Remodeling in asthma

Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.     

Airway smooth muscle: a modulator of airway remodeling in asthma

Asthma is a disease characterized, in part, by airway hyperresponsiveness and inflammation. Although asthma typically induces reversible airway obstruction, in some patients with asthma, airflow obstruction can become irreversible. Such obstruction might be a consequence of persistent structural changes in the airway wall caused by the frequent stimulation of airway smooth muscle (ASM) by contractile agonists, inflammatory mediators, and growth factors. Traditional concepts concerning airway inflammation have focused on trafficking leukocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Recent studies suggest that ASM cells might modulate airway remodeling by secreting cytokines, growth factors, or matrix proteins and by expressing cell adhesion molecules and other potential costimulatory molecules. These ASM cell functions might directly or indirectly modulate submucosal airway inflammation and promote airway remodeling.     

Cytokines and growth factors in airway remodeling in asthma

Airway remodeling in asthma is defined by several structural changes including epithelial cell mucus metaplasia, an increase in peribronchial smooth muscle mass, subepithelial fibrosis, and angiogenesis. Cytokines, chemokines, and growth factors released from inflammatory and structural cells in the airway are considered to play a pivotal role in the development of remodeling. Studies of allergen induced airway remodeling in transgenic mice suggest an important role for TGF-beta, VEGF, Th2 cytokines (IL-5, IL-9, IL-13), and epithelial derived NF-kappaB regulated chemokines in airway remodeling. Although studies of bronchial biopsies from human asthmatics also demonstrate expression of TGF-beta, VEGF, IL-5, IL-9, IL-13, and NF-kappaB regulated chemokines, further human intervention studies are required in which individual cytokines or chemokines are neutralized to define their role in airway remodeling.     

Regulation of airway smooth muscle cell immunomodulatory function: role in asthma

General agreement exists that in asthma, airway smooth muscle contracts, narrowing the airway lumen and thereby causing airflow obstruction and dyspnoea. New evidence is emerging that airway smooth muscle may also fulfil an immunomodulatory role by providing a rich source of pro-inflammatory cytokines and chemokines, polypeptide growth factors, extracellular matrix (ECM) proteins, cell adhesion receptors and co-stimulatory molecules. Together, the available data support a role for airway smooth muscle in actively perpetuating airway mucosal inflammatory processes including mast cell and leukocyte (T cell, neutrophil, eosinophil) activation and recruitment. Production of anti-inflammatory mediators by airway smooth muscle such as prostaglandin E(2) suggests that it is also capable of exerting a 'braking' effect on local inflammation. Recognition of this newly described property of airway smooth muscle makes it important to consider therapeutic targets for suppressing the synthesis and secretion of immunomodulatory mediators from this cell. However, it remains imperative to establish to what extent the secretory potential of airway smooth muscle is quantitatively important in vivo and in asthmatic subjects.     

Factors controlling smooth muscle proliferation and airway remodelling

It is clear that airway smooth muscle plays an important role in the hyperresponsiveness and remodelling that occur in the asthmatic airway. This is by virtue of its roles as a contractile cell, a cell that undergoes proliferation as part of the inflammatory response, a cell that actively participates in the inflammatory response via the production of cytokines and chemokines, and perhaps as a cell that undergoes migration. Now that airway smooth muscle cells cultured from asthmatic patients have been studied in vitro, it is apparent that there is an abnormality in the growth of these cells such that they grow more rapidly than cells derived from nonasthmatic patients. This raises the possibility of identifying the exact point(s) in the signal transduction pathways at which this abnormality occurs. To do this it is necessary to define precisely the mitogenic pathways that lead to proliferation in the airway smooth muscle cell, and this information is accumulating rapidly. The possibility is raised for new therapeutic targets that are aimed specifically at the airway smooth muscle, leading to an effective method for reversing or preventing the airway remodelling that accompanies chronic severe asthma.     

