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PATHOPHYSIOLOGICAL BASIS OF AS th ma In the current working definition of asthma, provided in the 1997 National Institutes of Health, Expert Pane] Report 2: Guide- lines for the Diagnosis and Management of Asthma (Murphy, 1997; see Chapter 1), the disease is characterized by two fundamental features, (1) an excessive sensitivity of the airways to a variety of endogenous and/or exogenous bronchoconstrictor agents, a fea- ture referred to as "bronchial hyperresponsiveness"; and (2) a pathophysiological link between bronchial hyperresponsiveness and the presence of inflammation of the airways. A major focus of research in the past two decades has been to identify the physi- ological, cellular, and molecular mechanisms that underlie the as- sociation between bronchial hyperresponsiveness and airways inflammation in establishing the asthmatic condition. This re- search has led to key advances in elucidating the roles of specific inflammatory cells and other processes in the pathobiology of asthma. While there is a wealth of information indicating or sug- gesting an association between environmental exposures and asthma outcomes, very little is known about the means by which the exposures bring about the changes that manifest as asthma. A better understanding of the molecular mechanisms regulating the recognition of and response to environmental exposures may lead to more safe and effective asthma interventions. This chapter 87
88 CLEARING THE AIR summarizes the state of the science regarding research on these mechanisms. AIRWAY INFLAMMATION IN ASTHMA Role of Mast Cells In the mid-1960s, immunogIobulin E (IgE) was first clearly identified as the principal mediating agent of the allergic proasthmatic response (Ishizaka et al., 1966~. Accordingly, in re- sponse to specific allergens bound to IgE molecules present on the surface of mast cells, basophils, and other cell types, a host of preformed cellular bronchoactive mediators are acutely released. In this manner, at least with respect to allergic asthma, IgE has been implicated as the fundamental inherent determinant of the "immediate" hypersensitivity airway response to allergen expo- sure. In accordance with this concept, allergic asthmatic individu- als classically present with elevated serum concentrations of IgE, which defines the atopic state. Moreover, the degree of elevation in serum IgE concentration has been linked to the severity of asthma and has been identified as an important risk factor in the development of the disease (Sears et al., 1991~. Antigen coupled to cell-bound IgE is now known to activate a number of proinflammatory cells, principally including the air- way mast cells. Upon activation of their high-affinity receptors for IgE, mast cells release a variety of preformed mediators in- cluding histamine, leukotrienes, various cytokines, and other proinflammatory molecules. This array of mast cell-derived me- diators largely serves to elicit the immediate airway hypersensi- tivity response to allergen exposure, which is characterized by acute constriction of the airways, airway mucosal gland secre- tion, and airway edema secondary to increased airway microvas- cular permeability. In addition to this "acute-phase" response, various mast cell-derived chemotactic mediators have been im- plicated further in the development of a subsequent "late-phase" response, hours after allergen exposure, which is characterized by prolonged or sustained bronchoconstriction associated with infiltration of the airways by a variety of inflammatory cell types (Lemanske and Kaliner, 1981-1982; Robertson et al., 1974~. Among
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 89 the mast cell-derived mediators importantly implicated in the development of the late-phase response are the cysteiny] leukotrienes, previously identified as siow-reacting substance of anaphylaxis (SRS-A). Other important proinflammatory media- tors of airway inflammation include eosinophi! chemotactic fac- tor (ECF), neutrophi] chemotactic factor (NCF), eotaxin, and oth- ers. The orchestrated release of these mediators apparently serves to propagate the airway inflammatory response and the associ- ated sustained constriction of the airways (Metzger et al., 1985; Strek and Leff, 1997~. As part of the proinflammatory late-phase response to aller- gen exposure, it has been demonstrated that the airways display nonspecific bronchial hyperresponsiveness to a variety of biologic and chemical agents, a feature that represents the pathognomonic functional disturbance in asthma. Moreover, particularly severe late-phase responses have also been associated with recurrent epi- sodes of exacerbation of asthma (Cartier et al., 1982~. Given this evidence, together with that stemming from the