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 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 (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), (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 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 and inflammatory stimuli induce the ...[fti1] (TNF- ␣) and production of mediators from the air - 1 ␤[fti2] way epithelium, which activates and recruits inflammatory cells. Inflamma - (IL-1 ␤)—can also acti - tory cells infiltrate the lungs and vate mast cells. Mast cells release mediators that augment the are one of the principal inflammatory response in the epithe - leukocytes that participate lium, creating a cycle of chronic in the allergic response. 10 inflammation. This process causes The airway epithelium bronchoconstriction and epithelial damage, and it can result in remodel - produces large amounts of ing of the airway. Abbreviation: IgE, inflammatory cytokines, immunoglobulin E. including TNF- ␣, IL-1 ␤, References 1, 2, 6, and 7. and IL-6. 10 These proteins have widespread effects on a wide variety of cells, including leukocytes, in the immune system. The effects serve to upregulate inflammatory genes, increase the release of cytokines and chemokines, and expand inflammatory cell numbers. 10 In addition, airway cells are a prime source of chemokines, potent chemoattractants for various leukocytes. Chemokines play an important role in the recruitment of inflammatory cells from circulation to the airways. The cell types recruited depend on the specific expressed on inflammatory cells. For example, CCL2 (also known as monocyte chemotactic protein 1 [MCP-1]) acti - vates chemokine receptor 2 (CCR2) Figure 3. Pathogenesis of allergic asthmatic inflammation. Allergens are endocytosed by anti - molecules on monocytes and T cells. 10 gen presenting cells (APCs) and presented to naive T cells. Environmental and inflammatory fac - Chemokine ligand 11 (ie, eotaxin) tors activate the respiratory epithelium to release thymic stromal lymphopoietin (TSLP) and acts as a potent chemoattractant for other inflammatory mediators that recruit leukocytes to the lung and skew the function of den - eosinophils by binding to CCR3. 10 dritic cells toward an allergic response. Dendritic cells induce the differentiation of T cells into T- Chemokine ligand 5 (ie, RANTES) helper 2 (Th2)-specific helper cells, as well as Th17 cells. The Th2 cells induce immunoglobulin E (IgE) antibody production from B cells via (IL-4) and IL-13 stimulation. can bind to CCR3 and CCR5 (which Immunoglobulin E binds to receptors on the surfaces of mast cells and basophils and, in the are expressed on T cells, eosinophils, presence of allergen, release mediators that induce bronchoconstriction and enhance the and ) and, thus, attracts a inflammatory response. Production of IL-5 from Th2 cells increases eosinophil levels. Inflamma - large number of inflammatory cells. 10 tory mediators released from eosinophils, T cells, macrophages, and result in dam - The chemokine ligand CXCL8 (ie, IL- age to the airway, bronchoconstriction, stimulation of epithelial cell inflammatory pathways, and remodeling of the lung. Abbreviations: CCL, chemokine ligand; GM-CSF, granulocyte- 8) activates the receptor CXCR1 on colony-stimulating factor; PGD2, prostaglandin D2; SCF, ; TNF- a, 10 neutrophils. After leukocytes travel to tumor necrosis factor-alpha. the airway, they produce inflammatory References 8, 10, 11,-14.

Ishmael • Inflammatory Response in the Pathogenesis of Asthma JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 11 • November 2011 • S13 Source Effect Lymphokines IL-4 T cells Increases production of IgE, increases number of Th2 cells

IL-5 T cells Increases number of eosinophils IL-9 T cells Increases number of mast cells IL-13 T cells, mast cells, basophils, eosinophils Increases production of IgE, induces airway remodeling

IL-17 T cells Increases number, induces production of cytokines by airway epithelium

Proinflammatory Cytokines IL-6 Epithelial cells, macrophages, mast cells Proinflammatory

IL-1 ␤ Epithelial cells, macrophages Proinflammatory TNF- ␣ Epithelial cells, macrophages, mast cells Proinflammatory

