Airway Inflammation in Asthma Chih-Yung Chiu 1,2, Kin-Sun Wong 2 1 Department of Pediatrics, Chang Gung Memorial Hospital, Keelung, Taiwan.

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1 REVIEW ARTICLE Chih-Yung Chiu 1,2, Kin-Sun Wong 2 1 Department of Pediatrics, Chang Gung Memorial Hospital, Keelung, Taiwan. 2 Division of Pediatric Pulmonology, Department of Pediatrics, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan, Taiwan. Abstract Airway inflammation is a prominent feature of asthma characterized by infiltration of eosinophils and other inflammatory cells to the airways. Airway production of chemokines, cytokines and adhesion molecules play an important role in the modulation of acute and chronic airway inflammation. Blocking these inflammatory mediators is believed to be of clinical benefit for chronic airway inflammation. Corticosteroids are widely used to treat various immune and inflammatory diseases. The most effective use of corticosteroids is in the treatment of asthma; however, they are ineffective in suppressing the inflammation seen in severe asthma. This article reviews the cells involved in inflammation and immunity associated with asthma. Pro-inflammatory cytokines and chemokines involved in asthma are also discussed. A fully understanding of the relationship between inflammatory cells and their inflammatory mediators may not only provide a useful therapeutic strategy but also an alternative in the treatment of corticosteroid-resistant asthma.(j Pediatr Resp Dis 2014;10:19-23) Key words: asthma, inflammatory cell, airway hyper-responsiveness INTRODUCTION Airway inflammation is a feature of lung diseases characterized by airway obstruction and excessive airway secretions. Asthma is the most common airway disease characterized by airway hyper-responsiveness (AHR), intermittent and reversible airway obstruction, and airway inflammatio. 1 The inflammation in asthma is mainly located in the larger conducting airways and small airways in more severe asthma. The airway inflammation can be divided into three stages. First, in the acute phase, allergic reaction to stimuli such as allergens or viruses leads to edema, smooth muscle contraction, and an increase in mucus production in the lungs. Second, a residual stimulus leads to the chronic phase which is characterized by epithelial cell denudation and the influx of inflammatory cells Correspondence: Chih-Yung Chiu, M.D. Address: Division of Pediatric Pulmonology, Department of Pediatrics, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan, Taiwan. No.222, Maijin Road, Keelung, Taiwan. Tel: ext Fax: pedchest@adm.cgmh.org.tw Received: May 26, Accepted: June 27, Journal compilation 2014 Taiwan Society of Pediatric Pulmonology such as mast cells, eosinophils and lymphocytes into airway tissue. In the third and final stage, chronic airway remodeling, which results from an increase in extracellular matrix proteins and vascular changes, may lead to a progressive loss of lung function. 2 Thickening of the airway smooth muscle cell layer, as a result of hyperplasia and hypertrophy, is more commonly seen in patients with severe asthma. 3 Airway inflammation can occur in response to exposure to particulates like pollens, pollutants, allergens and other substances. Airway epithelial cells are important in defense of the airways and are also activated by these stimuli to product inflammatory mediators. Airway production of chemokines, cytokines, adhesion molecules and inflammatory mediators play an important role in the modulation of airway inflammation in asthma. This article reviews the inflammatory and immune cells, and pro-inflammatory cytokines and chemokines involved in asthma. Inflammatory and Immune Cells in Asthma Many inflammatory cells are recruited to asthmatic airways or are activated in the airways. These include

