The role of the mast cell in the pathophysiology of asthma

There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma.     

Ultrastructure of airways in children with asthma

This study describes the histopathology and ultrastructure of bronchial mucosa in lung biopsies from two children with bronchial asthma in remission, and compares them with lung samples from two children who died in status asthmaticus. Light microscopy of all samples showed changes typical of bronchial asthma, e.g. mucus plugging, goblet cell hyperplasia, 'thickening of bronchial basement membrane', peribronchial smooth muscle hypertrophy and eosinophilic infiltration. Electron microscopy revealed that the mucus plugs consisted of moderately electron-dense floccular material containing degenerate epithelial cells, macrophages and cell fragments. The luminal surfaces of ciliated cells showed cytoplasmic blebs and abnormal cilia. Mast cells in various stages of degranulation were scattered between bronchial epithelial cells. The subepithelial hyaline layer, commonly referred to as "thickened basement membrane", consisted of collagen fibrils in plexiform arrangement. The basement membrane proper appeared intact. These electron microscopic changes, particularly the presence of mast cells and subepithelial collagen deposits, were also found in autopsy samples. This combined light and electron microscopic study shows that marked, possibly irreversible changes may be present in the lungs of patients with severe bronchial asthma, even when they are asymptomatic. These pulmonary changes could be the direct consequence of mast cell activation and the release of various mediators. No evidence of immune complex deposition was found.     

肥大细胞在支气管哮喘中的研究进展

支气管哮喘(哮喘)是呼吸系统的常见病和多发病,肥大细胞是其主要的反应细胞,目前关于肥大细胞在哮喘中作用的研究取得了新的进展,特别是肥大细胞蛋白酶及其抑制剂的深入研究和哮喘患者气道平滑肌束中肥大细胞数量明显增加并呈脱颗粒状态的发现,引起学者们极大的关注,本文将就肥大细胞在哮喘中的研究进展进行综述。     

Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways

BACKGROUND: Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. OBJECTIVE: The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. METHODS: Four experimental groups were formed: allergic asthma and rhinitis (n = 19); allergic rhinitis, no asthma (n = 18); atopic subjects, no asthma, no rhinitis (n = 8) and non-allergic healthy control subjects (n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer-assisted image analysis system. RESULTS: In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics (P < 0.05) and controls (P < or = 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics (P < 0.05) and controls (P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils (P = 0.05) and skin test reactivity (P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL-5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics (P < 0.001), but also in atopics without asthma and rhinitis (P = 0.02). CONCLUSIONS: This study shows that allergic inflammation, increased basement membrane thickness and epithelial desquamation are present in the lower airways of atopic subjects, even before the onset of clinical symptoms. Despite the presence of inflammatory cells, no structural changes could be assessed in nasal mucosa of allergic patients.     

Angiogenesis in asthma

Asthma is a chronic inflammatory disease of the airways characterized by infiltration and activation of inflammatory cells and by structural changes, including subepithelial fibrosis, smooth muscle cells hypertrophy/hyperplasia, epithelial cell metaplasia and angiogenesis. These structural changes are thought to correlate with asthma severity and to account for the development of progressive lung function deterioration. The mechanism underlying airway angiogenesis in asthma and its precise clinical relevance have not yet been completely elucidated. This review provides recent data showing the contribution of allergic inflammation in increased airway vascularity and potential therapeutical approaches in asthma treatment by acting on bronchial microvascular changes.     

Immunohistochemical characterization of the cellular infiltrate in airway mucosa of toluene diisocyanate (TDI)-induced asthma: comparison with allergic asthma.

Toluene diisocyanate (TDI) is the most prevalent agent in occupational asthma (OA) in Korea. The immuno-pathologic mechanism for TDI-induced bronchoconstriction remains to be clarified. We studied the immunohistochemical finding of inflammatory cells in bronchial mucosa in subjects with TDI-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with TDI-induced asthma. Six allergic asthma sensitive to house dust mite were enrolled as controls. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies to mast cell tryptase (AA1), secretary form of eosinophil cationic protein (EG2), pan T-lymphocyte (CD3) and neutrophil elastase (NE). There was a significant increase in the number of AA1+, EG2+ and NE+ cells in TDI-induced asthma compared to those of allergic asthma (p=0.02, p=0.04, p=0.03, respectively). No significant differences were observed in the number of CD3+ cells (p=0.27). These findings support the view that neutrophil recruitment together with eosinophil and mast cell, may contribute to the bronchoconstriction induced by TDI.     

