Current Reviews of Allergy and Clinical Immunology (Supported by a Grant from GlaxoSmithKline, Research Triangle Park, NC)
Airway remodeling in asthma: New insights

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Abstract

Continuing Medical Education examination

CONTINUING MEDICAL EDUCATION ARTICLE Credit can now be obtained, free for a limited time, by reading the following review. Please note the instructions listed below. Method of Physician Participation in Learning Process: The core material for this activity can be read in this issue of the Journal or online at the JACI Web site: www.mosby.com/jaci . The accompanying test may only be submitted online at www.mosby.com/jaci . Fax or other copies will not be accepted. Date of Original Release: February 2003. Credit may be obtained for this course until January 31, 2004. Copyright Statement: Copyright © 2003-2004. All rights reserved. List of Design Committee Members: Authors: Donna E. Davies, James Wicks, Robert M. Powell, Sarah M. Puddicomb, Stephen T. Holgate Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Activity Objectives (a) To understand the structural changes that occur in asthmatic airways. (b) To appreciate the importance of gene-environment interactions and the early life origins of asthma. (c) To recognize potential mechanisms of airway wall remodeling. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma and Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this educational activity for up to 1.0 hour in category I credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit he or she actually spent in the educational activity. Recognition of Commercial Support: This activity has not received external commercial support.

Section snippets

Historical perspective

In 1859, Henry Hide Salter1 was the first to describe asthma as a disease of reversible airway obstruction; in 1960, the definition was similar but with the inclusion of bronchial hyperresponsiveness (BHR). By 1997, the National Heart, Lung, and Blood Institute defined asthma as “a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T lymphocytes. In susceptible individuals this inflammation causes recurrent episodes of

Asthma: A disease of inflammation and remodeling

Immunohistochemical analysis of bronchial biopsy specimens has enabled detailed description of the inflammatory cells present in asthmatic airways. These infiltrates are characterized by the presence of mast cells, basophils, eosinophils, monocytes, and T lymphocytes of a TH2 inflammatory profile.5 Consequently, treatments have been developed to suppress this inflammatory response for therapeutic benefit.6 Some success has been achieved with the use of corticosteroids, leukotriene receptor

The epithelial mesenchymal trophic unit in asthma

Although asthma is a heritable trait, the increasing prevalence of this disorder over the last 30 years is too large and widespread to be caused by genetic change. This has led to the proposal that the increasing trends in asthma are due to changes in the environment acting on a susceptible genotype both in respect to disease induction and worsening of established disease.14 This proposal is supported by epidemiologic studies identifying multiple interacting environmental risk factors for

TH2 inflammation and the emtu: A new paradigm for asthma pathogenesis

TH2-type inflammation of the airways is a characteristic feature of asthma, irrespective of atopy. Although studies in transgenic mice suggest that IL-13 is able to cause remodeling changes when expressed as a transgene in the bronchial epithelium, we have found that IL-13 is only poorly able to induce myofibroblast transformation in comparison with TGF-β.49 Because IL-13 causes a corticosteroid-insensitive increase in the release of TGF-β2 from bronchial epithelial cells, it seems likely that

Early life origins of asthma

Thickening of the lamina reticularis in bronchial biopsy specimens from young children is present several years before asthma becomes clinically manifest.29 During lung development, epithelial and mesenchymal growth is also regulated by the balance of epidermal growth factor (EGF) and TGF-β signaling, as we suggest occurs in chronic asthma (Fig 4).

. The involvement of EGF and TGF-β in branching morphogenesis of the airways. EGF and TGF-β act in opposing fashion to promote or inhibit growth and

Phenotypic plasticity of airway myofibroblasts and smooth muscle

Evidence suggests that myofibroblasts play a central role in the EMTU by propagating and amplifying signals from the bronchial epithelium into the deeper layers of the submucosa through release of soluble mediators.49 Consistent with this, immunohistochemistry and electron microscopy clearly show that airway myofibroblasts and the smooth muscle bundles lie in close physical proximity in asthma.21 There is an also an increase in the number of myofibroblast-like cells in the lamina reticularis of

Phenotypic plasticity and mesenchymal cell abnormalities in asthma

Like the bronchial epithelium, the mesenchymal cells of the asthmatic EMTU also exhibit functional abnormalities. In our own studies we have found that fibro-blasts from asthmatic patients, but not those from healthy patients, proliferate in vitro in the absence of exogenous growth factors.78 Johnson et al79 have reported a similar phenotype in asthmatic smooth muscle cells, although in this case growth was still supported by the presence of serum factors. This shared hyperproliferative

Where next?

As implied in the National Heart, Lung, and Blood Institute definition, BHR is fundamental to disordered function in asthma. A significant advance in defining the genetic origin of BHR has come from a genome-wide screen that has led to the identification of ADAM33 , a member of the ADAM (a disintegrin and metalloprotease) family, as a novel asthma susceptibility gene encoded on chromosome 20p13.81 In the linkage case-control association and transmission disequilibrium tests and haplotype

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    Reprint requests: Stephen T. Holgate, Mailpoint 810, Level D Centre Block, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom.

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