TSLP Epithelial cells Activates dendritic cells, increases number of Th2 cells

Chemokines CCL2 Epithelial cells, macrophages, T cells Recruits monocytes, T cells, dendritic cells

CCL5 Epithelial cells, macrophages, T cells Recruits T cells, eosinophils, basophils CCL11 Epithelial cells, macrophages Recruits eosinophils CXCL8 Epithelial cells, macrophages, mast cells Recruits neutrophils

Growth Factors

GM-CSF Epithelial cells, macrophages, T cells Increases number of neutrophils and eosinophils

SCF Epithelial cells, smooth muscle cells, fibrob - Increases number of mast cells lasts, eosinophils

TGF- ␤ Eosinophils, epithelial cells, macrophages Increases fibrosis

VEGF Epithelial cells Induces angiogenesis

Epithelial Cell Epithelial cells Induces airway remodeling and mucus hypersecretion (EGF)

Eicosanoids

Leukotrienes Mast cells, eosinophils Airway hyperreactivity

PGD 2 Mast cells Airway hyperreactivity

Figure 4. Key inflammatory mediators in the pathogenesis of asthmatic inflammation. Abbreviations: CCL, chemokine ligand; CXCL, chemokine CXC ligand; EGF, epithelial cell growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IgE, immuno - globulin E; IL, interleukin; PGD 2, prostaglandin D2; SCF, stem cell factor; TGF- b, transforming growth factor b; Th2, T-helper 2 lymphocyte; TNF- a, tumor necrosis factor-alpha; TSLP, thymic stromal lymphopoietin; VEGF, vascular endothelial growth factor. References 7, 8, 10, 11-13, 16.