2 Chiu CY, et al. mast cells, macrophages, eosinophils, T lymphocytes, dendritic cells, basophils, neutrophils, and platelets. 4 In asthmatic patients, bronchial biopsies reveal an inflammatory infiltration predominated by eosinophils, mast cells and activated Th2 type lymphocytes. The interactions of inflammatory and immune cells involved in asthma are illustrated in Figure 1. Mast Cells In asthma, mast cells have a key role in initiating the acute broncho-constrictor response to allergens as they release several broncho-constrictors, including histamine, leukotrienes and prostaglandin D2. 5 Mucosal mast cells are recruited and maintained at the mucosal surface of the airways by stem-cell factor (SCF) the latter being released from epithelial cells. Mast cells present in the airway smooth muscle have also been reported to be linked to the airway hyper-responsiveness seen in asthma. 5 Dendritic Cells Dendritic cells are very effective antigen-presenting cells and play an important role in the initiation of allergen-induced responses in asthma. 6 Allergens are processed by myeloid dendritic cells through thymic stromal lymphopoietin (TSLP) produced by epithelial cells and mast cells. The maturation of dendritic cells is accompanied by the production of chemokines CCchemokine ligand 17 (CCL17) and CCL22, which can recruit activated Th2 cells expressing C-C chemokine receptor type 4 (CCR4). 7 Increased expression of these chemokines has been reported in the bronchial mucosa Figure 1. Interactions of Inflammatory and Immune Cells Involved in Asthma. Inhaled allergens activate sensitized mast cells by crosslinking surface-bound IgE molecules to release several bronchoconstrictor mediators, including histamine, leukotrienes and prostaglandin D2. Epithelial cells release stem-cell factor (SCF) to maintain mucosal mast cells at the airway surface. Allergens are processed by myeloid dendritic cells and thymic stromal lymphopoietin (TSLP) secreted by epithelial cells and mast cells induce the release of chemokines CC chemokine ligand 17 (CCL17) and CCL22, which act on CC chemokine receptor 4 (CCR4) to attract T helper 2 (Th2) cells. Th2 cells releases interleukin 4 (IL 4) and IL 13 to stimulate B cells to synthesize IgE, IL 9 to stimulate mast-cell proliferation and IL 5 to recruit eosinophils. Eosinophils are also recruited by CCL11 secreted from epithelial cells via CCR3. 20

3 of asthma patients. 7 Eosinophils Eosinophil infiltration is a characteristic feature of asthmatic airways. Eosinophils are derived from bone marrow precursors. The IL-5 released from Th2 lymphocytes is a unique mediator of eosinophil differentiation and survival in response to allergen provocation. In asthma, airway epithelial cells secrete eosinophil chemotactic factors, such as CCL11 resulting in the recruitment and accumulation of eosinophils in the airways. Other mediators such as eotaxins, CCL5 (RANTES) and CCL13 (MCP-4), expressed in epithelial cells are also involved in the migration of eosinophils from the circulation to the surface of airways. 8 Neutrophils In exacerbations of asthma triggered by viruses, there are increases in the numbers of neutrophils and eosinophils. 9 There is also increasing evidence that neutrophilic inflammation, which is poorly responsive to corticosteroids, plays a major role in the pathogenesis of asthma exacerbations. 10 Several neutrophil chemotactic factors may play roles in neutrophil migration into the respiratory tract. These mediators include leukotriene B4, CXCL8, CXCL1 and CXCL5 and they are derived from alveolar macrophages and epithelial cells. 11 A neutrophilic pattern of inflammation is commonly seen in patients with severe asthma due to the release of the chemokine neutrophilic CXCL8 from airway epithelial cells through IL-17 produced by Th17 cells. 12 T cells In asthmatic patients, there is an increase in the number of CD4 + T cells (predominantly T helper 2 (Th2) cells) in the airways. Secreted cytokines IL-4 and IL-13 from Th2 cells drive IgE production by B cells. Secreted IL-5 is also necessary for eosinophilic inflammation whilst IL-9 attracts and stimulates mast cell proliferation. 13 The recruitment of Th2 cells in the airway is dependent on several chemotactic mediators including the chemokines CCL17 and CCL22. 7 Pro-inflammatory Cytokines and Chemokines in Asthma In patients with asthma, pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6 are found in increased levels in the sputum and bronchial alveolar lavage (BAL) fluid and amplify inflammation. 14 Blocking these cytokines is believed to be of clinical benefit for airway inflammation. In addition to cytokines, chemokines (chemotactic cytokines) play a crucial role in the recruitment of different types of inflammatory cells from the blood to the airways in asthma. 15 There are two major families of chemokines that are defined and distinguished by the position of four conserved cysteine residues. The largest family is the CC chemokines which are named because the first two of the four cysteine residues are adjacent to each other. The second family is the CXC chemokines which have two cysteine residues in the same region, but with an interposed amino acid. 16 The pro-inflammatory cytokines and chemokines involved in airway inflammation in asthma are detailed below. TNF-α Many cells including macrophages, mast cells, T cells, epithelial cells, and airway smooth muscle cells have the capacity to produce and secrete TNF-α. TNF-α may play a key role in the airway hyper-responsiveness (AHR) of asthma. Blocking TNF-α has been reported to reduce AHR and improve lung function in patients with severe asthma. 17 IL-1β In asthma, IL-1β levels are increased in the airways of asthma patients and the cytokine activates cell signaling pathways of inflammation. IL-1 receptor antagonist (IL-1Ra) administration has been shown to result in reduction of AHR in mice, although human recombinant IL-1 Ra results in no improvement of disease in asthma patients. 18 IL-6 IL-6 levels are increased in induced sputum of asthmatic patients and the cytokine may play a role in the expansion of Th2 cells. It is positively correlated 21

