Asthma Pathology and Pathophysiology Roberto J. Barrios, MD; Farrah Kheradmand, MD; LaKeisha Batts, BS; David B.

Corr y, MD Context.Asthma has been defined as a chronic inflammatory disorder of the airways that is associated with recruitment of inflammatory cells and the clinical development of wheezing, shortness of breath, chest tightness, and cough. Asthma is a major public health issue. It affects 5% of the United States population and accounts for 2 million emergency department visits, 470 000 hospitalizations, and 4500 deaths annually. Objective.To review the pathophysiology and characteristic pathologic patterns of this disease and discuss the possible mechanisms of production of the lesions. Data Sources.We searched the literature using MEDLINE and OVID. We also searched related conference abstracts and bibliographies of selected studies. Conclusions.There has been a significant evolution in our understanding of asthma. Specific pathways and mechanisms in recent years have been studied; however, numerous mediators and cell receptors have raised new questions that remain to be answered. (Arch Pathol Lab Med. 2006;130:447451) PATHOPHYSIOLOGY OF ALLERGIC ASTHMA Our understanding of the pathophysiology of asthma has changed over the past decade. Although the precise basis for the development of airway inflammation in patients with asthma is not fully defined, recent developments in experimental models have helped us understand some basic mechanisms that take place in at least some forms of asthma. Mouse models are not exact replicas of human asthma; however, they have helped to understand some of the basic mechanisms involved in the production of this disease.1 Observations from mouse models of allergic asthma support many existing paradigms, although some novel discoveries in mice have yet to be verified in patients. Allergic asthma is a disease characterized by intermittent airway obstruction that causes difficulty in breathing and, in the most severe cases, death from asphyxiation. Ultimately, airway obstruction is mediated by hyperresponsive bronchial smooth muscle, secreted airway glycoproteins, and inflammatory debris produced by airway goblet cells and other cells, as well as edema or swelling of the airway wall. Studies during the past 35 years have revealed 2 principal immune mechanisms that lead to airway obstruction in the setting of allergic inflammation, both of which ultimately depend on the presence in the lung of a terminally differentiated subset of T helper cells, the T helper Accepted for publication December 12, 2005. From the Department of Pathology, The Methodist Hospital, Houston, Tex (Dr Barrios); and the Departments of Medicine and Immunology, Baylor College of Medicine, Houston, Tex (Drs Kheradmand and Corry, and Ms Batts). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Roberto J. Barrios, MD, The Methodist Hospital Department of Pathology, Room M227, 6565 Fannin St, Houston, TX 77030 (e-mail: rbarrios@tmh.tmc.edu).

cell type 2 (TH2 cell). The TH2 cells secrete a highly characteristic cytokine repertoire that includes interleukin-4 (IL-4), IL-5, IL-9, and IL-13, all of which contribute to the various manifestations of allergic inflammation and disease. The first TH2-dependent mechanism leading to airway obstruction, the type 1 or immediate hypersensitivity response, is mediated by immunoglobulin E (IgE), an antibody isotype that is produced by B cells activated by IL4. Circulating IgE is captured by immunoglobulin receptors (Fc receptor I [FcRI]) present on immune effector cells such as mast cells/basophils, eosinophils, and other airway cells. Subsequent encounters with antigen induce FcRI cross-linking, cellular activation, degranulation, and release of a variety of toxic inflammatory molecules that ultimately elicit obstruction.2 There are many potentially toxic substances released by degranulating eosinophils and basophils/mast cells, but of particular importance in asthma are the leukotrienes, lipid mediators of inflammation derived from arachidonic acid. These short-lived small molecules exist in a variety of isoforms, mostly as distinct products of various arachidonic acid-modifying enzymes. Acting through a variety of G protein-coupled receptors, leukotrienes induce or augment many features of asthma, including airway hyperresponsiveness, eosinophilia, and airway glycoprotein hypersecretion. A second TH2-dependent pathway underlying airway obstruction, the type 4 hypersensitivity response, was recognized through studies of immunoglobulin-deficient mice3 and is mediated through the TH2 cytokines IL-4 and IL-13.3,4 Both cytokines, but predominantly IL-13, act directly on airway smooth muscle and the epithelium to elicit airway hyperreactivity, enhanced glycoprotein production, and eosinophilia, the same features of disease elicited by leukotrienes. Despite the strikingly similar effect of IL4 and IL-13 and leukotrienes on airway disease, IL-4 and 448 Arch Pathol Lab MedVol 130, April 2006 Asthma: Pathology and PathophysiologyBa rrios et al IL-13 signal through an entirely different receptor complex that includes the chain of the IL-4 receptor,57 members of the Janus family of tyrosine kinases, and signal transducer and activator of transcription 6.810 Both IL-4 and IL-13 also contribute indirectly to disease by participating in type 1 immediate hypersensitivity reactions: IL4 is required (together with IL-9) for mast cell maturation11 and IgE secretion1214 and signals through chain of the IL-4 receptor, along with IL-5,15 mediate eosinophil recruitment to the lung.3 Thus, the pathophysiology of asthma reflects the coalescence of transcriptional events coordinated through multiple immune receptors, including FcRI, the leukotriene receptors, and chain of the IL4 receptor. GROSS FEATURES Most of the classic descriptions of the pathologic patterns of asthma have been derived from autopsy studies. 1618 These studies based on individuals who died in status asthmaticus describe overinflation of the lungs and mucus plugs occluding medium-sized bronchi, small bronchi, and bronchioles. In recent articles, however, there are descriptions derived from bronchoscopic biopsies.1927

