Asthma is characterized by the action of airway leading to reversible airflow obstruction in association with airway hyperresponsiveness (AHR) and airway inflammation (Holgate, 2012). The disease is affecting more than 300 million persons all over the world, with approximately 250,000 annual deaths (Bousquet et al., 2007). In the last couple of decades, as the inhaled corticosteroid has become the major treatment agent for asthma, the mortality of asthma has decreased (Wijesinghe et al., 2009). Meanwhile, allergic diseases, such as asthma, have markedly increased in the past half centuries associated with urbanization (Alfvén et al., 2006). Children have the greatest percentage of asthma compared with other generation groups (Centers for Disease Control and Prevention, 2011). Then, it is expected that the number of the patients will increase by more than 100 million by 2025 (Masoli et al., 2004).

Generally, most asthma starts from childhood in relation to sensitization to common inhaled allergens, such as house dust mites, cockroaches, animal dander, fungi, and pollens. These inhaled allergens stimulate T helper type 2 (Th2) cell proliferation, subsequently Th2 cytokines, interleukin (IL)-4, IL-5 and IL-13 production and release. Many basic and clinical studies suggested that airway inflammation was a central key to the disease pathophysiology. The existence of chronic airway inflammation in asthma has been recognized for over a century. The inflammation is induced by the release of potent chemical mediators from inflammatory cells.  Analysis of Asthma from a Pathological Point of View Essay.Resulted of chronic airway inflammation, airway remodeling, characterized by thickening of all compartments of the airway wall, is occurred and may have profound consequences on the mechanics of airway narrowing in asthma and contribute to the chronicity and progression of the disease.

As allergic sensitization, allergen can be taken up by dendritic cells (DCs), which process antigenic molecules and present them to naїve T helper cells. Consequently the activation of allergen-specific Th2 cells is occurred, the cells play an important role in developing the asthma. Nowadays, it is known that Th17 cells and Th9 cells also modulate the disease. Th17 cells produce IL-17A, IL-17F, and IL-22. These cytokines induce airway inflammation and IL-17A enhance smooth muscle contractility.

Allergic diseases are caused by inappropriate immunological responses to allergens without pathogenesis driven by a Th2-mediated immune response. The hygiene hypothesis has been used to explain the increase in allergic diseases since industrialization and urbanization, and the higher incidence of allergic diseases in more developed countries. The hypothesis has now expanded to include exposure to symbiotic bacteria and parasites as important modulators of immune system development, along with infectious agents (Grammatikos, 2008). Recently, asthma has not been recognized as a simple Th2 disease, which is characterized by IgE elevation and relatively eosinophilia. Th17 and Th9 cell subtype are known to contribute the inflammation or enhancing smooth muscle contraction or stimulating mast cells.

HISTOPATHOLOGY OF ASTHMATIC AIRWAY

Asthma is considered in terms of its hallmarks of reversible airflow obstruction, non-specific bronchial hyperreactivity and chronic airway inflammation (American Thoracic Society, 1987). Osler (1892) mentioned in the classic textbook, the inflammatory process, affecting the conducting airways with relative sparing of the lung parenchyma. Huber and Koesser (1922) provided a comprehensive perspective of the histopathological features of asthma. That is, the lungs are usually hyperinflated as a consequence of extensive mucous plugging in segmental, subsegmental bronchus and peripheral airways, but the lung parenchyma in general, remains relatively intact in subjects who die in exacerbation, so-called status asthmatics.  Analysis of Asthma from a Pathological Point of View Essay.The composition of mucous includes cellular debris from necrotic airway epithelial cells, an inflammatory cells including lymphocytes, eosinophils, and neutrophils, plasma protein exudate, and mucin that is produced by goblet cells (Unger, 1945; Bullen, 1952; Dunnill, 1960; Messer et al., 1960). The airway epithelium typically shows sloughing of ciliated columnar cells, with goblet cell and squamous cell metaplasia as a sign of airway epithelial repair. There is increased thickness of the subepithelial basement membrane, however, some studies have established that the true basal lamina is of normal thickness, and the apparent increase in thickness is related to accumulation of other extracellular matrix components beneath the basal lamina (Roche et al., 1989). The asthmatic airway showed a thickness with inflammatory cell infiltration consisting of an admixture of T lymphocytes and eosinophils, mast cells (Carroll et al., 1997; Hamid et al., 1997). Interestingly, prominent neutrophil infiltrates have been reported to be a specific feature of the clinical entity of sudden onset fatal asthma (Sur et al., 1993).