The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma

While asthma is an inflammatory disorder of the airways involving mediator release from mast cells and eosinophils and orchestrated by T cells, inflammation alone is insufficient to explain the chronic nature of the disease and its progression. Evidence is presented that the epithelium is fundamentally disordered in chronic asthma manifest by increased fragility, and an altered phenotype to one that secretes mucus, mediators, cytokines, chemokines and growth factors. Epithelial injury is mediated by exogenous factors such as air pollutants, viruses and allergens as well as by endogenous factors including the release of proteolytic enzymes from mast cells (tryptase, chymase) and eosinophils (MMP-9). Following injury, the normal epithelium should respond with increased proliferation driven by ligands acting on epidermal growth factor (EGF) receptors or through transactivation of the receptor. The epithelial response to these stimuli in asthma appears to be impaired despite upregulation of CD44 capable of enhancing presentation of EGF ligands to epidermal growth factor receptors (EGFR). Because the epithelium is 'held' in this repair phenotype, it becomes a continuous source of proinflammatory products as well as growth factors that drive airway wall remodelling.     

Exercise-induced asthma: is it the right diagnosis in elite athletes?

Exercise-induced asthma, as recognized in asthmatic subjects, is an exaggerated airway response to airway dehydration in the presence of inflammatory cells and their mediators. The airway narrowing is primarily caused by contraction of bronchial smooth muscle. The milder airway narrowing documented in response to exercise in elite athletes and otherwise healthy subjects may simply be the result of the physiologic responses and pathologic changes in airway cells arising from dehydration injury. These changes, which include excessive mucus production and airway edema, would serve both to cause cough and to amplify the narrowing effects of normal bronchial smooth muscle contraction, resulting in symptoms. These changes are more likely to occur in healthy subjects who exercise intensely for long periods of time breathing cold air, dry air, or both. Under these conditions, the ability to humidify inspired air may be overwhelmed, causing significant dehydration of the airway mucosa and an increase in osmolarity, even in small airways. In addition to dehydration injury, airway narrowing to pharmacologic and physical agents may occur as a result of injury caused by large volumes of air containing irritant gases, particulate matter, or allergens being inspired during exercise. As a result, the airways may become inflamed, and the airway smooth muscle may become more sensitive. These events could result in the same exaggerated airway response to dehydration, as documented in asthmatic subjects.     

Differences in airway remodeling between asthma and chronic obstructive pulmonary disease

The functional consequence of asthma and chronic obstructive pulmonary disease (COPD) is airflow limitation, which is mostly reversible in asthma and not fully reversible in COPD. In both diseases, inflammatory conditions are associated with cellular and structural changes, referred to as remodeling, and these structural changes may lead to thickening of the airway wall, thereby promoting airway narrowing and airflow limitation. However, the pattern of infilatrated cells and the pattern of structural changes occur differently in the two diseases. In asthma, CD4+, T lymphocytes, eosinophils, and mast cells are the predominant cells involved, whereas COPD, CD8+, T lymphocytes, and macrophages are predominantly involved. In severe cases of asthma and COPD, neutrophil infiltration becomes evident. Regarding structural changes, epithelial injury and early thickening of reticular basement membrane are highly characteristic of the airway wall of asthmatics. Increases in airway smooth muscle mass occur in large airways of severe asthmatics and in small airways of patients with COPD. Thickening of the airway wall, golblet cell hyperplasia, mucous gland hypertrophy, and the luminal obstruction caused by inflammatory exudates and mucous are features of both asthma and COPD. Squamous epithelial metaplasia and airway wall fibrosis are commonly observed characteristics of COPD. Destruction and fibrosis of the alveolar wall occur in COPD but not in asthma. The remodeling processes accompanied by chronic inflammatory infiltrates interact in a complex fashion and contribute to the development of airflow limitation in both asthma and COPD.     

Endotoxin and pro-inflammatory cytokines stimulate endothelin-I expression and release by airway epithelial cells

Endothelin is a potent bronchoconstrictor peptide first identified as a novel vasoconstrictor produced by vascular endothelial cells. Recent reports suggest that airway epithelial cells are also capable of releasing this active peptide. To investigate the regulatory mechanism of endothelin expression, we studied the effects of endotoxin and pro-inflammatory cytokines such as interleukin-1 and tumour necrosis factor on the expression and release of endothelin-1 by airway epithelial cells. Both endotoxin and the cytokines stimulated endothelin-1 release by human bronchial epithelial cells. Northern blot analysis showed increased expression of preproendothelin-1 mRNA by these factors. These results suggested that airway epithelial cells might play a role in the local airway smooth muscle tone through the production of endothelin, which might be upregulaled by inflammatory products in the airways.     