These studies have provided a bronchoscopic and pathologic description of early and mild forms of the disease. It is well known that overinflation is seen in asthmatic patients. This gross appearance is seen in individuals who die in status asthmaticus, but the lungs may appear normal between attacks. The lungs fill the chest cavity during status asthmaticus and do not collapse when the pleural space is opened. Overdistention must be distinguished from emphysema because emphysema implies destruction of alveolated parenchyma, which rarely occurs in asthmatic patients, most likely because the asthmatic attacks are intermittent. In contrast, bronchiectasis can be seen as a complication of asthma and has been described in 15% to 20% of patients.16,18 MICROSCOPIC FEATURES Airways of asthmatic patients may be normal or they may show only mild histologic changes between asthmatic attacks. Mucous plugs made of heavily viscous inspissated mucus fill both bronchi and bronchioles (Figure 1). These plugs appear to be produced by both submucosal gland hypertrophy and goblet cell hyperplasia. It has been reported that the proportion of both mucin and goblet cells in the epithelium may be up to 3 times higher in asthmatic patients than in controls.28 Airway Remodeling A series of progressive structural changes of the airways is known as airway remodeling. These changes most likely occur as a result of repeated episodes of inflammation with production of matrix proteins and growth factors by inflammatory cells.29 It is also possible that repeated damage to the epithelium, with subsequent repair, may lead to airway remodeling.30 It is conceivable that airways that undergo significant remodeling may not respond to bronchodilators because of reduced elasticity, increased muscle mass, and mucosal edema31. Airway Epithelium A number of well-known changes occur in the airway epithelium of asthmatic patients. Goblet cell hyperplasia is a common histopathologic finding, although not specific for asthma.32,33 Other common findings are the presence of mucus plugs34 and squamous metaplasia (Figure 2). Areas of denuded epithelium are seen occasionally. It has been proposed that patients with significant epithelial desquamation present with persistent rather than intermittent asthma26 as a result of direct exposure of nerve endings to factors that would trigger the inflammatory response22; whorls of detached epithelium may form Creola bodies and Curschmann spirals. The airway wall can be thickened from edema, an increase in smooth muscle, and an increase in the size of the submucosal mucous glands. Airways are infiltrated by eosinophils (Figures 3 through 5). Mucus may contain many eosinophils with Charcot-Leyden crystals.35 Reticular Basement Membrane Light microscopy has revealed that what has been interpreted in the old literature as basement membranes are usually thicker in asthmatic individuals than in nonasthamtic individuals.16,22 However, in a manner reminiscent of the situation seen by the pathologist in collagenous colitis, what light microscopic studies refer to as basement

membrane thickening has been determined by ultrastructural and immunohistochemical studies to be deposition of types III and V collagen as well as fibronectin beneath the true basement membrane that is usually of normal thickness22 (Figure 4). The mechanism of production of this reticular basement membrane is controversial but it has been suggested that activated eosinophils are involved through the production of cytokines such as transforming fibroblast growth factor (TGF-), which is a potent profibrotic cytokine.36 In some studies, basement membrane in central airways from nonasthmatic individuals measures between 6 and 10 m, but in asthmatic patients it ranges from 11 to 22 m.37 Bronchial Submucosal Glands Bronchial submucosal glands are increased in size in individuals with asthma, but at some stage, patients with chronic bronchitis also show increased bronchial submucosal glands, which is the basis for the Reid index in chronic bronchitis.3841 In fact, increased bronchial submucosal glands apparently are found in individuals with recent onset of asthma rather than in patients with longstanding asthma.42 Smooth Muscle Patients dying of status asthmaticus have a 2-fold to 3fold increase in the amount of airway smooth muscle, especially in the medium-sized bronchi. This finding has been well documented by several morphometric studies. 4345 Smooth muscle thickness in asthmatic patients appears to increase with age.46 It has been proposed that myofibroblasts play a role in this smooth muscle thickening and also in the reticular basement membrane thickening because of the production and deposition of fibronectin in the bronchial mucosa.47 Presence of myofibroblasts has been associated with local expression of TGFproduced by eosinophils and fibroblasts48; some studies show that basal TGF-1 levels in the airways are elevated in atopic asthma. The TGF-1 is upregulated 24 hours after allergen stimulation.49 It is thought that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-1