Nowadays investigators can easily obtain lung tissue and bronchoalveolar lavage (BAL) specimens from the patients with asthma (Salvato, 1968; Djukanovic et al., 1991). Results of studies of BAL (Robinson et al., 1992) and lung tissue specimens (Minshall et al., 1998) have strongly implicated a role for cytokines produced by the Th2 subset of CD4+ T cells in the pathogenesis of asthma. For example, IL-13 plays an important role in regulating the airway inflammation in asthma (Wills-Karp et al., 1998; Zhu et al., 1999).

In recent years, there has been increasing interest in the mechanism of airway wall remodeling in asthma, owing to the increasing realization that airway inflammation alone is not enough to explain the chronicity or progression of asthma (Holgate et al., 1999). The nature of airway remodeling may be considered in terms of extracellular matrix deposition. Analysis of Asthma from a Pathological Point of View Essay. It is postulated that the injured airway epithelium acts as a continuous stimulus for airway remodeling (Holgate et al., 1999), and this is supported by results of recent cell culture experiments examining interactions of bronchial epithelial cells with myofibroblasts in response to injurious stimuli (Zhang et al., 1999). The remodeling is predicted to have little effect on baseline respiratory mechanics, the physiological effects of extracellular matrix accumulation are predicted to result in an exaggerated degree of narrowing for a given amount of airway smooth muscle (ASM) contraction.

Airway wall thickening is greater in the asthmatic patients than normal subjects, and severe patients have greater (Awadh et al., 1998). This thickness is due to an increase in ASM mass and mucous glands (Johns et al., 2000). The airflow limitation is also compounded by the presence of increased mucous secretion and inflammatory exudate (Chiappara et al., 2001). Thus, the results from many studies have supported that airway remodeling related to airway inflammation. Surprisingly, physical force generated by ASM in bronchoconstriction without additional inflammation induces airway remodeling in patients with asthma (Grainge et al., 2011). Despite these recent advances, further work is necessary to establish a causal relationship between airway remodeling and the severity of asthma (Bento and Hershenson, 1998).

AIRWAY EPITHELIUM

The structural changes in the asthmatic airway result from interdependent inflammatory and remodeling processes (Chiappara et al., 2001). In the processes, inflammation occurs common features, vascular congestion, exudaution, and inflammatory cell recruitment to the interstitial tissue. Furthermore mucus secretion and desquamation of epithelial cells are increased. The chronic inflammatory changes develop epithelium-mesenchymal interactions (Holgate et al., 2000). The number of myofibroblasts, which deposit collagens, increases in the understructure of epithelium, the proximity of the smooth muscle layer and the lamina reticularis in the patients. Subepithelial collagens cause thickening and increasing density of the basement membrane.Analysis of Asthma from a Pathological Point of View Essay.

The airway inflammation gives damage to the epithelium and damaged epithelial cells will be repaired in the injury-repair cycle. Some studies showed that epithelial cells of untreated asthmatic patients had low level expression of proliferating markers, despite extensive damage, revealing a potential failure in the epithelial injury-repair cycle in response to local inflammation and inhaled agents (Bousquet et al., 2000). Injury to the epithelium results in a localized and persistent increase in epidermal growth factor (EGF) receptor, a mechanism that may cause the epithelium to be locked in a repair phenotype (Puddicombe et al., 2000). Epithelial cells which are in repair phase produced some profibrotic mediators, including transforming growth factor-β (TGF-β), fibroblast growth factor and endothelin, which regulate fibroblast and myofibroblast to release collagen, elastic fiber, proteoglycan, and glycoprotein and these substances induce airway wall thickening (Holgate et al., 2000). Myofibroblast is a rich source of collagen types I, II, and V, fibronectin and tenascin that also accumulate in the airway wall and induce thickening lamina reticularis (Roche et al., 1989; Brewster et al., 1990). This process may contribute phenomena by augmentation of airway narrowing because the inner airway wall volume increases.