Bronchial hyperresponsiveness and airway wall remodelling induced by exposure to allergen for 9 weeks.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.     

The impact of the prostaglandin D2 receptor 2 and its downstream effects on the pathophysiology of asthma

Current research suggests that the prostaglandin D₂ (PGD₂) receptor 2 (DP₂) is a principal regulator in the pathophysiology of asthma, because it stimulates and amplifies the inflammatory response in this condition. The DP₂ receptor can be activated by both allergic and nonallergic stimuli, leading to several pro-inflammatory events, including eosinophil activation and migration, release of the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 from T helper 2 (Th2) cells and innate lymphoid cells type 2 (ILCs), and increased airway smooth muscle mass via recruitment of mesenchymal progenitors to the airway smooth muscle bundle. Activation of the DP₂ receptor pathway has potential downstream effects on asthma pathophysiology, including on airway epithelial cells, mucus hypersecretion, and airway remodelling, and consequently might impact asthma symptoms and exacerbations. Given the broad distribution of DP₂ receptors on immune and structural cells involved in asthma, this receptor is being explored as a novel therapeutic target.     

The role of mast cells and basophils in inflammation

Mast cells are positioned in the asthmatic airways so that they are able to respond to the inhaled environment. During active disease, the cells are primed to secrete an array of preformed and newly generated inflammatory mediators including histamine, neutral proteases and heparin sulphate, prostaglandins and cysteinyl leukotrienes as well as an array of cytokines and chemokines that are involved in leucocyte recruitment and activation. These cells are a potent source of mediators in both allergen- and exercise-induced asthma and possibly in asthma provoked by other stimuli such as adenosine and inhaled air pollutants. The important role played by mast cells in maintaining airway dysfunction in asthma is underpinned by the efficacy of mediator inhibitors, such as those interfering with the release or action of the leukotrienes, agents that inhibit mast cell activation such as sodium cromoglycate and the recently studied E-20 humanized monoclonal antibody that binds to and removes IgE. The recent discovery of novel inhibitory pathways involving inhibitory motifs (ITIMS) on critical cell surface signalling molecules has opened up new possibilities for preventing mast cell activation. Future research will focus on more effective ways for inhibiting the mast cell's contribution to asthma and understanding what role this unique cell has in the pathogenesis of airway wall remodelling.     

Modulation of calcium homeostasis as a mechanism for altering smooth muscle responsiveness in asthma

Airway hyperresponsiveness remains a defining characteristic of asthma. Traditional views assert that airway smooth muscle is an important structural effector cell in the bronchi that modulates bronchomotor tone induced by contractile agonists. New evidence, however, suggests that abnormalities in airway smooth muscle functions, induced by variety of extracellular stimuli, may play an important role in the development of airway hyperresponsiveness. Studies using isolated bronchial preparations or cultured cells show that inflammatory mediators and cytokines may alter calcium homeostasis in airway smooth muscle and render the cells nonspecifically hyperreactive to agonists.     

Epithelial differentiation is a determinant in the production of eotaxin-2 and -3 by bronchial epithelial cells in response to IL-4 and IL-13

The composition of the airway epithelium is dynamic and epithelial differentiation is regulated by endogenous mediators as well as inhaled substances. In atopic asthma the differentiation of the epithelium is altered. Various studies have addressed the ability of cultured airway epithelial cells to release the eosinophil-attractant chemokines eotaxin, eotaxin-2 and eotaxin-3 using epithelial cell lines or poorly differentiated primary cells. Since little is known about the role of the epithelial differentiation state in the response of epithelial cells to stimuli that increase production of mediators such as the eotaxins, we analyzed the effect of differentiation state on the production of the eotaxins. In particular, we investigated the effects of the Th2 cytokines IL-4 and IL-13 on eotaxin-2 and -3 production by primary human bronchial epithelial cells and examined whether their production is affected by epithelial cell differentiation using both submerged and air-liquid interface (ALI) cultures. The results show that both IL-4 and IL-13 increase eotaxin-2 and -3 mRNA expression and protein release in submerged- and ALI-cultures. Moreover, epithelial differentiation in ALI-cultures appeared an important determinant in the regulation of eotaxin-2 and -3. Mucociliary differentiation of the epithelial cells was induced by culture in the presence of a high concentration of retinoic acid (RA), whereas low concentrations of RA resulted in a flattened squamous epithelial phenotype. Mucociliary differentiated ALI-cultures expressed and released more eotaxin-3 upon stimulation with IL-4/IL-13, whereas eotaxin-2 production was predominantly found in squamous differentiated ALI-cultures. TNFalpha reduced IL-4-induced eotaxin-2 release in submerged cultures but not in ALI-cultures; no effects on eotaxin-3 synthesis were observed. The results indicate that epithelial differentiation is an important determinant in Th2 cytokine-induced eotaxin-2 and -3 release by airway epithelial cells. These findings may provide new insights into the role of airway epithelial differentiation and Th2 cytokines in the pathogenesis of inflammatory lung disorders such as asthma.     

