The Inflammatory Response in the Pathogenesis of Asthma Faoud T. Ishmael, MD, PhD It is now clear that asthma is not a single disease, but rather a Ast hma is a highly prevalent disease syndrome that can be caused by multiple biologic mechanisms. that involves a complex interplay of en - Thus, asthma encompasses many disease variants with different vironmental factors, airflow obstruction, etiologic and pathophysiologic factors. bronchial hyperresponsiveness, and in - flammation. The dominant feature that leads to clinical symptoms is smooth logical processes that drive the disease. response (Figure 2). 1,2,6,7 Central to this muscle contraction and inflammation, Recent efforts have attempted to process is an interaction between genes which results in narrowing of the airway classify asthma according to objective and environment, resulting in an ab - and obstruction. 1,2 Numerous triggers phenotypes. 4 Analysis of these pheno - normal immune response to allergens can induce bronchoconstriction, in - types is based on observable characteris - and other environmental triggers in ge - cluding allergic responses, respiratory tics, such as symptoms, biochemical netically susceptible individuals. 8,9 infections, exercise, irritants, and properties, immunologic features, histo - The immunohistopathologic features nonsteroidal anti-inflammatory drugs in logic and morphologic characteristics of of asthma include epithelial injury and select patients 1,2 . Persistent inflamma - tissue, and response to treatment. Lot - infiltration of inflammatory cells, con - tion in the airway may lead to structural vall et al 5 described a classification sisting of eosinophils, lymphocytes, mast changes, such as mucus hypersecretion, scheme of asthma endotypes, summa - cells, and phagocytes. 1,2,6,7 Inflammatory smooth muscle hyperplasia, subepithe - rized in Figure 1, that is based on the use mediators released by these cells are the lial fibrosis, blood vessel proliferation, of these criteria. effectors of chronic inflammation. These and infiltration of inflammatory cells. 1,2 There are likely to be molecular dif - mediators include cytokines and other The concepts underlying asthma ferences even within endotypes, as well products that are classified into the fol - pathogenesis have dramatically evolved as overlap in inflammatory features lowing groups (summarized in Figure 4): over the past 25 years, and understand - between endotypes—highlighting the lymphokines (immunomodulatory cy - ing of this complex disease continues to complexity of this disease and the need tokines released by T cells), proinflam - increase. It is now clear that asthma is for continued research. Nevertheless, a matory cytokines (cytokines that pro - not a single disease, but rather a syn - common thread underlying all endo - mote and amplify the inflammatory drome that can be caused by multiple types is the presence of airway inflam - response), chemokines (cytokines that biologic mechanisms. Thus, asthma mation, though each endotype has are chemoattractants for leukocytes), encompasses many disease variants distinct immunologic features. The pres - growth factors (factors that promote cell with different etiologic and pathophysi - ent review focuses on the inflammatory survival), and eicosanoids (lipid media - ologic factors. response in patients with allergic asthma. tors that have multiple effects in the air - Several approaches have been used The mechanisms described in this re - way). 10 The products released from to classify variants of asthma with the view also apply to other endotypes. leukocytes and epithelial cells induce goal of maximizing the efficacy of treat - bronchospasm, damage the epithelium, ment. Clinically, asthma can be de - Orchestrated Interplay stimulate airway cells, and recruit addi - scribed based on symptoms that are ei - The inflammatory response in the air - tional leukocytes—creating a cycle of ther intermittent or persistent, and these ways of patients with asthma involves inflammation that becomes chronic. 10 symptoms are further classified in terms an orchestrated interplay of the respira - Over time, persistent changes in the of severity (ie, mild, moderate, or se - tory epithelium, innate immune system, structure of the airway can occur, such vere). 