Asthma

Pathogenesis Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways. One of the main aims of treatment is to reduce this inflammation. Pathology The pathology of asthma has been revealed through examining the lungs at autopsy of patients who have died of asthma and from bronchial biopsies in patients with usually mild asthma. The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells. The degree of inflammation is poorly related to disease severity and may be found in atopic patients without asthma symptoms. The inflammation is reduced by treatment with IC . A characteristic finding is thic!ening of the basement membrane due to subepithelial collagen deposition. This feature is also found in patients with eosinophilic bronchitis presenting as cough who do not have asthma and is, therefore, li!ely to be a mar!er of eosinophilic inflammation in the airway as eosinophils release fibrogenic factors. The epithelium is often shed or friable, with reduced attachments to the airway wall and increased numbers of epithelial cells in the lumen. The airway wall itself may be thic!ened and edematous, particularly in fatal asthma. Another common finding in fatal asthma is occlusion of the airway lumen by a mucous plug, which is comprised of mucous glycoproteins secreted from goblet cells and plasma proteins from lea!y bronchial vessels There is also vasodilation and increased numbers of blood vessels "angiogenesis#. $irect observation by bronchoscopy indicates that the airways may be narrowed, erythematous, and edematous. The pathology of asthma is remar!ably uniform in different types of asthma, including atopic, nonatopic, occupational, aspirin%sensitive, and pediatric asthma. These pathologic changes are found in all airways, but do not extend to the lung parenchyma& peripheral airway inflammation is found particularly in patients with severe asthma. The involvement of airways may be patchy and this is consistent with bronchographic findings of uneven narrowing of the airways.

Histopathology of a small airway in fatal asthma. The lumen is occluded with a mucous plug, there is goblet cell metaplasia, and the airway wall is thic!ened, with an increase in basement membrane thic!ness and airway smooth muscle. Inflammation There is inflammation in the respiratory mucosa from the trachea to terminal bronchioles, but with a predominance in the bronchi "cartilaginous airways#. Considerable research has identified the ma'or cellular components of inflammation, but it is still uncertain how inflammatory cells interact and how inflammation translates into the symptoms of asthma "Fig. 254-2#. There is good evidence that the specific pattern of airway inflammation in asthma is associated with airway hyperresponsiveness "A()#, the physiologic abnormality of asthma, which is correlated with variable airflow obstruction. The pattern of inflammation in asthma is characteristic of allergic diseases, with similar inflammatory cells seen in the nasal mucosa in rhinitis. (owever, an indistinguishable pattern of inflammation is found in intrinsic asthma, and this may reflect local

rather than systemic Ig* production. Although most attention has focused on the acute inflammatory changes seen in asthma, this is a chronic condition, with inflammation persisting over many years in most patients. The mechanisms involved in persistence of inflammation in asthma are still poorly understood. uperimposed on this chronic inflammatory state are acute inflammatory episodes, which correspond to exacerbations of asthma. +any inflammatory cells are !nown to be involved in asthma with no !ey cell that is predominant Inflammation in the airways of asthmatic patients leads to airway hyperresponsiveness and symptoms. O,, sulfur dioxide. The pathophysiology of asthma is complex with participation of several interacting inflammatory cells, which result in acute and chronic inflammatory effects on the airway. +ast Cells +ast cells are important in initiating the acute bronchoconstrictor responses to allergens and several other indirectly acting stimuli such as exercise and hyperventilation "via osmolality or thermal changes#, as well as fog. Activated mast cells are found at the airway surface in asthma patients and also in the airway smooth%muscle layer, whereas this is not seen in normal sub'ects or patients with eosinophilic bronchitis. +ast cells are activated by allergens through an Ig*% dependent mechanism, and binding of specific Ig* to mast cells renders them more sensitive to activation. The importance of Ig* in the pathophysiology of asthma has been highlighted by clinical studies with humani-ed anti%Ig* antibodies, which inhibit Ig*%mediated effects, reduce asthma symptoms, and reduce exacerbations. There are, however, uncertainties about the role of mast cells in more chronic allergic inflammatory events. +ast cells release several bronchoconstrictor mediators, including histamine, prostaglandin $,, and cysteinyl%leu!otrienes, but also several cyto!ines, chemo!ines, growth factors, and neurotrophins. +acrophages and $endritic Cells +acrophages, which are derived from blood monocytes, may traffic into the airways in asthma and may be activated by allergens via low affinity Ig* receptors ".c )II#. +acrophages have the capacity to initiate a type of inflammatory response via the release of a certain pattern of cyto!ines, but these cells also release anti%inflammatory mediators "e.g., I/%01# and, thus, their roles in asthma are uncertain. $endritic cells are speciali-ed macrophage%li!e cells in the airway epithelium, which are the ma'or antigen%presenting cells. $endritic cells ta!e up allergens, process them to peptides, and migrate to local lymph nodes where they present the allergenic peptides to uncommitted T%lymphocytes to program the production of allergen%specific T cells. Immature dendritic cells in the respiratory tract promote T(, cell differentiation and re2uire cyto!ines such as I/%0, and tumor necrosis factor "T3.% #, to promote the normally preponderant T(0 response. The cyto!ine thymic stromal lymphopoietin "T /P# released from epithelial cells in asthmatic patients instructs dendritic cells to release chemo!ines that attract T(, cells into the airways. *osinophils