Eosinophils seem to contribute to airway remodeling in several ways, including through release of eosinophil-derived TGF-β, cationic proteins, and cytokines, as well as through interactions with mast cell and epithelial cells. Many of these factors can directly activate epithelium and mesenchymal cells, deeply related to the development of airway remodeling (Kariyawasam and Robinson, 2007; Aceves and Broide, 2008; Venge, 2010). Analysis of Asthma from a Pathological Point of View Essay. Eosinophil-derived cytokines are in the modulation of Th2 responses that trigger macrophage production of TGF-β1, which serves as a stimulus for extracellular matrix production (Fanta et al., 1999; Holgate, 2001). TGF-β1 induced epithelial to mesenchymal transition (EMT) in alveolar epithelial cells and could contribute to enhance fibrosis in idiopathic lung fibrosis (Wilson and Wynn, 2009). TGF-β1 might also contribute to enhance airway remodeling through EMT. Indeed, anti-TGF-β1 treatment inhibits EMT in airway epithelial cells (Yasukawa et al., 2013).

Airway epithelium is a barrier in the frontline against stimuli from the environment, but in asthmatic epithelium is defective in barrier function with incomplete formation of tight junctions, that prevent allergen from penetrating into the airway tissue (Xiao et al., 2011). The defect would induce that a proportion of the asthma-related had biological properties to infiltrate the epithelial barrier and trigger a danger signal to DCs. Components of house dust mite, cockroach, animal, and fungal can disrupt epithelial tight junctions and activate protease-activated receptors (Jacquet, 2011). The defective epithelial barrier function has also been described in the pathophysiology of other allergic disease. Therefore, healthy barrier function is important to avoid sensitization and development in allergic disease. Analysis of Asthma from a Pathological Point of View Essay.

AIRWAY SMOOTH MUSCLE

Abnormalities of asthmatic ASM structure and morphology have been described by Huber and Koesser (1922) in the first quarter of twentieth century when they reported that smooth muscle from the patients who died by acute exacerbation was increase much greater than in those who died from another disease. Airflow limitation mainly due to reversible smooth muscle contraction is a most important symptom of the disease. Therefore, ASM plays a material role in asthma. Abnormal accumulation of smooth muscle cells is another mechanism of airway remodeling. Some in vivo animal studies confirmed that prolonged allergen exposure increase smooth muscle thickness in the airway (Salmon et al., 1999). It is still unknown whether the phenomenon is occurred by fundamental changes in the phenotype of the smooth muscle cells, is caused by structural or mechanical changes in the non-contractile elements of the airway wall. There are two different ways by which cyclic generation of length and force could influence ASM contracting and airway narrowing. The processes, which are myosin binding and plasticity, have different biochemical and physical mechanisms and consequences. They have the potential to interact and to have a fundamental effect on the contractual capacity of smooth muscle and its potential to cause excessive airway narrowing (King et al., 1999).

Like other muscles, ASM is also provoked to contract with intracellular calcium ions (Ca²⁺), which comes from the extracellular environment through voltage-dependent calcium channel or from the sarcoplasmic reticulum stores (Figure ​Figure11). The source of Ca²⁺ surge in ASM is mainly from intracellular sarcoplasmic reticulum stores rather than from the extracellular Ca²⁺ seen in cardiac, skeletal, and vascular muscle cells. Ligands to G-ptotein coupled receptor (GPCR), such as acetylcholine and methacholine, induce the activation of phospholipase C (PLC), which in turn leads to the formation of the inositol triphosphate (IP₃; Chen et al., 2012). Then, IP₃ occurs to release Ca²⁺ from sarcoplasmic reticulum (SR) stores, then Ca²⁺ forms a calcium-calmodulin comlex, activates MLC kinase (MLCK) which phosphorylates regulatory MLCs (rMLCs) forming phosphorylated-MLC (p-MLC; Berridge, 2009). Finally, this mechanism occurs to the activation of actin and myosin crossbridges resulting in shortening and contraction (Gunst and Tang, 2000).Analysis of Asthma from a Pathological Point of View Essay.