recent applica- tion of flexible bronchoscopy to obtain bronchoalveolar ravage (BAL) fluid for analysis of Jung cellular infiltrates (Riedler et al., 1995), the recruitment of eosinophils and T lymphocytes in the lung has been identified as a key feature in the trafficking of in- flammatory cells in the airways and in the establishment of bron- chial hyperresponsiveness. Role of Fosinophils Peripheral blood and airway tissue eosinophilia have long been recognized in association with asthma. In more recent years, considerable insight has been gained into the role of the airway eosinophilic infiltration in the pathobiology of the disease. Ac- cordingly, activation of airway eosinophils, resulting in release from their granules of preformed mediators, has been implicated in producing constriction of airway smooth muscle, bronchial hyperresponsiveness, recruitment of other inflammatory cell types, and airway tissue (e.g., epithelium) damage. In mediating these diverse actions, eosinophils release a variety of cationic pro- teins including major basic protein (MBP), eosinophi] cationic pro- tein (ECP), eosinophi! derived neurotoxin (EDN), eosinophi! per
So CLEARING THE AIR oxidase (EPO), and unique to eosinophils, lysophopholipase pro- tein, which forms the Charcot-Leyden crystals that are character- istically found in asthmatic sputum specimens. In addition, eosi- nophils also secrete such enzymes as collagenase, 13-glucuronidase, acid phosphatase, and others (Strek and Leff, 1997~. Among these secreted products, MBP has been found to produce damage to the airway epithelial cell lining, inhibit air- way ciliary beat activity, stimulate eicosanoid production, and enhance histamine release from mast cells (Gleich et al., 1974~. ECP is neurotoxic, has ribonuclease activity, and also causes dam- age to the airway epithelium (Motojima et al., 1989), whereas EPO has been associated with inducing increases in lung microvascu- lar permeability (Yoshikawa et al., 1993~. Collectively, these eosi- nophil functions, together with the generation of toxic oxygen radicals, have been implicated in establishing a number of the histological and physiological perturbations that characterize the asthmatic airway. In accordance with this evidence, an associa- tion between airway eosinophilia and the clinical presentation of asthma severity and bronchial hyperresponsiveness has been well documented (Strek and Leff, 1997~. It remains to be established, however, whether this associative relationship is also mechanisti- cally causative. Role of T lymphocytes T helper (TH) lymphocytes have also been implicated impor- tantly in the regulation of various immune functions, including the development of allergic inflammation of the airways. In this regard, TH cells have been phenotypically partitioned into two profiles of differentiated cell function. These are represented by cells expressing either a TH1 or a TH2 profile of cytokine release upon activation. TH cells expressing the TH1 phenotype generate cytokines, including interleukin-2 (IL-2), IL-12, and interferon gamma (IFN-~), which, although generally associated with host defense against infection, also act to modulate airway function. Indeed, in this regard, it has been demonstrated that the TH1- type cytokines, notably IFN-y, largely play a protective role in countering the IgE-dependent expression of allergic responses and atopic asthma (Coffman and Carty, 1986; Lack and Gelfand,
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 91 1996; Pene et al., 1988~. In contrast, lymphocytes of the TH2 phe- notype release cytokines (e.g., IL-4 and IL-5) that have been im- plicated in orchestrating various proinflammatory humoral and cellular immune responses, including IgE synthesis and eosino- phi! recruitment and activation, both of which are characteristic features of the inflammatory state in asthmatic airways (Koning et al., 1997; Romagnani, 1995~. In this connection, it has been re- cently demonstrated that both TH1- and TH2-type cytokines may, independent of the presence of inflammatory cells, directly exert potent opposing actions on the airway smooth muscle itself (Hakonarson et al., 1999~. Accordingly, TH2-type cytokines have been shown to facilitate expression of the proasthmatic pheno- type of altered airway smooth muscle responsiveness, whereas TH1 cytokines were found to act directly on the airway smooth muscle to attenuate its proasthmatic phenotype (Hakonarson et al., 1999~. In light of the above information pertaining to the roles of TH1 and TH2 lymphocytes, a popular contemporary paradigm states that the expression of the asthmatic state reflects a relative imbalance between TH1- and TH2-type cytokine production and action. Thus, an induced upregulated TH2 cytokine response, to- gether with a relatively downregulated