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4 Pathophysiological Basis of Asthma
Pages 87-104

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From page 87... ... This research has led to key advances in elucidating the roles of specific inflammatory cells and other processes in the pathobiology of asthma. While there is a wealth of information indicating or suggesting an association between environmental exposures and asthma outcomes, very little is known about the means by which the exposures bring about the changes that manifest as asthma. Read the entire page →
From page 88... ... Upon activation of their high-affinity receptors for IgE, mast cells release a variety of preformed mediators including histamine, leukotrienes, various cytokines, and other proinflammatory molecules. This array of mast cell-derived mediators largely serves to elicit the immediate airway hypersensitivity response to allergen exposure, which is characterized by acute constriction of the airways, airway mucosal gland secretion, and airway edema secondary to increased airway microvascular permeability. Read the entire page →
From page 89... ... Accordingly, activation of airway eosinophils, resulting in release from their granules of preformed mediators, has been implicated in producing constriction of airway smooth muscle, bronchial hyperresponsiveness, recruitment of other inflammatory cell types, and airway tissue (e.g., epithelium) damage. Read the entire page →
From page 90... ... In addition, eosinophils also secrete such enzymes as collagenase, 13-glucuronidase, acid phosphatase, and others (Strek and Leff, 1997~. Among these secreted products, MBP has been found to produce damage to the airway epithelial cell lining, inhibit airway ciliary beat activity, stimulate eicosanoid production, and enhance histamine release from mast cells (Gleich et al., 1974~. Read the entire page →
From page 91... ... There exists substantial evidence in support of this concept, based largely on recent clinical studies conducted in children and adults. These studies have reported that relative to nonallergic or nonasthmatic individuals, both serum and BAL fluid samples isolated from atopic asthmatic patients reveal significantly increased levels of the TH2 cytokines IL-4 and IL-5, in association with relatively decreased levels of the TH2-type cytokine IFN-y (Hamid et al., 1991; Umetsu and DeKruyff, 1997; Ying et al., 1995~. Read the entire page →
From page 92... ... Together with their sequential interaction with cytokines or chemokines and other chemoattractants, cell adhesion molecules contribute importantly to the process of recruitment and activation of specific inflammatory cells at the primary inflammatory focus. The cell adhesion molecules have been classified into three families that include the selecting, integrins, and immunogiobulin supergene family (Albelda et al., 1994; Springer, 1990~. Read the entire page →
From page 93... ... Thus, these findings, together with those from a series of related studies, have lent extended support to the above concept of cell adhesion molecule-dependent regulation of allergic inflammatory reactions and bronchial hyperresponsiveness in asthmatic individuals following inhaled antigen challenge (Georas et al., 1992; Montefort et al., 1994; Ohkawara et al., 1995; Takahashi et al., 1994~. Collectively, this evidence underscores the need to further identify the mechanistic interplay between specific inflammatory cells, cell adhesion mol Read the entire page →
From page 94... ... I IL-R I Cytokines, Chemokines, I ~ ~Eosinoph) I Leukotrienes I ~J 1 Late-Phase Response Airway Hyperresponsiveness Airway Inflammation Epithelial Cell Damage ~ I Recurrent Wheezing Chronic Inflammation Chronic Hyperresponsiveness Airway Remodelling Chronic Asthma . Read the entire page →
From page 95... ... activation and the release of various eosinophil-derived mediators, as well as activation of other cell types (e.g., basophils and mononuclear celIs) , serve to further perpetuate the airway inflammatory response and produce the state of chronic airway inflammation, perturbed airway function, and structural remodeling of the airway that characterizes the atopic asthmatic phenotype. Read the entire page →
From page 96... ... Although substantial evidence exists in support of an important association between airway inflammation and altered airway function, implicating a complex interplay between activated inflammatory cells, airway epithelial cells, and airway smooth muscle (ASM) , the cellular and molecular mechanisms underlying the functional perturbations in ASM responsiveness in asthma remain to be identified. Read the entire page →
From page 97... ... Accordingly, in concert with the effects of inflammatory cell-derived mediators and growth factors, ASM cells have also been shown to intrinsically express various cell adhesion molecules, extracellular matrix proteins, and as noted above, various cytokines or chemokines. The localized release of such a diverse collection of extracellular autocrine and paracrine stimuli appears to induce ASM cell proliferation, at least in part, by stimulating certain common intra Read the entire page →
From page 98... ... Use of the candidate gene approach in asthma is dependent on information about potential mechanisms related to the development of the disease process. Finally, an approach involving a genome-wide search, wherein polymorphic DNA markers are measured throughout the human genome, followed by linkage analysis, has been applied to asthmatic individuals and their familial relations. Read the entire page →
From page 99... ... While we know that asthma is a genetically predisposed condition that is associated with chronic inflammation of the airways, ongoing research continues to uncover a multiplicity of cellular and molecular mechanisms involved in regulating the phenotypic expression of the disease. Importantly, these mechanisms are activated largely in response to a variety of environmental factors, includ Read the entire page →
From page 100... ... Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. American Journal of Respiratory and Critical Care Medicine 153~2~:551-556. Read the entire page →
From page 101... ... 1999. Regulation of TH1and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle. Read the entire page →
From page 102... ... 1995. In situ expression of the cell adhesion molecules in bronchial tissues from asthmatics with air flow limitation: in vivo evidence of VCAM-1/VLA-4 interaction in selective eosinophil infiltration. Read the entire page →
From page 103... ... American Journal of Respiratory and Critical Care Medicine 152~1~:163-168. Robertson DG, Kerigan AT, Hargreave FE, Chalmers R Read the entire page →
From page 104... ... 1994. Soluble intracellular adhesion molecule 1 in bronchoalveolar ravage fluid of allergic subjects following segmental antigen challenge. Read the entire page →

From page 87...

... This research has led to key advances in elucidating the roles of specific inflammatory cells and other processes in the pathobiology of asthma. While there is a wealth of information indicating or suggesting an association between environmental exposures and asthma outcomes, very little is known about the means by which the exposures bring about the changes that manifest as asthma.

4 Pathophysiological Basis of Asthma Pages 87-104

4 Pathophysiological Basis of Asthma
Pages 87-104