*osinophil infiltration is a characteristic feature of asthmatic airways. Allergen inhalation results in a mar!ed increase in activated eosinophils in the airways at the time of the late reaction. *osinophils are lin!ed to the development of A() through the release of basic proteins and oxygen%derived free radicals. *osinophil recruitment involves adhesion of eosinophils to vascular endothelial cells in the airway circulation due to interaction between adhesion molecules, migration into the submucosa under the direction of chemo!ines, and their subse2uent activation and prolonged survival. 4loc!ing antibodies to I/%5 causes a profound and prolonged reduction in circulating and sputum eosinophils, but is not associated with reduced A() or asthma symptoms, although in selected patients with steroid%resistant airway eosinophils, there is a reduction in exacerbations. *osinophilic inflammation is also found in patients with chronic cough "eosinophilic bronchitis# who do not have A() or clinical features of asthma. Increasing evidence suggests that eosinophils may be important in release of growth factors involved in airway remodeling, in exacerbations but not in A(). 3eutrophils Increased numbers of activated neutrophils are found in sputum and airways of some patients with severe asthma and during exacerbations, although there is a proportion of patients even with mild or moderate asthma who have a predominance of neutrophils. The roles of neutrophils in asthma that are resistant to the anti%inflammatory effects of corticosteroids are currently un!nown. T /ymphocytes T lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cyto!ines, resulting in the recruitment and survival of eosinophils and in the maintenance of a mast cell population in the airways. The na6ve immune system and the immune system of asthmatics are s!ewed to express the T(, phenotype, whereas in normal airways T(0 cells predominate. T(, cells, through the release of I/%5, are associated with eosinophilic inflammation and, through the release of I/%7 and I/%08, are associated with increased Ig* formation. )ecently, bronchial biopsies have demonstrated a preponderance of natural !iller C$79 T lymphocytes that express high levels of I/%7. )egulatory T cells play an important role in determining the expression of other T cells, and there is evidence for a reduction in a certain subset of regulatory T cells "C$79C$,59# in asthma that is associated with increased T(, cells. tructural Cells tructural cells of the airways, including epithelial cells, fibroblasts, and airway smooth%muscle cells, are also important sources of inflammatory mediators such as cyto!ines and lipid mediators, in asthma. Indeed, because structural cells far outnumber inflammatory cells, they may become the ma'or sources of mediators driving chronic inflammation in asthmatic airways. In addition, epithelial cells may have !ey roles in translating inhaled environmental signals into an airway inflammatory response, and are probably ma'or target cells for IC . Inflammatory +ediators +any different mediators have been implicated in asthma, and they may have a variety of effects on the airways that could account for the pathologic features of asthma "Fig. 254-4#. +ediators such as histamine, prostaglandin $,, and cysteinyl%leu!otrienes contract airway smooth muscle, increase microvascular lea!age, increase airway mucus secretion, and attract other inflammatory cells. 4ecause each mediator has many effects, the role of individual mediators in the