S14 • JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 1 • November 2011 Ishmael • Inflammatory Response in the Pathogenesis of Asthma cytokines, which, in turn, act as potent serve as gatekeepers of the immune sys - from the binding of antigen to existing activators of the inflammatory response tem. Through the production of an antibody-receptor complexes, an imme - in epithelial cells. This activation results assortment of mediators and cell surface diate response occurs (ie, within min - in a perpetual cycle of chronic inflam - molecules, dendritic cells have the ca - utes), forming the basis for immediate hy - mation in which the epithelium and pability of inducing tolerance or elicit - persensitivity reactions. leukocytes activate each other. ing an immune response. 15 Dendritic Other cytokines produced by Th2 The epithelium also releases growth cells can further control the nature of cells are capable of activating other factors that augment the inflammatory the immune response by promoting dif - leukocytes and playing key roles in al - response and induce structural changes ferentiation of CD4+ T cells into vari - lergic inflammation. Interleukin 5 is a and remodeling of the airways. Granu - ous types of T-helper (Th) cells with potent survival factor for eosinophils, locyte-macrophage colony-stimulating specific functions. 15,16 The stimulation which are central effector cells in pa - factor (GM-CSF) prolongs eosinophil of 1 type of response vs another type of tients with asthma. 17 Systemic adminis - and neutrophil survival, while stem cell response is based on the nature of the tration of IL-5 to patients with asthma factor (SCF) increases the survival and mediators produced by dendritic cells, increases circulating eosinophils and activation of mast cells. 10 Vascular en - which, in turn, is influenced by products their precursors from the bone mar - dothelial growth factor (VEGF) stimu - of the epithelium (ie, TSLP and other row. 18 Blockade of IL-5 with monoclon - lates angiogenesis and may contribute to cytokines) and other signals from the al antibodies in animal studies has re - vascular leak and airway edema. 10 environment. 15,16 Expression of IL-4, duced eosinophil numbers in the blood Transforming growth factor ␤ (TGF- ␤) OX40L, and the cluster of differentia - and lungs and inhibited allergen-induced is a multifunctional growth factor that tion (CD) marker CD86 promote dif - asthma. 19 The role of IL-5 in disease in induces proliferation of fibroblasts and ferentiation of T cells into T-helper 2 humans is complex and may be more im - airway smooth muscle cells, as well as (Th2)-specific helper cells, which are portant in patients with certain asthma the deposition of extracellular matrix central to allergic diathesis. 15,16 phenotypes (eg, the severe late-onset hy - components. 10 In conjunction with cy - T-helper 2 lymphocytes drive the for - pereosinophilic endotype). T helper cells tokines, these factors play a crucial role mation of allergic reaction and activa - also release IL-9, which occurs in elevat - in initiating and propagating the chronic tion of inflammatory cells via the pro - ed concentrations in the airways of inflammatory response and in the re - duction of cytokines crucial to allergic patients with asthma and in mice modeling of the airway that occurs over disease. 8 The T-cell receptors and co- with experimentally induced asthma. 20 time in patients with asthma. stimulatory molecules on the surfaces of promotes mast cell growth, Th2 cells engage allergen-specific B cells. tissue eosinophilia, and produc tion of Allergic Response and Production of IL-4 and IL-13 promote other Th2 cytokines. 21 T-Helper 2 Lymphocytes antibody class switching in B cells to syn - A class of Th cells known as Th17 The central component of allergic asth - thesize IgE antibodies. 8 The Th2 cells cells has recently been identified as a ma is the development of an im - and allergen-specific B cells can differen - component in asthmatic inflamma - munoglobulin E (IgE) antibody-mediat - tiate into memory cells, facilitating and tion. 22 In mouse models, allergen sensi - ed response to allergens that requires the quickening future allergic responses. tization causes Th17 cells to home to interaction of a number of leukocytes. Immunoglobulin E is secreted from the lungs, where they enhance neu - Inhaled allergens are endocytosed by B cells into circulation, where it binds to trophilic infiltration and augment Th2- antigen presenting cells (APCs), which high-affinity Fc ⑀R1 receptors on the sur - mediated eosinophilic inflammation. 22 are usually dendritic cells in the airways faces of mast cells (in interstitial tissue) T-helper 17 cells secrete IL-17, which that function in surveying the environ - and basophils. 8 Immunoglobulin E con - has been shown to occur in elevated ment for pathogens. Dendritic cells trav - tinues to be synthesized even in the levels in the airway and blood of pa - el to lymph nodes and present antigens absence of allergen, and IgE is maintained tients with asthma. 22 The IL-17 family on the cell surface via major histocom - on the surfaces of mast cells and ba - consists of 6 members (A-F), which patibility complex proteins; they also in - sophils. Upon the next encounter with emerging evidence suggests are involved teract with CD4+ naive T cells that con - allergen, the antigen binds to membrane- in numerous other inflammatory dis - tain receptors specific to the antigen. bound IgE, stimulating release of such eases, including rheumatoid arthritis, Dendritic cells are crucial to the de - mediators as histamine, leukotrienes, and multiple sclerosis, inflammatory bowel velopment of an immune response and cytokines. 8 Because this process results disease, and psoriasis. 22