And the contraction is also regulated by calcium sensitivity of myosin light chain (MLC; Kudo et al., 2012). The p-MLC is regulated by MLC phosphatase (MLCP) which converts p-MLC back to inactive MLC. MLCP is negatively controlled by Ras homolog gene family, member A (RhoA) and its target Rho Kinase such as Rho-associated, coiled-coil containing protein kinase (ROCK) which phosphorylates myosin phosphatase target subunit 1 (MYPT-1). Upregulation of the RhoA/Rho kinase signaling pathway inducing to inhibition of MLCP would result in increased levels of p-MLC and subsequently increased ASM contraction force. Increased levels of RhoA protein and mRNA were found in airway hyperresponsive animal models and this is probably medicated through inflammatory cytokines, such as IL-13 and IL-17A that themselves directly enhance the contractility of ASM (Chiba et al., 2009; Kudo et al., 2012). Analysis of Asthma from a Pathological Point of View Essay. For IL-17A, sensitized mouse conditional lacking integrin αvβ8 on DCs shows attenuated reactivity against IL-17A-induce antigen challenge. This is induced by that IL-17A itself enhances the contractile force of ASM, through RhoA/Rho kinase signaling change.

Airway smooth muscle cells also contribute to the inflammatory mechanisms and airway remodeling of asthma. The proactivating signals, including viruses and immunoglobulin E could convert ASM cells into a proliferative and secretory cell in asthma. Naureckas et al. (1999) demonstrated the presence of smooth muscle mitogens in the BAL fluids from asthmatic individuals who underwent allergen challenge. Smooth muscle proliferation is also caused by the production of matrix metalloproteinase (MMP)-2, which has been demonstrated to be an important autocrine factor that is required for proliferation (Johnson and Knox, 1999). Production of MMP-2 from smooth muscle cells suggests that ASM contributes to the extracellular matrix turnover and airway remodeling. These cells may also participate in chronic airway inflammation by interacting with both Th1- and Th2-derived cytokines to modulate chemoattractant activity for eosinophils, activated T lymphocytes, and monocytes/macrophages (Teran et al., 1999).

In addition, recent studies demonstrated that eosinophils can also contribute to airway remodeling during an asthma by enhancing ASM cell proliferation. Halwani et al. (2013) verified that preventing eosinophil contact with ASM cells using specific antibodies or blocking cysteinyl leukotrienes derived from eosinophils was associated with inhibition of ASM proliferation. Moreover, ASM-synthesized cytokines seem to direct the eosinophil differentiation and maturation from progenitor cells, which can promote perpetuation of eosinophilic inflammation and consequently the tissue remodeling in asthma (Fanat et al., 2009)Analysis of Asthma from a Pathological Point of View Essay..  It was also reported that TGF-β alone induces only weak mitogenic effect on ASM cells, however, it synergistically stimulates ASM proliferation with methacholine which is agonist for the muscarinic receptor (Oenema et al., 2013). These smooth muscle cell proliferations related to airway remodeling can be the target to treat asthma.

EPITHELIAL TO MESENCHYMAL TRANSITION ON ASTHMA

As airway remodeling on asthma attracts investigators interested in airway remodeling on asthma, EMTs are recognized to be more important in asthma than before. EMTs are biological processes that epithelial cells lose their polarity and cell adhesion resulted in fragility of tight junction and gain migratory and invasive properties to change their cell formation to mesenchymal cells (Kalluri and Neilson, 2003). It is essential for processes including mesoderm formation and neural tube formation in the development and recently has also been reported to involve in wound healing, in organ fibrosis and in cancer metastasis. First, EMTs were found in the embryogenesis. Epithelial cells are different from mesenchymal cells in their phenotype. Epithelial cells connect each other, forming tight junction. These cells have polarity in cytoskeleton and bound to basal lamina. For mesenchymal cells, the polarity is lost and shaped in spindle. Lately, EMTs are divided into three subtypes, developmental (Type I), fibrosis, tissue regeneration and wound healing (Type II), and cancer progression and metastasis (Type III; Kalluri and Weinberg, 2009).