pathophysiology of asthma is not yet clear. Although the multiplicity of mediators ma!es it unli!ely that preventing the synthesis or action of a single mediator will have a ma'or impact in clinical asthma, recent clinical studies with antileu!otrienes suggest that cysteinyl%leu!otrienes have clinically important effects. Many cells and mediators are involved in asthma and lead to several effects on the airways.

Cyto!ines +ultiple cyto!ines regulate the chronic inflammation of asthma. The T(, cyto!ines I/%7, I/%5, and I/%08 mediate allergic inflammation, whereas proinflammatory cyto!ines such as T3.% and I/%0 , amplify the inflammatory response and play a role in more severe disease. Thymic

stromal lymphopoietin is an upstream cyto!ine released from epithelial cells of asthmatics that orchestrates the release of chemo!ines that selectively attract T(, cells. ome cyto!ines such as I/% 01 and I/%0, are anti%inflammatory and may be deficient in asthma. Chemo!ines Chemo!ines are involved in attracting inflammatory cells from the bronchial circulation into the airways. *otaxin "CC/00# is selectively attractant to eosinophils via CC)8 and is expressed by epithelial cells of asthmatics, whereas CC/0: "TA)C# and CC/,, "+$C# from epithelial cells attract T(, cells via CC)7 hemo!ines in asthma. Tumor necrosis factor "T3.% # and other triggers of airway

epithelial cells release thymus and activationregulated chemo!ine "TA)C, CC/0:# and macrophage%derived chemo!ine "+$C, CC/,,# from epithelial cells that attract T(, cells via activation of their CC)7 receptors. These promote eosinophilic inflammation directly through the release of interleu!in "I/#%5 and indirectly via the release of I/%7 and I/%08, which induce eotaxin "CC/00# formation in airway epithelial cells. Oxidative tress There is increased oxidative stress in asthma as activated inflammatory cells such as macrophages and eosinophils that produce reactive oxygen species. *vidence for increased oxidative stress in asthma is provided by the increased concentrations of ;%isoprostane "a product of oxidi-ed arachidonic acid# in exhaled breath condensates and increased ethane "a product of lipid peroxidation# in the expired air of asthmatic patients. Increased oxidative stress is related to disease severity, may amplify the inflammatory response, and may reduce responsiveness to corticosteroids. 3itric Oxide

3itric oxide "3O# is produced by several cells in the airway by 3O synthases, particularly airway epithelial cells and macrophages. The level of 3O in the expired air of patients with asthma is higher than normal and is related to the eosinophilic inflammation. Increased 3O may contribute to the bronchial vasodilation observed in asthma. *xhaled 3O is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not yet used routinely in clinical practice. Transcription .actors Proinflammatory transcription factors such as nuclear factor% 4 "3.% 4# and activator

protein%0, are activated in asthmatic airways and orchestrate the expression of multiple inflammatory genes. +ore specific transcription factors that are involved include nuclear factor of activated T cells and <ATA%8, which regulate the expression of T(, cyto!ines in T cells. *ffects of Inflammation The chronic inflammatory response has several effects on the target cells of the airways, resulting in the characteristic pathophysiologic changes associated with asthma. Asthma may be regarded as a disease with continuous inflammation and repair proceeding simultaneously. Important advances continue to be made in our understanding of these changes, but, despite these new insights, the relationship between chronic inflammatory processes and asthma symptoms is often not clear. Airway *pithelium Airway epithelial shedding may be important in contributing to A() and may explain how several mechanisms, such as o-one exposure, virus infections, chemical sensiti-ers, and allergen exposure, can lead to its development, as all of these stimuli may lead to epithelial disruption. *pithelial damage may contribute to A() in a number of ways, including loss of its barrier function to allow