TH1 cytokine response, is considered to underlie the cellular and humoral airway inflam- matory responses and bronchoconstrictor responsiveness in asthma (Ackerman et al., 1994; Corrigan et al., 1995; Robinson et al., 1992~. There exists substantial evidence in support of this con- cept, based largely on recent clinical studies conducted in chil- dren and adults. These studies have reported that relative to nonallergic or nonasthmatic individuals, both serum and BAL fluid samples isolated from atopic asthmatic patients reveal sig- nificantly increased levels of the TH2 cytokines IL-4 and IL-5, in association with relatively decreased levels of the TH2-type cytokine IFN-y (Hamid et al., 1991; Umetsu and DeKruyff, 1997; Ying et al., 1995~. Moreover, it has been demonstrated that mono- nuclear cells isolated from serum or BAL fluid samples from atopic asthmatic patients also display a similar altered TH1- ver- sus TH2-type profile of cytokine release when the celIs are stimu- lated with antigen (i.e., favoring the TH2-type cytokine response). Finally, in extended support of the paradigm of altered TH1- ver
92 CLEARING THE AIR sus TH2-type cytokine expression in asthma, it has been demon- strated that treatment of asthmatic patients with corticosteroids reduces their airway constrictor hyperresponsiveness and BAL fluid levels of IL-4 and IL-5, as well as the number of cells ex- pressing these cytokines, while IFN-y levels and cells expressing IFN-y in the Jung are increased (Bentley et al., 1996; Leung et al., 1995; Robinson et al., 1993~. In view of the above compelling body of evidence, current research into the pathobiology of asthma is largely directed at elucidating those mechanisms that regulate the expression of the TH1 and TH2 profiles of cytokine expression in the lung. In this regard, among the principal areas of research pursuit are studies directed at identifying the genetic basis for development of the TH1 or TH2 phenotype, as well as the influence of allergic and other environmental factors in modulating the TH1-TH2 cytokine balance. Role of Cell Adhesion Molecules The localized accumulation of inflammatory cells, particu- iarly eosinophils and lymphocytes, in the asthmatic airway is, in large part, regulated by the actions of cell adhesion molecules. Together with their sequential interaction with cytokines or chemokines and other chemoattractants, cell adhesion molecules contribute importantly to the process of recruitment and activa- tion of specific inflammatory cells at the primary inflammatory focus. The cell adhesion molecules have been classified into three families that include the selecting, integrins, and immunogiobu- lin supergene family (Albelda et al., 1994; Springer, 1990~. Members of all of these families play critical roles in regulating leukocyte-endothelial cell interactions and other functions. Ac- cordingly, in the initial phase of inflammatory cell recruitment from the tissue microvasculature in response to specific chemo- tactic stimuli, the tethering and rolling behavior (i.e., margination) of circulating leukocytes toward the affected site is mediated by the actions of E- and P-selectins on the vascular endothelium and by the action of L-selectin on the leukocyte surface. Thereafter, the integrin family of adhesion molecules, when bound to their respective counterreceptors in endothelial and other cell types,
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 93 contributes to enhanced adhesion of the selected leukocytes. Fi- nally, firm leukocyte adhesion is followed by transmigration of the inflammatory cells through the endothelial cell junctions (dia- pedesis) and their directed movement along a chemotactic gradi- ent to the tissue inflammatory site. Given the above sequence of events, in recent years a host of studies have examined the roles of cell adhesion molecules in the pathogenesis of the airway inflammatory response in asthma. Al- though many mechanistic processes remain unidentified, the ac- cumulated data to date support the general notion that mast cell and TH2 lymphocyte activation, occurring following exposure to a sensitizing antigen, elicits the release of a host of soluble media- tors, which in turn induce airway endothelial cells to upregulate their expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1~. This effect, together with the stimulated release of specific chemo- attractants, subsequently mediates the recruitment of specific leu- kocytes, most notably eosinophils and lymphocytes, into the air- way tissue. In accordance with this concept, Wegner and col- leagues (1990) demonstrated that ICAM-1 expression in bronchial endothelium and epithelium is increased after antigen challenge in Ascaris-sensitized monkeys. Moreover, this effect was associated with airway eosinophi! recruitment