Type II EMT involves in wound healing, resulted that it contributes airway remodeling in asthma after airway epithelial injury induced by inflammation. Type II EMT indicates that epithelial tissue can be expressed plasticity (Thiery and Sleeman, 2006). It is initiated by extracellular signals, such as connection with extracellular matrix; collagen or hyaluronic acids and by growth factors; TGF-β and EGF. Among those signals, TGF-β is established how it plays important role in airway remodeling and EMT (Phipps et al., 2004; Boxall et al., 2006; Hackett et al., 2009).  Analysis of Asthma from a Pathological Point of View Essay.TGF-β induces the expression of α-smooth muscle actin and vimentin and the downregulation of E-cadherin expression, inducing the dissolution of polarity of the epithelial cell and intercellular adhesion. The such physiological effects of TGF-β signaling in the system have been shown to depend on microenvironment. Bone morphogenesis protein (BMP)-7 fails to attenuate TGF-β-induced EMT, however, one of the family member BMP-4 plays the role of EMT in the airway (Molloy et al., 2008; Hackett et al., 2009). This TGF-β-induced attenuation of intercellular adhesion and wound repair in EMT can be enhanced by the proinflammatory cytokines tumor necrosis factor (TNF)-α (Camara and Jarai, 2010). Furthermore, it was showed that house dust mite, through EGF receptor enhanced TGF-β-induce downregulation of E-cadherin in the bronchial epithelial cells (Heijink et al., 2010). And house dust mite and TGF-β synergistically induced expression of mesenchymal markers vimentin and fibronectin. In chronic house dust mite-exposure model, the airway epithelial cells were shown to elevate TGF-β expression and nuclear phosphorylated Smad3. And in these cells, the tight-junction protein was dissolved, occluding and expressed α-smooth muscle actin and collagen (Johnson et al., 2011). Inhaled allergens might modify EMT, cooperating with cytokines which also promote asthma. Analysis of Asthma from a Pathological Point of View Essay

MAST CELLS AND EOSINOPHILS

Mact cells can induce the activation of mesenchymal cells (Holgate, 2000). The serine protease, tryptase which is released from degranulating mast cells is a potent stimulant of fibroblast and smooth muscle cell proliferation, and is capable of stimulating synthesis of type I collagen by human fibroblasts. A major mechanism involved in the regulation of fibroblast proliferation appears to be cleavage and activation of protease activated receptor-2 on fibroblasts (Akers et al., 2000). Mast cells may also influence the development of airway remodeling in asthma by releasing large amounts of plasminogen activator inhibitor type1. Moreover, Sugimoto et al. (2012) have shown that other mast cell proteases regulate airway hyperreactivity. Mice lacking αvβ6 integrin are protected from exaggerated airway narrowing. Mast cell proteases are differentially expressed, in mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in wild-type (WT) mice and mMCP-4 increased at baseline in β6-deficient mice. MCPs from intraepithelial mast cell and their proteolytic substrates could be regulate airway hyperreactivity.

Eosinophils are circulating granulocytes and at relatively low levels in the bloodstream, upto 3% of white blood cells. These are the major cell types that can be recruited to sites of inflammatory responses (Huang et al., 2009; Isobe et al., 2012; Uhm et al., 2012). The function of eosinophils in asthma is related to their release of toxic granule proteins, reactive oxygen species (ROS), cytokines, and lipid mediators (Liu et al., 2006). The recruit of eosinophils into the epithelium and eosinophilic inflammation is involved in the pathogenesis of asthma. Analysis of Asthma from a Pathological Point of View Essay. The proinflammatory mediators derived by eosinophil are major contributors to inflammation in asthma, including airway epithelial cell damage and desquamation, airway dysfunction of cholinergic nerve receptors, AHR, mucus hypersecretion, and airway remodeling, characterized by fibrosis and collagen deposition (Kay, 2005; Watt et al., 2005; Kanda et al., 2009; Walsh, 2010). Eosinophils are likely to contribute to airway remodeling with release of eosinophil-derived mediators such as TGF-β, secretion of cationic proteins, and cytokines, as well as having interactions with mast cell and epithelial cells. Those factors can directly activate epithelium and mesenchymal cells (Venge, 2010). Moreover, recent data demonstrated that eosinophils can also contribute to airway remodeling with ASM cell proliferation.

