The following information about inflammation in asthma was originally developed for a healthcare professional audience and was published in the Medical Scientific Update, a publication of the National Jewish Health Office of Professional Education.
Inflammation in Asthma
by Sally Wenzel, MD
Table of Contents
Asthma is associated with a wide range of symptoms and signs, including wheezing, cough, chest tightness, shortness of breath and sputum production.
The symptoms and signs evolve from three basic characteristics that underlie the disease and its exacerbations: airway obstruction, airway hyperresponsiveness and airway inflammation.
Airway obstruction and hyperresponsiveness represent the classic physiology of asthma, and their contribution to the disease process and symptomatology have been well recognized for some time. Appreciation of the role of airway inflammation in asthma has evolved more recently.
Airway obstruction and hyperresponsiveness represent the classic physiology of asthma.
Today asthma experts consider airway inflammation a central feature of asthma pathogenesis and its clinical manifestations. In fact, airway inflammation likely plays a critical role in airway obstruction and hyperresponsiveness.
In recent years, clinical and scientific knowledge of asthma has evolved from a model of episodic constriction of bronchial smooth muscle to a model which involves chronic airway inflammation. Evidence of inflammation is present at the onset of symptoms in newly diagnosed asthmatic patients. Accordingly, treatment algorithms for asthma have emphasized treatment of the underlying inflammation, as well as the bronchoconstrictive symptoms. By acquiring a better understanding and appreciation of the inflammatory process, physicians can employ treatments to inhibit specific steps in the process and improve control over asthma and its symptoms.
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Inflammatory disorders involve a potentially wide range of cell types and cellular mediators, which will be discussed briefly later on. The multiplicity of cellular factors makes inflammation and inflammatory disorders quite complex.
A number of models have been developed to explain inflammation. One that seems especially pertinent to asthma is the inflammatory cascade, outlined below. The model suggests that asthma-associated inflammation occurs as a seven-step process:
Although in some patients, allergic processes are difficult or impossible to find, experts believe that a large percentage of asthma is allergy associated. An allergic clinical state must evolve from sensitization to a particular allergen. Sensitization must occur before the cellular triggering phase can begin.
An allergic clinical state can evolve after sensitization to a particular allergen. Sensitization must occur before the cellular triggering phase can begin.
Sensitization occurs as a result of presentation of an antigen to a T-lymphocyte. Dendritic cells, monocytes, and even B-lymphocytes are likely to be involved in the process. The antigen is processed and delivered to a T-lymphocyte, which responds by changing from a naive lymphocyte to an allergic type of cell (T-Helper 2, or TH-2), emitting signals through the cytokine networks. The cytokines find their way to B-lymphocytes, which react by becoming plasma cells producing IgE specific for the antigen. The IgE then attaches to mast cells where it can bind allergen, thereby completing the sensitization or antigen presentation phase, the first step in the inflammatory cascade.
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Genetically predisposed individuals exposed at an early age to indoor aeroallergens, occupational antigens and respiratory viral infections become sensitized to certain allergens. Any number of factors may stimulate an exacerbation of the disease, including allergens and environmental agents, many through triggering of mast cells.
Allergens are the most extensively studied of the asthma stimuli.
Allergens are the most extensively studied of the asthma stimuli. The issue of whether all cases of asthma require a specific stimulus remains unresolved and controversial. However, recent studies have provided evidence that most, if not all, asthma does have an allergic basis that may involve IgE. Especially persuasive evidence has come from research showing a high prevalence of asthma in association with early-age exposure to specific allergens and from the findings that asthma probability rises with an individual's serum IgE level and is almost non-existent in individuals with low IgE levels. Recent studies suggest that IgE and the triggered mast cells can cause long-term asthmatic inflammation, as blocking IgE limits both early and late reactions to allergen, as well as decreasing associated inflammation. However, it is likely IgE and related proteins are not involved in all forms of asthma.
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Within the conceptual framework of the inflammatory cascade, stimulation activates a complex communication network. Signaling cells issue biological commands that lead to recruitment of inflammatory cells into the airways.