and the manifes- tation of bronchial hyperresponsiveness; and both these phenom- ena were inhibited by pretreatment of the animals with a mono- clonal blocking antibody to ICAM-1 (Weaner et al., 1990~. Comparably, upregulated VCAM-1 expression has also been cor- related with increased IL-4 and IL-13 expression, in association with infiltration of eosinophils, macrophages, and T lymphocytes in allergen-induced late phase cutaneous reactions in atopic indi- viduals (Yin" et al., 1997~. Thus, these findings, together with those from a series of related studies, have lent extended support to the above concept of cell adhesion molecule-dependent regula- tion of allergic inflammatory reactions and bronchial hyper- responsiveness in asthmatic individuals following inhaled anti- gen challenge (Georas et al., 1992; Montefort et al., 1994; Ohkawara et al., 1995; Takahashi et al., 1994~. Collectively, this evidence underscores the need to further identify the mechanistic interplay between specific inflammatory cells, cell adhesion mol
94 CLEARING THE AIR ecules, and the changes in airway function that characterize the asthmatic condition. Current understanding of the above proposed mechanisms related to the role of inflammation in the pathophysiology of al- lergic asthma is summarized schematically in Figure 4-1. In the development of the immune and inflammatory responses in the airways, the inhaled sensitizing antigen is initially processed by antigen-presenting cells and then the antigen protein is bound to a complex of intercellular co-stimulatory molecules that includes major histocompatibility complex (MHC) class II, T cell receptor, and B7/CD28 molecules. This interaction leads to CD4+ T helper cell activation (Banchereau and Steinman, 1998~. The latter results Inhaled Allergen ~ - · ~ Presenting EARTH] ~ ~ Lymphocyte) ' ~ Symphony JO Allergen-Bound \ / IgE Complex, ~ (a) ILc4 - ) | Cytok~nes | IL-13 1 1 1 Histamine Eicosanoids Tryptase Acute-Phase Response Bronchoconstriction Mucus Hypersecretion Microvascular Leak - - - FIGURE 4-1 Proinflammatory mechan .\ . I IL-R I Cytokines, Chemokines, I ~ ~Eosinoph) I Leukotrienes I ~J 1 Late-Phase Response Airway Hyperresponsiveness Airway Inflammation Epithelial Cell Damage ~ I Recurrent Wheezing Chronic Inflammation Chronic Hyperresponsiveness Airway Remodelling Chronic Asthma . - - ~sms in allergic asthma. MBP, EPO, ECP, Cytokines, etc.
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 95 in the subsequent differentation of T cells into those expressing either a TH1- or TH2-type profile of cytokine release. The TH2 phenotype is generally proinflammatory in nature in the airways, as represented by the release of the cytokines IL-4, IL-13, and IL- 5. Among other functions, these cytokines act to direct IgE syn- thesis and to recruit and activate eosinophils. In the presence of IgE bound to an inhaled antigen, the high-affinity surface recep- tors for IgE (i.e., Fc£RI) found on the surface of mast cells (also basophils) are activated, which leads to the release of various pre- formed mediators. Among these, histamine, tryptase, and certain eicosanoids are key mast cell-derived mediators that are largely responsible for eliciting the acute-phase response to the inhaled antigen. Other mast cell-derived mediators including leukotrienes and specific cytokines (e.g., IL-4, IL-5, IL-6, and IL-13) act coop- eratively to orchestrate the subsequent late-phase proinflamma- tory response (Shimizu and Schwartz, 1997~. These events, to- gether with eosinophi! activation and the release of various eosinophil-derived mediators, as well as activation of other cell types (e.g., basophils and mononuclear celIs), serve to further per- petuate the airway inflammatory response and produce the state of chronic airway inflammation, perturbed airway function, and structural remodeling of the airway that characterizes the atopic asthmatic phenotype. Apart from the above contemporary view related to the role of airway inflammation in the pathophysiology of allergic asthma, it is well recognized that respiratory inhalation of nonbiological (nonallergenic) agents (e.g., certain particulates, noxious gases, tobacco smoke) can also trigger acute asthma symptoms, poten- tially in the absence of any concomitant airway inflammation. Under these circumstances, it is generally believed that the mechanism underlying such asthmatic reactions is related to "nonspecific" irritant effects of the offending inhaled agent in the lung, which are attributed to the activation of specific broncho- active reflexes. These reflexes are characteristically mediated by airway irritant receptors and/or receptors associated with small pulmonary c-type neural fibers that release specific neuropeptides in the Jung (e.g., substance P) (Undem and Riccio, 1997~.