Ishmael • Inflammatory Response in the Pathogenesis of Asthma JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 11 • November 2011 • S15 upregulates a diverse set of cytokines, Mast cells are also the primary pro - well-defined. They may be more preva - chemokines, adhesion molecules, and ducers of cysteinyl leukotrienes, lipid lent in certain phenotypes than in oth - growth factors. 22 Its exact role in asthma mediators derived from arachadonic ers. 29,30 Macrophages are present in high and allergic disease and its interplay acid. 24-26 Leukotrienes bind to their G numbers in the airways and synthesize with Th2 pathways and other leukocyte protein-coupled receptors on the cell many inflammatory cytokines and pathways are areas of active research surfaces of structural airway cells. There chemokines. 29 Neutrophils may occur in with implications for the understanding they produce smooth muscle contrac - increased numbers in the airways of pa - of disease pathogenesis and treatment. tion, increase vascular permeability of tients with severe asthma, particularly small blood vessels, enhance secretion in smokers. 30 Their pathogenic role re - Effector Cells in the of mucus, and recruit leukocytes to the mains to be determined, but it may ac - Inflammatory Response airway. 27 Cysteinyl leukotrienes play an count for a lack of glucocorticoid effects Stimulation of T cells and epithelial important role in asthma, and their in - in some patients. 30 cells causes the activation and recruit - hibition with leukotriene antagonists is T cells are now recognized to play ment of other effector leukocytes to the effective in the treatment of patients important effector roles in patients with airway, and mediators produced by these with asthma. 27 asthma. 31 produced cells result in chronic inflammation, tis - Mast cells also release inflammatory from Th2 cells has been the focus of sue damage, and remodeling. Mast cells cytokines, chemokines, and proteases much research as a therapeutic target. are the central effector cell in allergic that contribute to airway inflamma - It induces airway hyperresponsiveness disease and are present in increased tion. 24,25,28 These mediators stimulate an and has numerous effects on structure, numbers in the airways of patients with inflammatory response in the epitheli - such as subepithelial fibrosis, airway asthma. 23 Binding of allergen to IgE on um, directly damage the airway, and re - smooth muscle proliferation, and gob - the cell surface induces a signal trans - cruit more leukocytes to the airway. let cell hyperplasia. 32 Interleukin 13 in - duction cascade that results in the re - Increased numbers of eosinophils are duces inflammation by acting primari - lease of mediators. The release of hista - present in the airways of most patients ly on the airway epithelium, and mine and prostaglandin D2 (PGD2) with asthma. The recruitment, growth, it increases eosinophil numbers by up - results in bronchoconstriction. 24-26 and survival of eosinophils are promoted regulating multiple chemokines, in - by factors released from airway epithe - cluding CCL11. 32 Induction of lial cells, Th2 cells, and mast cells. The chemokines may also be important in Did you know? Th2 cytokine IL-5 is central to lung fibrosis, as suggested by mouse eosinophil survival, as is GM-CSF, studies demonstrating that the block - Asthma is a heterogeneous, chronic inflammatory disease of the airways which is derived from the epithelium ade of CCL2, CCL3, and CCL6 abro - that is characterized by airway and mast cells. 17 Chemokines, particu - gates lung remodeling. 10 hyperresponsiveness, obstruction, larly CCL5 and CCL11, recruit Furthermore, IL-13 has been pro - and inflammatory cell infiltrates. eosinophils to the airway. 10 Eosinophils posed to be associated with glucocorti - The pathogenesis of the disease express a variety of proinflammatory cy - coid resistance, with the level of involves a complex interaction of genetic, environmental, and immune tokines, Th2 cytokines, and chemokines IL-13 being elevated in patients with factors. Interactions between airway that can activate mast cells and stimulate glucocorticoid-insensitive asthma. 32 epithelial cells, antigen presenting the epithelium. 17 In addition, eosinophils Glucocorticoids regulate the level of cells, allergic cells, and other inflam - can present antigen to T cells and release many cytokines and chemokines at matory leukocytes are central to dis - growth factors such as TGF- —high - transcriptional and posttranscriptional ease progression. Cytokines and ␤ other inflammatory mediators are lighting the importance of eosinophils in levels, and research has shown that the effectors of allergic inflammation multiple facets of asthmatic inflamma - IL-13 can directly affect the phosphory - and orchestrate the chronic inflam - tion. 17 The role of eosinophils in asthma lation of the glucocorticoid receptor to mation and structural changes in the may vary with different phenotypes, and alter its function. 32-35 Thus, IL-13 pro - respiratory tract. The author reviews patients with severe asthma are noted to vides an attractive therapeutic target the interplay of these factors in the inflammatory response in the patho - have elevated numbers of eosinophils. 2 that might be beneficial to consider in genesis of asthma. Phagocytes are also present in asth - many asthma phenotypes, including matic airways, though their role is not steroid-insensitive asthma.