Nerve-mast cell and smooth muscle-mast cell interaction mediated by cell adhesion molecule-1, CADM1.

Mast cells are a native composer of connective tissue of the skin dermis and intestinal and respiratory mucosa. Independent lines of accumulated evidence indicate the existence of an intensive bidirectional crosstalk between mast cells and sensory nerves and suggest that mast cells and sensory nerves may be viewed as a functional unit, which could be of crucial importance in neuroimmunological pathways. Mast cells appear to have a property of influencing smooth muscle function via not only such nerve-mast cell effects, but also direct pathways. In bronchial asthma, mast cells infiltrate the airway smooth muscle layer, and interact directly with smooth muscle cells, suggesting pathogenic roles for mast cells in airway obstruction. Current studies on mast cell biology identified a novel adhesion molecule of mast cells, namely cell adhesion molecule-1, CADM1. This molecule is unique, because it serves as not only simple glue but also appears to promote functional communication between nerve and mast cells and between smooth muscle and mast cells.     

Mast cells regulate procollagen I (alpha 1) production by bronchial fibroblasts derived from subjects with asthma through IL-4/IL-4 delta 2 ratio

BACKGROUND: Asthma is characterized by inflammation and remodeling. Mast cells are generally increased in bronchial mucosa of subjects with asthma. These cells release a wide variety of cytokines and mediators that have the capacity to stimulate other resident cells such as smooth muscle cells and fibroblasts. OBJECTIVE: This study was designed to evaluate whether mast cells modulate collagen production by bronchial fibroblasts isolated from subjects with asthma and normal subjects through cytokine production. METHODS: Human mast cells were cocultured for 72 hours with primary bronchial fibroblasts isolated from bronchial biopsies of subjects with mild asthma and normal controls. Procollagen I (alpha1), IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2 gene expression by bronchial fibroblasts and IL-4 and IL-4delta2 gene expression by mast cells were quantified by real-time RT-PCR. IL-4 production was also measured by ELISA in culture supernatants. RESULTS: Procollagen I (alpha1) gene expression by fibroblasts from subjects with asthma was significantly higher compared with cells from normal controls when cocultured with mast cells. Mast cells expressed IL-4 isoform and IL-4delta2, an alternative splice variant of IL-4. Coculture significantly increased the expression of IL-4 but not IL-4delta2 by mast cells when they were cultured with fibroblasts from subjects with asthma compared with cells from normal controls. Neutralization of IL-4 abrogated collagen mRNA expression. There was no significant change in IL-4Ralpha or IL-13Ralpha1. However, IL-13Ralpha2 gene expression was significantly reduced in fibroblasts from subjects with asthma. CONCLUSION: These results suggest that inflammatory process may regulate airway remodelling through crosstalk between inflammatory and structural cells. Targeting this crosstalk may have therapeutic application. CLINICAL IMPLICATIONS: Understanding mechanisms that govern airway remodeling and collagen deposition in asthma is a step toward therapeutic management of this disease. In this work, we found that mast cell-fibroblast crosstalk may be a potential future target to control some aspects of airway remodeling.     

Identification of basophils by immunohistochemistry in the airways of post-mortem cases of fatal asthma

There is increasing evidence for the role of basophils in the pathogenesis of bronchial asthma. To examine the presence of basophils in the airways of patients with fatal asthma by immunohistochemistry, we stained lung tissues from four post-mortem cases who had died from severe asthmatic attacks and four controls with a monoclonal antibody raised against tryptase (AA-1) and anti-IgE. Mast cells and basophils were identified in the bronchioles as AA-1- and anti-IgE-positive cells, and anti-IgE-positive cells, respectively. Airway mast cells were found beneath the basement membrane, near blood vessels in the submucosa, and adjacent to the submucosal glands, and scattered throughout the muscle bundles. There was a significant increase of mast cells in the asthma group compared with the control group (203.5+/-84.6/mm2, mean+/-s.d. vs 37.7+/-8.7/mm2, P<0.05, n=4). In contrast, basophils were observed in the airway lumen, in the bronchial epithelium and in the submucosa. The number of basophils in the bronchioles was 81.8+/-55.5/mm2 (n = 4); however, basophils were not found at all in the airways of the control group. Although eosinophils, B lymphocytes and macrophages bear low affinity IgE receptors and could react with anti-IgE, the location of these cells in the close sections did not correspond closely with basophils. The presence of basophils in lung tissues obtained from fatal asthma patients supports the view that basophils play a role in the pathogenesis of bronchial asthma.     