96 CLEARING THE AIR THE AIRWAY SMOOTH MUSCLE IN ASTHMA Role in Altered Airway Responsiveness The characteristic functional perturbations of the asthmatic airway are its heightened contractile responsiveness to broncho- constrictor agents (e.g., mediators, neurotransmitters) and im- paired relaxation responsiveness to bronchodilatory agents (i.e., beta-adrenergic drugs, prostaglandin Ed. Although substantial evidence exists in support of an important association between airway inflammation and altered airway function, implicating a complex interplay between activated inflammatory cells, airway epithelial cells, and airway smooth muscle (ASM), the cellular and molecular mechanisms underlying the functional perturbations in ASM responsiveness in asthma remain to be identified. In this regard, it is relevant to note that based on studies using isolated asthmatic and antigen-sensitized airways, the impaired relaxation responsiveness to beta-adrenergic receptor agonists does not ap- pear to be related to reductions in either the density or the affinity of beta-adrenergic receptors in asthmatic ASM (Bad et al., 1992; Sharma and leffery, 1990; Spina et al., 1989; van Koppen et al., 1989~. Rather, the changes in responsiveness of asthmatic ASM appear to be fundamentally linked to perturbations in certain key postreceptor-coupled transmembrane signal transduction mecha- nisms that regulate ASM contraction and relaxation. In recent years, this concept has received considerable attention and evi- dence has been accumulated demonstrating that, under atopic asthmatic conditions, the sensitized ASM displays attenuated beta-adrenoceptor-induced accumulation of cyclic adenosine monophosphate (cAMP), the key intracellular second messenger that mediates ASM relaxation. Moreover, in related studies, it has been shown that both the impaired beta-adrenoceptor-coupled accumulation of cAMP and the attenuated relaxation responsive- ness in atopic asthmatic-sensitized ASM are largely attributable to an induced increased expression and action of the receptor- coupled G protein Go, which inhibits adenylate cycIase and, hence, agonist-mediated cAMP accumulation (Hakonarson et al., 1995~. The changes identified in transmembrane signaling and tis
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 97 sue responsiveness in isolated atopic asthmatic ASM has raised the possibility that mechanisms intrinsic to the ASM itself con- tribute importantly to its autocrine induction of the proasthmatic phenotype. In support of this new concept, recent studies have demonstrated that under in vitro conditions of passive sensitiza- tion of isolated ASM with atopic asthmatic serum, the sensitized ASM itself is induced to release various proinflammatory cyto- kines, including IL-113 (Hakonarson et al., 1997), as well as both TH1- and TH2-type cytokines (Hakonarson et al., 1999~. In turn, these cytokines apparently act in an autocrine fashion to elicit proasthmatic changes in ASM responsiveness. Moreover, in ex- tending this concept, the release of such proinflammatory cytokines, as well as the potential release of certain chemokines (Elias et al., 1997; Ghaffar et al., 1999; John et al., 1997) by the sensitized ASM itself, may further facilitate the recruitment of in- flammatory cells into the airway tissue and thereby propagate the local inflammatory reaction in the asthmatic airway. Role in Airway Remodeling An additional important characteristic feature of asthmatic airways, particularly in the setting of chronic severe asthma, is the presence of an increase in ASM tissue mass, reflecting ASM cell hyperplasia and/or hypertrophy. This remodeling of the air- ways, together with a disruption of the airway epithelium and altered airway tissue extracellular matrix, may contribute impor- tantly to the presence of the fixed (i.e., acutely nonreversible) air- way narrowing that is often seen in long-standing severely asth- matic individuals. Although the precise mechanisms regulating airway remodeling remain to be identified, in recent years there has been considerable progress in our understanding of certain processes that control ASM cell growth. Accordingly, in concert with the effects of inflammatory cell-derived mediators and growth factors, ASM cells have also been shown to intrinsically express various cell adhesion molecules, extracellular matrix pro- teins, and as noted above, various cytokines or chemokines. The localized release of such a diverse collection of extracellular autocrine and paracrine stimuli appears to induce ASM cell pro- liferation, at least in part, by stimulating certain common intra