S16 • JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 1 • November 2011 Ishmael • Inflammatory Response in the Pathogenesis of Asthma Final Notes 11. Schleimer RP, Kato A, Kern R, Kuperman D, 26. Robinson DS. The role of the mast cell in Asthma is a chronic inflammatory dis - Avila PC. Epithelium: at the interface of innate asthma: induction of airway hyperresponsiveness and adaptive immune responses [review]. by interaction with smooth muscle? J Allergy Clin ease that comprises multiple phenotypes J Allergy Clin Immunol. 2007;120(6):1279-1284. Immunol. 2004;114(1):58-65. and inflammatory triggers. These phe - 12. Schleimer RP, Kato A, Peters A, et al. Ep - 27. Montuschi P, Peters-Golden ML. Leuko- notypes share common inflammatory ithelium, inflammation, and immunity in the triene modifiers for asthma treatment. Clin Exp features, though their specific immuno - upper airways of humans: studies in chronic rhi - Allergy. 2010;40(12):1732-1741. nosinusitis [review]. Proc Am Thorac Soc. 2009; logic pathways may differ mechanisti - 6(3):288-294. 28. Boyce JA. The biology of the mast cell. cally. As we dissect these mechanisms at Allergy Asthma Proc. 2004;25(1):27-30. 13. Kato A, Schleimer RP. Beyond inflamma - the molecular level, the treatment of pa - tion: airway epithelial cells are at the interface of 29. Peters-Golden M. The alveolar macrophage: tients with asthma can be tailored to innate and adaptive immunity. Curr Opin Im - the forgotten cell in asthma. Am J Respir Cell Mol munol. 2007;19(6):711-720. Biol. 2004;31(1):3-7. specific phenotypes. Targeting the mediators and cells described in the 14. Ciencewicki J, Trivedi S, Kleeberger SR. Oxi - 30. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, dants and the pathogenesis of lung diseases [review]. Rex MD, Martin RJ. Bronchoscopic evaluation present review represent the basis of cur - J Allergy Clin Immunol. 2008;122(3):456-468. of severe asthma. Persistent inflammation associ - rent asthma treatment and highlight ated with high dose glucocorticoids. Am J Respir 15. Lambrecht BN, Hammad H. The role of den - Crit Care Med. 1997;156(3 pt 1):737-743. the potential for development of novel dritic and epithelial cells as master regulators of therapeutic agents in the future. allergic airway inflammation. Lancet. 2010; 31. Lloyd CM, Hessel EM. Functions of T cells in 376(9743):835-843. asthma: more than just T(H)2 cells. Nat Rev Im - munol. 2010;10(12):838-848. References 16. Liu YJ. Thymic stromal lymphopoietin and 1. Barnes PJ. Immunology of asthma and chronic OX40 ligand pathway in the initiation of 32. Rael EL, Lockey RF. Interleukin-13 signaling obstructive pulmonary disease [review]. Nat Rev dendritic cell-mediated allergic inflammation. and its role in asthma. World Allergy Org J. Immunol. 2008;8(3):183-192. J Allergy Clin Immunol. 2007;120(2):238-244. 2011;4(3):54-64.