How Much Do We Know about Atopic Asthma： Where Are We Now？

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.     

Mast cell myositis: a new feature of allergic asthma?

There is some evidence that, in asthma, mast cells infiltrate the airway smooth muscle layer and, as a consequence, alter the functional and structural properties of myocytes. This inflammation so-called mast-cell myositis, probably contributes to both bronchial hyperresponsiveness and airway remodelling. Previous observations have pointed out the presence of mast cells within airway smooth muscle of atopic patients and recent data obtained in asthmatic patients demonstrate that this infiltration is more important in asthmatic patients with atopy. Although the mechanism of such a mast cell attraction remains to be fully understood, experimental data demonstrate that, upon stimulation by tryptase or cytokines, smooth muscle cells can attract mast cells through the production of TGF-beta1 or SCF. Once at the site of inflammation, activated mast cells are responsible for an important extracellular deposition of inflammatory products that may facilitate the increase in smooth muscle mass. In addition, comparison of asthmatic patients with and without atopy suggests that mast cell myositis is closely related with atopy.     

Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma

Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness. Acute and chronic inflammation is orchestrated by cytokines from recruited inflammatory cells, airway myofibroblasts and myocytes. Airway myocytes exhibit functional plasticity in their capacity for contraction, proliferation, and synthesis of matrix protein and cytokines. This confers a principal role in driving different components of the airway remodeling process, and mediating constrictor hyperresponsiveness. Functional plasticity of airway smooth muscle (ASM) is regulated by an array of environmental cues, including cytokines, which mediate their effects through receptors and a number of intracellular signaling pathways. Despite numerous studies of the cellular effects of cytokines on cultured airway myocytes, few have identified how intracellular signaling pathways modulate or induce these cellular responses. This review summarizes current understanding of these concepts and presents a model for the effects of inflammatory mediators on functional plasticity of ASM in asthma.     

Epithelium-derived chemokines induce airway smooth muscle cell migration

Background The remodelling of airway smooth muscle (ASM) associated with asthma severity may involve the migration of ASM cells towards the epithelium. However, little is known about the mechanisms of cell migration and the effect of epithelial-derived mediators on this process.
Objective The main objective of the current study is to assess the effects of epithelial-derived chemokines on ASM cell migration.
Methods Normal human ASM cells were incubated with supernatants from cells of the bronchial epithelial cell line BEAS-2B and normal human bronchial epithelial (NHBE) cells. To induce chemokine production, epithelial cells were treated with TNF-α. Chemokine expression by epithelial cells was evaluated by quantitative real-time PCR, ELISA and membrane antibody array. To identify the role of individual chemokines in ASM cell migration, we performed migration assays with a modified Boyden chamber using specific neutralizing antibodies to block chemokine effects.
Results Supernatants from BEAS-2B cells treated with TNF-α increased ASM cell migration; migration was increased 1.6 and 2.5-fold by supernatant from BEAS-2B cells treated with 10 and 100 ng/mL TNF-α, respectively. Protein levels in supernatants and mRNA expression by BEAS-2B cells of regulated on activation, normal T cell expressed and secreted (RANTES) and IL-8 were significantly increased by 100 ng/mL TNF-α treatment. The incubation of supernatant with antibodies to RANTES or IL-8 significantly reduced ASM cell migration, and the combined antibodies further inhibited the cell migration. The migratory effects of supernatants and inhibiting effects of RANTES and/or IL-8 were confirmed also using NHBE cells.
Conclusion The results show that chemokines from airway epithelial cells cause ASM cell migration and might potentially play a role in the process of airway remodelling in asthma.