3 However, this classification sys - and adaptive immunity that initiates as subepithelial fibrosis, mucus hyper - tem does not address the underlyingbio - and drives a chronic inflammatory secretion and goblet cell hyperplasia, Ishmael • Inflammatory Response in the Pathogenesis of Asthma JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 11 • November 2011 • S11 Examples of asthma endotypes Endotype Clinical Features Proposed Mechanism Treatment Response Allergic asthma Allergen-associated symptoms, Th2 dominant Responds to glucocorticoids allergic rhinitis, childhood onset, and omalizumab history of eczema Allergic bronchopulmonary Severe mucus production, adult Colonization of airways by Responds to glucocorticoids aspergillosis onset, long duration fungi and antifungals API-positive preschool >3 episodes per year, family Th2 dominant Responds to daily inhaled wheezer* history of asthma glucocorticoids Aspirin-sensitive asthma Nasal polyposis, often severe Eicosanoids-related Responds to antileukotrienes, asthma, aspirin sensitivity, aspirin desensitization adult onset Severe late-onset Severe exacerbations, late-onset Nonatopic, mechanisms Often dependent on oral hypereosinophilic asthma disease, peripheral blood unclear glucocorticoids eosinophilia Exercise-induced Symptoms related to exercise, Dehydration of airways Mixed response to bronchospasm frequently in elite athletes glucocorticoids *API, asthma predictive indices: children with repeated wheezing episodes and history of atopic dermatitis, parental asthma, or aeroallergen sensitivity, and peripheral eosinophila, wheezing unrelated to common cold, or sensitization to food allergen. Adapted from Journal of Allergy and Clinical Immunology, 127(2), Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome, 355-360, 2011, with permission from Elsevier. Figure 1. Examples of asthma endotypes as desribed by Lotvall et al. 5 *Asthma merous stimuli, such as allergens, infec - receptors. 14 These stimuli modulate the predictive index (API) includes children tious agents, pollutants, and oxidants. functions of the airway epithelium and with repeated wheezing episodes and As such, the respiratory epithelium is an induce the production of mediators that history of atopic dermatitis, parental integral part of innate immunity and the attract and activate leukocytes and aug - asthma, aeroallergen sensitivity, peripheral eosinophilia, wheezing unrelated to com - inflammatory response, and it is capable ment the development of an allergic mon cold, or sensitization to food allergen. of producing numerous mediators that response (Figure 3). Abbreviation: Th2, T-helper 2 lymphocyte. can prime and activate many arms of One of the central cytokines whose the immune system. 11,12 production is stimulated by the epithe - epithelial cell injury, smooth muscle hy - Numerous stimuli are capable of elic - lium is thymic stromal lymphopoietin pertrophy, and angiogenesis. 1,2 The in - iting an inflammatory response from ep - (TSLP), which induces key changes in terplay between cells and the mediators ithelial cells. Components of microbes, dendritic cells, the antigen-presenting that drive the inflammatory response including nucleic acids and glycopro - cells that deliver allergens to T cells in are described in the following sections. teins, bind to such pattern recognition the first phase of an allergic response. receptors as toll-like receptors to stimu - Thymic stromal lymphopoietin in - Respiratory Epithelium late production of cytokines and duces the release of chemokine ligand and Asthma chemokines. 11-13 Pollutants and oxi - 17 (CCL17) and CCL22 from dendrit - The respiratory epithelium, formerly dants can alter the structure and activi - ic cells, an important process in recruit - thought to serve only as a barrier and ty of proteins, lipids, and nucleic acids to ing T cells to the airways. In addition, medium for gas transfer, is now known affect signaling pathways or to injure TSLP increases the expression of to play a central role in the inflammato - cells. 14 Proteases, including those found OX40 ligand (OX40L), a receptor that ry response. It serves as a primary inter - in many allergens, can activate immune is important in skewing the dendritic face between the external environment signal transduction pathways by modu - cell-mediated activation of T cells and the host, and it is exposed to nu - lating the activity of protease activated toward an allergic response. Thymic S12 • JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 1 • November 2011 Ishmael • Inflammatory Response in the Pathogenesis of Asthma stromal lymphopoietin— Figure 2. Cycle of chronic inflamma - in concert with other tion in patients with asthma. Allergic epithelial-derived inflam - inflammation develops from an inter - play between the respiratory epitheli - matory cytokines, such as um and leukocytes. Environmental tumor necrosis factor and inflammatory stimuli induce the ...[fti1] (TNF- ␣) and production of mediators from the air - interleukin 1 ␤[fti2] way epithelium, which activates and recruits inflammatory cells. Inflamma - (IL-1 ␤)—can also acti - tory cells infiltrate