflammatory mediators and cytokines have been implicated. Asthmatic airway tissue is rarely available for in vitro pharmacological studies and evidence for enhanced contraction is limited. Recent evidence suggests that an abnormality in beta adrenoceptor function may contribute to impairment of relaxation, but further work needs to be done. Passive sensitization of non-asthmatic airways in vitro provides a good model for the study of the mechanisms underlying airway hyperresponsiveness, and will be the subject of more intensive study in the future.
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ABSTRACT: There is growing evidence indicating the existence of a causal relationship between abnormal airway smooth muscle (ASM) function and airway hyper-responsiveness, a poorly understood feature of asthma that can be defined as an excessive bronchospastic response. In recent years, there has been a veritable explosion of articles suggesting that ASM exposed to proasthmatic cytokines can elicit a hyper-responsive state to contractile G-protein-coupled receptor (GPCR) agonists. Aberrant airway responsiveness could result from abnormal calcium signaling, with changes occurring at various levels of GPCR-associated signal transduction. This review presents the latest observations describing novel mechanistic models that could explain the involvement of ASM in airway hyper-responsiveness. This review will discuss the role of ASM in beta(2)-agonist-mediated bronchial hyper-responsiveness and the clinical significance of cell-cell contact between ASM and mast cells recently described to be intimately infiltrated within the ASM tissues in asthmatic patients. The possibility that allergens could trigger airway hyper-responsiveness by directly acting on ASM via activation of immunoglobulin E receptors, FcepsilonRI and FCepsilonRII will also be discussed. These important findings further support the notion that targeting ASM could offer new treatment for many features of asthma, including airway hyper-responsiveness. Future therapeutic intervention includes: the prevention of ASM-inflammatory cell physical and/or functional interaction, the inhibition of Immunoglobulin E receptor-dependent signal transduction, and the abrogation of cytokine-dependent pathways that modulate receptor-associated calcium metabolism.
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