98 CLEARING THE AIR cellular signaling pathways (Panettieri and Grunstein, 1997~. Moreover, the complex interaction between these signaling path- ways likely determines the ultimate manifestation of airway re- modeling via a coordinated regulation of promitogenic and antipro-liferative (i.e., apoptosis) intracellular signals. THE GENETICS OF ASTHMA There exists a substantial long-standing body of evidence that predisposition to asthma represents an inheritable phenomenon. Epidemiologic and immunologic studies have demonstrated that there is an increased prevalence of asthma within families and that monozygotic twins depict greater concordance than do dizy- gotic twins (Duffy et al., 1990; Edfors-Lubs, 1971~. An inheritable basis for atopy has also been reported with respect to the expres- sion of serum IgE (Pirson et al., 1991; Sibbald et al., 1980~. Despite this strongly suggestive evidence, the genes responsible for asthma remains unidentified. This deficiency in our current un- derstanding of the genetic basis of asthma is largely reflective of the notion that like many other common diseases, asthma repre- sents a polygenic disorder in which the phenotypic manifestation of the disease is greatly influenced by environmental factors. Different approaches have been used to identify and map the genes causing asthma. One approach involves complex segrega- tion analysis, followed by linkage analysis using the most com- patible genetic paradigm identified by the segregation analysis. In addition, linkage analysis also has been applied in analyzing affected pairs of relatives without a predefined specific genetic model. Another approach, referred to as the candidate gene ap- proach, is based on testing for simple associations with specific polymorphisms of potentially relevant genes in affected and un- affected individuals. Use of the candidate gene approach in asthma is dependent on information about potential mechanisms related to the development of the disease process. Finally, an ap- proach involving a genome-wide search, wherein polymorphic DNA markers are measured throughout the human genome, fol- lowed by linkage analysis, has been applied to asthmatic indi- viduals and their familial relations. To date, the collection of evidence based on the above analy
PATHOPHYSIOLOGICAL BASIS OF ASTHMA 99 ses of potential genetic determinants of asthma has identified a variety of candidate genes related to the disease. Accordingly, studies have reported that genes contained within the cytokine cluster on chromosome 5 (encoding IL-3, IL-4, IL-5, IL-9, and IL- 13), chromosome 11 (encoding the high-affinity receptor for IgE, Fc£RI), chromosome 12 (encoding insulin-like growth factor, stem cell factor, IFN-y, and Stat 6), and chromosome 16 (encoding the IL-3 receptor) may possibly contribute to the development of asthma and atopy (Borish, 1999; Daniels et al., 1996; Marsh et al., 1994~. Moreover, there is mounting evidence in support of the involvement of genes that regulate antigen presentation (i.e., MHC class II genes), as well as T lymphocyte responses (i.e., T cell receptor gene) (Blumenthal et al., 1992; Marsh et al., 1981~. Finally, polymorphisms have been reported in genes encoding the ,8-adrenergic receptor, 5'-lipoxygenase, and leukotriene C4 syn- thase (Borish, 1999; Chandrasekharappa et al., l990~. Collectively, this information highlights the complexity of the molecular ge- netics of asthma. Moreover, it emphasizes that much more re- search, based on combining data from genetic analyses with those identifying pathophysiological processes involved in asthma, is needed to ultimately determine the genetic basis of asthma, as well as the potential development of new strategies for therapeu- tic intervention. CONCLUSION In the past, the quest to understand asthma was a process much like that of blind men trying to understand the elephant impressions of the beast were based largely on the part of the animal that was touched. In recent years, however, the synthesis of evidence stemming from the diversity of basic and clinical re- search studies on asthma has led to major advances in our overall understanding of the pathobiology of this disease. While we know that asthma is a genetically predisposed condition that is associated with chronic inflammation of the airways, ongoing re- search continues to uncover a multiplicity of cellular and molecu- lar mechanisms involved in regulating the phenotypic expression of the disease. Importantly, these mechanisms are activated largely in response to a variety of environmental factors, includ
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