Bronchial blood flow and microvascular permeability in the pathophysiology of asthma

Bronchial smooth muscle contraction is not the only causative factor of airway narrowing in asthma. Other components, such as mucosal and submucosal oedema and mucosal inflammation, also intervene in the processes leading to bronchial obstruction. Re-analyzing the role of the tracheo-bronchial circulation is therefore necessary, since participation of the latter, through modification of bronchial blood flow and/or alteration of microvascular permeability, very likely modifies mucosal thickness of the bronchial wall and/or clearance of bronchoactive substances from the airways. This also implies that more attention should be paid on the vascular actions of compounds which are either currently prescribed or under development for future treatment of asthma.     

Physiopathology of asthma

Bronchial asthma is a unique disease; knowledge of the pathophysiology increases rapidly and underlines that is more a syndrome than a disease. Indeed a new definition has been recently proposed: desquamative eosinophilic chronic bronchitis. The airway obstruction, which is responsible for the wheezing breathlessness, is the consequence of a spasm but also an inflammation. After activation of the resident cells in the airways (mast cells, epithelial cells and alveolar macrophages), mediators are released and - in cooperation with the nervous system-recruit inflammatory cells from blood and bone marrow (mainly eosinophils). A kind of vicious circle seems to amplify the initial (allergic or not) event. Desquamation of the epithelium and disposition of collagen on the basement membrane take a quite long time to be cleared after an asthma attack. Mechanisms of repair must be studied in order to improve treatment. Bronchial asthma is not really a disease; indeed a lot of precipitating agents are able to induce and increase bronchial hyperreactivity. Allergy is the most important factor; but environment, hormones and other infectious agents could be quite important in many patients.     

钙调素在豚鼠过敏性哮喘发病过程中的作用

目的和方法：给致敏豚鼠吸入卵蛋白建立速发型过敏性哮喘的动物模型,观察呼吸系总阻抗（ＲＩ）及豚鼠支气管平滑肌钙调素（ＣａＭ）活性的变化。结果：哮喘组ＲＩ明显高于正常组（Ｐ〈０．０１）,支气管平滑肌ＣａＭ活性低于正常组（Ｐ〈０．０５）,山莨菪碱（６５４－２）有增加支气管平滑肌ＣａＭ活性的作用,异搏定对其无影响。结论：支气管平滑肌ＣａＭ活性下降在哮喘的发病过程中起重要作用。     

Dynamics of mast cells in the nasal mucosa of patients with allergic rhinitis and non-allergic controls: a biopsy study

Mast cell degranulation is thought to be an important component of the pathogenesis of allergic rhinitis. Quantitative studies on mast cells in nasal mucosa after allergen exposure have given widely divergent results, ranging from an overall decrease via redistribution to an overall increase. We investigated this problem by employing a combination of anti-IgE and toluidine blue staining of biopsy specimens. In allergic patients anti-IgE was found to identify all mast cells and toluidine blue to detect mast cells that were not (totally) degranulated. The study was composed of two parts done in different patient groups. In the first part of the study biopsies were performed in 23 patients with isolated grass-pollen allergy, once during natural provocation in the summer and once in the winter. Biopsies were also performed in 12 controls. Non-allergic controls were found to have the same number of mast cells in the lamina propria as asymptomatic allergic patients. The controls seldom have mast cells in the epithelium. The patients with isolated grass-pollen allergy showed an increase in the numbers of mast cells in the lamina propria during natural provocation and the same seemed to occur in the epithelium as well. During natural provocation almost all of the mast cells in the epithelium and half of those in the lamina propria were degranulated. In the second part of the study 17 patients with isolated grass-pollen allergy and four controls were challenged daily with allergen extract during a 2-week period in the winter. During this period biopsies were performed at eight different occasions, i.e. once before, six occasions during and once after the provocation period. The results of this part of the study showed that during provocation mast cells migrate to the surface of the nasal mucosa, where they become degranulated, and that the pool of mast cells in the lamina propria was apparently replenished by migration of mast cells from the vessels in the lamina propria. The total number of mast cells in the lamina propria remained approximately the same while the mast cells residing in an increasingly thick layer measured from the basal membrane into the lamina propria became degranulated. After 2 weeks, 82% of the mast cells in the lamina propria was degranulated and it was only in the deepest layers that some toluidine blue positive cells were found.(ABSTRACT TRUNCATED AT 400 WORDS)     