penetration of allergens& loss of en-ymes "such as neutral endopeptidase# that degrade certain peptide inflammatory mediators& loss of a relaxant factor "so called epithelial%derived relaxant factor#& and exposure of sensory nerves, which may lead to reflex neural effects on the airway. .ibrosis In all asthmatic patients, the basement membrane is apparently thic!ened due to subepithelial fibrosis with deposition of types III and = collagen below the true basement membrane and is associated with eosinophil infiltration, presumably through the release of profibrotic mediators such as transforming growth factor% . +echanical manipulations can alter the phenotype of airway epithelial cells in a profibrotic fashion. In more severe patients, there is also fibrosis within the airway wall, which may contribute to irreversible narrowing of the airways. Airway mooth +uscle There is still debate about the role of abnormalities in airway smooth muscle in asthmatic airways. In vitro airway smooth muscle from asthmatic patients usually shows no increased responsiveness
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to constrictors. )educed responsiveness to

%agonists has also been reported in postmortem or %receptors is not

surgically removed bronchi from asthmatics, although the number of reduced, suggesting that

%receptors have been uncoupled. These abnormalities of airway

smooth%muscle may be secondary to the chronic inflammatory process. Inflammatory mediators may modulate the ion channels that serve to regulate the resting membrane potential of airway smooth%muscle cells, thus altering the level of excitability of these cells. In asthmatic airways there is also a characteristic hypertrophy and hyperplasia of airway smooth muscle, which is presumably the result of stimulation of airway smooth%muscle cells by various growth factors such as platelet% derived growth factor "P$<.# or endothelin%0 released from inflammatory or epithelial cells. =ascular )esponses There is increased airway mucosal blood flow in asthma. The bronchial circulation may play an important role in regulating airway caliber, since an increase in the vascular volume may contribute to airway narrowing. Increased airway blood flow may be important in removing inflammatory mediators from the airway, and may play a role in the development of exercise%induced asthma. There is an increase in the number of blood vessels in asthmatic airways as a result of angiogenesis in response to growth factors, particularly vascular%endothelial growth factor. +icrovascular lea!age from postcapillary venules in response to inflammatory mediators is observed in asthma, resulting in airway edema and plasma exudation into the airway lumen. +ucus (ypersecretion Increased mucus secretion contributes to the viscid mucous plugs that occlude asthmatic airways, particularly in fatal asthma. There is evidence for hyperplasia of submucosal glands that are confined to large airways and of increased numbers of epithelial goblet cells. I/%7 and I/%08

induce mucus hypersecretion in experimental models of asthma. 3eural *ffects =arious defects in autonomic neural control may contribute to A() in asthma, but these are li!ely to be secondary to the disease, rather than primary defects. Cholinergic pathways, through the release of acetylcholine acting on muscarinic receptors, cause bronchoconstriction and may be activated reflexly in asthma. Inflammatory mediators may activate sensory nerves, resulting in reflex cholinergic bronchoconstriction or release of inflammatory neuropeptides. Inflammatory products may also sensiti-e sensory nerve endings in the airway epithelium such that the nerves become hyperalgesic. 3eurotrophins, which may be released from various cell types in airways, including epithelial cells and mast cells, may cause proliferation and sensiti-ation of airway sensory nerves. Airway nerves may also release neurotransmitters, such as substance P, which have inflammatory effects. Airway )emodeling

everal changes in the structure of the airway are characteristically found in asthma, and these may lead to irreversible narrowing of the airways. Population studies have shown a greater decline in lung function over time than in normal sub'ects& however, most patients with asthma preserve normal or near%normal lung function throughout life if appropriately treated. This observation suggests that the accelerated decline in lung function occurs in a smaller proportion of asthmatics, and these are usually patients with more severe disease. There is some evidence that the early use of IC may reduce the decline in lung function. The characteristic structural changes are increased airway smooth muscle, fibrosis, angiogenesis, and mucus hyperplasia