Robert A. Goldstein, MD, PhD; William E. Paul, MD; Dean D. Metcalfe, MD; William W. Busse, MD; Elena R. Reece, MD
Asthma is characterized by inflammation, reversible airway obstruction, and increased airway responsiveness to various stimuli.It has received wide public attention in recent years because of increasing morbidity and deaths particularly among black persons. The important role of inflammation in the immunopathogenesis of asthma has led to a newer therapeutic approach directed at interrupting this inflammatory process. Among immune regulatory pathways involved in asthma pathogenesis, two lymphokines appear to be particularly important in controlling IgE production. Interleukin-4 is required for IgE production; without it, IgE production is inhibited. Interferon-γ can diminish cell priming for interleukin-4 production. Thus, the interplay of these two cytokines will determine whether cells that can make interleukin-4 will be produced and, therefore, whether IgE will be produced in response to allergic stimuli. Further, in response to appropriate stimuli, mast cells and eosinophils are attracted to airways and release cytokines, lipid mediators, and preformed substances that cause inflammation. Modern asthma treatment is directed at interrupting this inflammatory process and places a much greater emphasis on use of anti-inflammatory agents, such as aerosolized or parenteral corticosteroids, and on nonsteroidal anti-inflammatory agents, such as cromolyn sodium and nedocromil sodium. Research advances without therapeutic application, however, limit success. Projects such as the National Institute of Allergy and Infectious Diseases' National Cooperative Inner-City Asthma Study, which is directed toward underserved populations, are intended to identify more clearly the factors responsible for increasing morbidity and to develop appropriate therapeutic interventions.
Symbols represent observed rates; lines represent predicted trends based on log-linear regression analysis. From the National Center for Health Statistics, National Hospital Discharge Survey. Reproduced from Gergen and Weiss , with permission from the publisher.
Groups of five BALB/c mice were infected (or not infected) with 600 third-stage larvae and treated with varying amounts of ascitic fluid containing monoclonal anti-IL-4 antibody, during inoculation and 7 days later. Thirteen days after infection, the mice were bled and serum IgE levels were measured. Data adapted from Finkleman and associates , with permission from the publisher.
CD4+ T cells (10 ) from mice transgenic for the α and β chains of T-cell receptors specific for a cytochrome C peptide (88-104), in association with I-E , were cultured for 4 days with dendritic cells (DC) from B10.A mice (2.5 × 10 ), peptide 88-104 (0.1 µmol/L), IL-2 (10 U/mL) with or without IL-4 (1000 U/mL). The cells were then washed and restimulated with peptide and dendritic cells. Interleukin-4 and interferon-γ concentrations were measured 36 hours later. 11B11 is a specific monoclonal anti-IL-4 antibody. Adapted from Seder and coworkers , with permission from the publisher.
Human mast cells arise from CD34+ pluripotential progenitor cells under the influence of interleukin-3 (IL-3), stem cell factor (SCF), and local tissue factors. G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte macrophage colony-stimulating factor; IFN-γ = interferon-γ; Fc RI = high-affinity IgE[4 receptor; T Mast Cell = mucosal mast cell; TC Mast Cell = connective tissue mast cell.
Ag = antigen.
IL-3 = interleukin-3; GM-CSF = granulocyte macrophage colony-stimulating factor; IL-5 = interleukin-5; C3b = complement protein 3b; IgG = immunoglobulin G; IgA = immunoglobulin A; PAF = platelet-activating factor; EGF's = epidermal growth factors; MBP = major basic protein; ECP = eosinophil cationic protein; EPO = eosinophil peroxidase; EDN = eosinophil-derived neurotoxin; LTC = leukotriene C ; PGE = prostaglandin E ; O Radicals = oxygen radicals; TGF-α = transforming growth factor-α; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α; MIP-1 α = macrophage inflammatory peptide-1 α.
An inflammatory stimulus (chemical, physical, infectious, or other) activates a primary effector system that releases chemical mediators and initiates cell-independent effector systems (for example, complement) that directly produce inflammation. This activation also results in the recruitment of a secondary effector system that amplifies the inflammatory process. Anti-inflammatory systems (arrows with negative signs) act at several sites within the cycle to suppress and contain inflammation. Reproduced from Raphael and Metcalfe with permission from the publisher.
All therapy must include patient education about prevention, including environmental control when appropriate. PEFR = peak expiratory flow rate. Reproduced from the National Heart, Lung, and Blood Institute with permission.
Closed circles represent budesonide, and open circles represent placebo ( < 0.009). S.E.M. = standard error of the mean. Reproduced from Juniper and colleagues with permission from the publisher.
Closed circles represent budesonide, and open circles represent placebo ( < 0.0001). PC = provocation concentration that causes a 20% decrease in forced expiratory volume in 1 second; S.E.M. = standard error of the mean. Reproduced from Juniper and colleagues with permission from the publisher.
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Robert A. Goldstein, William E. Paul, Dean D. Metcalfe, William W. Busse, Elena R. Reece. Asthma. Ann Intern Med. 1994;121:698–708. doi: 10.7326/0003-4819-121-9-199411010-00011
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Published: Ann Intern Med. 1994;121(9):698-708.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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