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EXTRACELLULAR MATRIX

The airways of asthmatic patients showed excess accumulation of extracellular matrix components, particularly collagen, in the subepithelial connective tissue and adventitia of the airway wall (Kuwano et al., 1993; Gillis and Lutchen, 1999). The cellular interactions in mast cells and fibroblasts through protease activated receptor-2 may contribute an abnormal mesenchymal cell proliferation, and may account for the increased number of fibroblasts and myofibroblasts that are found in the airways of asthmatic subjects. Fibroblasts retain the capacity for growth and regeneration, and may evolve into various cell types, including smooth muscle cells that subsequently become myofibroblasts. Myofibroblasts can contribute to tissue remodeling by releasing extracellular matrix components such as elastin, fibronectin and laminin (Vignola et al., 2000). It was seen that the numbers of myofibroblasts in the airway of asthmatic subjects increased and their number appeared to correlate with the size of the basement reticular membrane (Holgate et al., 2000). Smooth muscle cells also have the potential to alter the composition of the extracellular matrix environment. The reticular basement membrane thickening is a characteristic typical feature of the asthmatic airways. It appears to consist of a plexiform deposition of immunoglobulins, collagen types I and III, tenascin and fibronectin (Jeffery et al., 2000), but not of laminin.

Remodeling processes of the extracellular matrix are less known than the thickening of the lamina reticularis. Most asthmatic subjects present with an abnormal superficial elastic fiber network, with fragmented fibers (Bousquet et al., 2000). In the deeper layer of elastic fibers is also abnormal, the fibers often being often patchy, tangled, and thickened. Analysis of Asthma from a Pathological Point of View Essay. Some studies using transmission electron microscopy have shown that an elastolytic process occurs in asthmatic patients, and in some patients disruption of fibers has been observed. In the case of fatal asthma, fragmentation of elastic fiber has also been found in central airways, and was associated with marked elastolysis (Mauad et al., 1999). These bundles are seen to be hypertrophied as a result of an increased amount of collagen and myofibroblast matrix deposition occurring during exaggerated elastic fiber deposition (Carroll et al., 1997). Loss of lung elastic recoil force has been shown in adults with persistent asthma and irreversible expiratory airflow obstruction. Persistent asthmatic patients have severe abnormal flow-volume curves in expiration at both high and low lung volumes, and hyperinflation can be seen by residual volume, at forced residual capacity and total lung capacity (Gelb and Zamel, 2000). The increased elastolysis is part of a more complex process that regulates the size of a submucosal network formed by elastic fibers dispersed in a collagen and myofibroblast matrix (Chiappara et al., 2001). These features induce changes in airway, as demonstrated by airway compliance, particularly in those patients who are suffering from asthma for long period, supporting the concept that chronic inflammation and remodeling of the airway wall may result in stiffer dynamic elastic properties of the asthmatic airway (Brackel et al., 2000). Furthermore, disruption of elastic fibers may contribute to a reduction in the preload and afterload for smooth muscle contraction. Though it is difficult to associate aspects of remodeling with disease severity or degree of airways obstruction and hyperresponsiveness (Mauad et al., 2007), some investigators indicated that smooth muscle remodeling is related to the severity of asthma (James et al., 2009). It has shown that the clinical expression of asthma (Brightling et al., 2002), AHR (Siddiqui et al., 2008) and impaired airway relaxation (Slats et al., 2007) are associated with mast cell counts in the ASM layer in asthma. The deposition of extracellular matrix inside and outside the smooth muscle layer in asthma also seems to be related to its clinical severity and is altered as compared to healthy controls (Araujo et al., 2008; Klagas et al., 2009). Yick et al. (2012) have shown that extracellular matrix in ASM was related to the dynamics of airway function in asthma. Analysis of Asthma from a Pathological Point of View Essay.