T-lymphocytes, macrophages and monocytes are activated in symptomatic asthma, as indicated by the expression of the IL-2 receptor, TNF-alpha and other activation markers. Expression of these markers appears to correlate with disease activity, and, perhaps more importantly, steroid therapy decreases expression of the markers. Th2 cytokines, such as IL-4/IL-13 are also likely important in the signaling phase to enhance later inflammation. Recent studies also suggest that resident cells, such as epithelial cells, may play a role in increasing inflammatory responses. Research at National Jewish Health and other centers currently focuses on defining the role of specific T-cell subsets in asthma.
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During the triggering and signaling processes, substances are produced that induce leukocyte migration into the airways. At various times after allergen challenge, migration may involve eosinophils, neutrophils, lymphocytes and monocytes. The migration begins within two hours and may continue for up to 48 hours.
One possible explanation for migration of inflammatory cells is the release of chemo attractant mediators by signaling cells. Alternatively, signaling cells may release cytokines that up regulate adhesion molecules that stimulate cellular migration into a focus of inflammation. The up regulation correlates with the size of the eosinophil response in the airways.
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Following migration into the airways, inflammatory cells require activation to produce the physiologic changes associated with asthma symptomatology. Activation probably occurs after the cells' exposure to cytokines and other potential activators found in inflamed lungs. Potential activating substances include interleukin-1, interleukin-5, tumor necrosis factor-alpha, and chemokines such as eotaxin and IL-8.
Considerable evidence exists to indicate that eosinophils are activated in the lungs of asthmatic patients.
Considerable evidence exists to indicate that eosinophils are activated in the lungs of asthmatic patients. Levels of major basic protein have been shown to be elevated in biopsy specimens, broncho-alveolar lavage fluid and sputum. In sputum, levels of eosinophils rise with increasing disease activity and have been shown to predict exacerbations and decline with anti-inflammatory treatment. However, therapies targeted towards eosinophils (anti IL-5) have thus far been disappointing in therapy
A limited amount of data suggest that other cells, such as monocytes/macrophages and epithelial cells are also activated during the late asthmatic response (LAR) to allergen exposure or other challenges. The data include evidence of increased expression of low-affinity IgE receptor and increased macrophage production of IL-6 and TNF-alpha following allergen exposure.
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Evidence continues to accumulate to suggest that the inflammatory processes of asthma lead to tissue alterations (including stimulation and damage) at the level of the epithelium, basement membrane, smooth muscle and nerves.
Epithelium. The airways of asthmatic patients exhibit abnormal epithelium with increased mucus-secreting cells, possibly a result of exposure to enzymes, growth factors and other proteins released by inflammatory cells. The damage may intensify the effects of bronchoconstricting stimuli to transform the stimuli into major factors in airway reactivity. Studies in animal models of asthma suggest a possible role for the nonadrenergic, noncholinergic system in the airway epithelial damage. A number of neuropeptides have been linked to bronchoconstriction and response to allergen challenge.
Subepithelial Basement membrane. Evidence suggests that the subepithelial basement membrane or associated connective tissue is altered in asthmatic patients. For example, connective tissue adjacent to the basement membrane exhibits a different collagen composition and increased collagen deposition. Eosinophils likely contribute to the thickened SBM.
Smooth muscle and nerves. Pathologic studies indicate that asthmatic smooth muscle may be both hyperplastic and hypertrophied. In vivo, a thickened airway structure could be more reactive or exhibit more constriction.
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The discovery that asthma involves chronic underlying inflammation has given rise to the hypothesis that abnormal or incomplete resolution of inflammation may play a role in the disease and its exacerbations. Particularly compelling evidence of abnormal resolution has come from investigations of occupational asthma, wherein removing an individual from the workplace does not lead to resolution of inflammation or symptoms.
Reasons for the abnormal (or absent) resolution remain largely unknown. Potential clues may come from improved understanding of the wide variability of asthma patients' response to allergen exposure. Wide variations in the type, intensity and duration of response have been observed.
Recent studies in asthma suggest a lowered level of anti-inflammatory mediators such as lipoxins.
More research is needed to confirm the lack of resolution in the inflammatory process and to identify associated underlying mechanisms. Better understanding of the resolution process could help explain the differences among mild, moderate and severe asthma and lead to the development of more effective therapies.