4 Chiu CY, et al. with increased IL-13 levels resulting in inflammatory amplification in asthma. 19 IL-6 is also found in increased levels in the serum of patients with asthma exacerbation, especially induced by virus infection. 20 CC Chemokines Eosinophils express CCR3 which mediates the chemotactic response to several chemokines, including CCL11 (also known as eotaxin) and CCL5 (also known as RANTES), all of which show increased levels in the airways of patients with asthma, especially in airway epithelial and smooth muscle cells CXC Chemokines CXCL8 and CXCL1 (also known as growth regulated oncogene α [GRO-α]) activate mainly CXCR1 and CXCR2 respectively and play a crucial role in the recruitment of neutrophils into the airways. CXCL1 and CXCL8 levels are shown to be positively correlated with increase in neutrophil count. 11 CXCL8 has also been reported to be increased in the airways and sputum of patients with severe asthma and during 24, 25 exacerbations. In conclusion, airway inflammation is a prominent feature of asthma characterized by infiltration of eosinophils and other inflammatory cells to the airways. Airway production of chemokines, cytokines and adhesion molecules play an important role in the modulation of acute and chronic airway inflammation. Blocking these inflammatory mediators is believed to be of clinical benefit for chronic airway inflammation. REFERENCES 1. Lundback B, Dahl R. Assessment of asthma control and its impact on optimal treatment strategy. Allergy 2007;62: Jeffery PK. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004;1: Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 2003;167: Chedevergne F, Le Bourgeois M, de Blic J, Scheinmann P. The role of inflammation in childhood asthma. Arch Dis Child 2000;82 Suppl 2, II Brightling CE, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346: Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 2008;8: Ying S, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 2005;174: Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008;8: Wark PA, Gibson PG. Asthma exacerbations. 3: Pathogenesis. Thorax 2006;61: Martinez FD. Managing childhood asthma: challenge of preventing exacerbations. Pediatrics 2009;123 Suppl 3:S Wu Q, et al. Elevated levels of the chemokine GRO-1 correlate with elevated oligodendrocyte progenitor proliferation in the jimpy mutant. J Neurosci 2000;20: Bullens DM, et al. IL-17 mrna in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res 2006;7: Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol 2009;21: Renauld JC. New insights into the role of cytokines in asthma. J Clin Pathol 2001;54: Blease K, Lukacs NW, Hogaboam CM, Kunkel SL. Chemokines and their role in airway hyperreactivity. Respir Res 2000;1: Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354: Berry MA, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006;354: Rosenwasser LJ. Biologic activities of IL-1 and

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