2. Holgate ST. Pathogenesis of asthma [review]. 17. Blanchard C, Rothenberg ME. Biology of 33. Ishmael FT, Fang X, Galdiero MR, et al. Role Clin Exp Allergy. 2008;38(6):872-897. the eosinophil [review]. Adv Immunol. 2009; of the RNA-binding protein tristetraprolin 101:81-121. in glucocorticoid-mediated gene regulation. 3. National Asthma Education and Prevention J Immunol. 2008;180(12):8342-8353. Program. Expert panel report 3 (EPR-3): guide - 18. Stirling RG, van Rensen EL, Barnes PJ, lines for the diagnosis and management of asth - Chung KF. Interleukin-5 induces CD34(+) 34. Ishmael FT, Fang X, Houser KR, et al. ma, summary report 2007. J Allergy Clin Immunol. eosinophil progenitor mobilization and eosinophil The human glucocorticoid receptor as an RNA- 2007;120(5 suppl):S94-S138. CCR3 expression in asthma. Am J Respir Crit Care binding protein: global analysis of glucocorticoid Med. 2001;164(8 pt 1):1403-1409. receptor-associated transcripts and identification 4. Wenzel SE. Asthma: defining of the persistent of a target RNA motif. J Immunol. 2011; adult phenotypes. Lancet. 2006;368(9537): 19. Tanaka H, Komai M, Nagao K, et al. Role of 186(2):1189-1198. 804-813. interleukin-5 and eosinophils in allergen-in - duced airway remodeling in mice. Am J Respir 35. Stellato C. Glucocorticoid actions on airway 5. Lotvall J, Akdis CA, Bacharier LB, et al. Asth - Cell Mol Biol. 2004;31(1):62-68. epithelial responses in immunity: functional ma endotypes: a new approach to classification of outcomes and molecular targets. J Allergy Clin disease entities within the asthma syndrome. 20. Zhou Y, McLane M, Levitt RC. Th2 cy - Immunol. 2007;120(6):1247-1263. J Allergy Clin Immunol. 2011;127(2):355-360. tokines and asthma. Interleukin-9 as a therapeutic target for asthma. Respir Res. 2001;2(2):80-84. 6. Holgate ST. The sentinel role of the airway ep - ithelium in asthma pathogenesis. Immunol Rev. 21. Oh CK, Raible D, Geba GP, Molfino NA. Faoud T. Ishmael, MD, PhD, is in the 2011;242(1):205-219. Biology of the interleukin-9 pathway and its ther - Department of Medicine and Biochemistry apeutic potential for the treatment of asthma. In - and Molecular Biology, Section of Allergy 7. Holgate ST, Roberts G, Arshad HS, Howarth flamm Allergy Drug Targets. 2011;10(3): 180-186. PH, Davies DE. The role of the airway epitheli - and Immunology, Milton S. Hershey um and its interaction with environmental fac - 22. Park SJ, Lee YC. Interleukin-17 regulation: Medical Center, at The Pennsylvania State tors in asthma pathogenesis. Proc Am Thorac Soc. an attractive therapeutic approach for asthma. University College of Medicine in Hershey. 2009;6(8):655-659. Respir Res. 2010;11:78. Dr. Ishmael can be contacted by e-mail at [email protected]. 8. Levine SJ, Wenzel SE. Narrative review: 23. Brightling CE, Bradding P, Symon FA, Hol - the role of Th2 immune pathway modulation gate ST, Wardlaw AJ, Pavord ID. Mast-cell infil - in the treatment of severe asthma and its pheno - tration of airway smooth muscle in asthma. types. Ann Intern Med. 2010;152(4):232-237. N Engl J Med. 2002;346(22):1699-1705.

9. Vercelli D. Gene-environment interactions in 24. Boyce JA. Mast cells: beyond IgE. J Allergy asthma and allergy: the end of the beginning? Clin Immunol. 2003;111(1):24-32. Curr Opin Allergy Clin Immunol. 2010;10(2): 145-148. 25. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast 10. Barnes PJ. The cytokine network in asthma cells as “tunable” effector and immunoregulato - and chronic obstructive pulmonary disease. ry cells: recent advances. Annu Rev Immunol. J Clin Invest. 2008;118(11):3546-3556. 2005;23:749-786.

Ishmael • Inflammatory Response in the Pathogenesis of Asthma JAOA • Supplement 7 (The Whole Patient) • Vol 111 • No 11 • November 2011 • S17