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Ongoing research has identified numerous cells and mediators that may be involved in the airway inflammation associated with asthma. The multiplicity of these cells and substances points to the complexity of the disease and to the many unanswered clinical and research questions that await clarification in further research. Key inflammatory cells and mediators identified thus far include:
- Mast cells. A primary triggering mechanism for the IAR with recent data suggesting involvement in chronic inflammation, as well.
- Dendritic cells. Implicated in the antigen processing and presentation associated with later stages of the asthmatic response.
- Eosinophils. Migration into lungs is associated with inflammation and bronchoconstriction. The cells directly or indirectly produce a host of enzymes, proteins and mediators linked to tissue alteration and injury in asthma. Closely associated with the LAR, symptoms and exacerbations.
- Lymphocytes. Possibly the overall cellular coordinator of the varied processes and interactions that constitute the inflammatory response in asthma.
- Products of the arachidonic acid cascade: leukotrienes, prostaglandins and thromboxane, all of which are known mediators of inflammation.
- Cytokines and growth factors, including the interleukins, TGF-ß, and TNF-alpha implicated in activities ranging from mast cell production and growth to inflammation-associated eosinophil migration to activation of various inflammatory cells and proteins.
- Preformed inflammatory mediators, such as histamine, proteases and eosinophil major basic protein.
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Controlling inflammation has become a central objective of asthma therapy. Better control of inflammation is essential to better control of the disease and may open the door to alteration of the disease course. Control of inflammation can occur at several levels. In allergy-driven asthma, environmental measures are very important, as they eliminate disease "triggers." Specifically, in humid regions, removing all unnecessary carpeting and upholstery (especially in bedrooms) diminishes dust mites' ability to thrive.
Controlling inflammation has become a central objective of asthma therapy.
The allergen burden can be further minimized by encasing pillows and mattresses in plastic and washing all bedding in very hot water. Individuals allergic to animal dander should keep pets out of the house.
Pharmacologically, inflammation control has been accomplished primarily by use of corticosteroids. Inhaled or oral steroids have been shown to decrease populations of inflammatory cells and cytokines in the airways of asthmatics. Improvement in inflammation is associated with improvement in pulmonary symptoms. The effect likely relates to an interruption in the inflammatory cascade. Certain other drugs (such as theophylline, anti-leukotriene, and anti-IgE) may have anti-inflammatory effects as well, but the effects are milder. Improvement in the understanding of asthmatic inflammation has enhanced the ability to design drugs that target specific components of the inflammatory process. Researchers at National Jewish Health are actively involved in the study of these new therapies, including inhibitors of IgE, modulators of TH-2 cytokines, as well as molecules that block the adhesion of inflammatory cells and more non-specific immunomodulators.. These specific drugs should improve our understanding of inflammation and hopefully lead to its improved treatment.
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References
- Wenzel SE. Severe Asthma in Adults. Am J Respir Crit Care Med. 2005 Jul 15;172(2):149-60. Epub 2005 Apr 22.
- Djukanovic R et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004 Sep 15; 170(6):583-93. Epub 2004 Jun 1.
- Fahy JV et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 1997 Jun; 155(6):1828-34.
- Wenzel SE. Asthma as an inflammatory disease. Ann Allergy 1994; 72: 261-71.
- Robinson, DS et al. Evidence for a predominant TH2-type bronchoalveolar lavage T lymphocyte population in atopic asthma. New Engl J Med 1991; 326: 298-304.
Author: Inflammation in Asthma
Sally Wenzel, M.D ., Senior Faculty Member, Department of Medicine, National Jewish Health; Professor of Medicine, UCHSC
Faculty:
Mark Boguniewicz, M.D ., Faculty Member, Pediatric Allergy/Immunology and Atopic Dermatitis Program; Associate Professor of Pediatrics, UCHSC
Richard Martin, M.D ., Head Division of Pulmonary Medicine, National Jewish Health; Professor of Medicine, UCHSC
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This information has been approved by Sally Wenzel, MD (March 2006). Original publication date Fall 1996; updated March 2006.