The role of the mast cell in asthma: induction of airway hyperresponsiveness by interaction with smooth muscle?

In a recent study, the difference between asthma and eosinophilic bronchitis (a condition characterized by cough but not airway hyperresponsiveness or airflow obstruction) was infiltration of airway smooth muscle (ASM) by mast cells. Mast cells produce a variety of lipid mediators, chemokines, cytokines, and enzymes that may interact with ASM cells to cause hyperreactivity to constrictive stimuli and proliferation, and activated ASM can produce stem cell factor and other chemokines, cytokines, and growth factors that may act in recruitment, differentiation, and retention of mast cells. Mast cell infiltration of the airways in asthma is T-cell-dependent, and TH2 cytokines from T cells and other sources act in mast cell expansion from circulating and tissue precursors. The recent data on interactions of mast cells and ASM suggest that this could be an important contributor to airway hyperresponsiveness in asthma. Why this occurs in asthma and how it is sustained remain to be established.     

Airway remodelling in the pathogenesis of asthma

The inflammatory and remodelling processes that underlie asthma result from a highly complex interaction between various cell types. Apart from inflammatory cells, such as eosinophils, activated T cells, mast cells and macrophages, structural tissue cells such as epithelial cells, fibroblasts and smooth muscle cells can also play an important effector role through the release of a variety of mediators, cytokines and chemokines. This results in an acute inflammatory response that is characterized by vascular leakage, mucus hypersecretion, epithelial shedding and widespread airway narrowing. At the same time, through the release of mediators, cytokines, chemokines and growth factors, epithelial and mesenchymal cells cause persistence of the inflammatory infiltrate and induce structural changes in the airway wall, such as increased thickness of the basement membrane, increased collagen deposition, changes in bronchial microcirculation, and smooth muscle hypertrophy and hyperplasia. The end result of airway inflammation and remodelling is an increased thickness of the airway wall, leading to a reduced baseline airway calibre and exaggerated airway narrowing.     

Issues in exercise-induced asthma

It is concluded that challenge by exercise and ISH induces asthma by the same mechanism, the protective effect of water vapor is evidence that the events that lead to bronchial smooth muscle contraction begin in the airway lumen, it is the loss of water rather than the loss of heat from the airways that is the primary stimulus to EIA and HIA, the mechanism by which water loss induces asthma is by increasing the osmolarity of the epithelial fluid, in some subjects with asthma, cooling of the airways enhances the response to water loss, the increase in osmolarity stimulates the production and release of bronchoactive substances from mast cells and epithelial cells, vagal afferent pathways are activated by changes in osmolarity and by the released mediators, and vagal efferent activity may be modified by alpha-adrenoceptor antagonists and SCG.     

Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma

BACKGROUND: Airway smooth muscle infiltration by mast cells is a feature of asthma and not eosinophilic bronchitis. In asthma, Th2 cytokines have been implicated as playing a critical role in the development of airway inflammation and hyper-responsiveness. Whether inflammatory cells within the airway smooth muscle release these cytokines is unknown. METHODS: We have undertaken a comparative immunohistochemical study in bronchial biopsies from 14 subjects with asthma, 10 with eosinophilic bronchitis and eight normal controls recruited from two centres. RESULTS: The median number of IL-4+ cells/mm2 smooth muscle was significantly higher in subjects with asthma than eosinophilic bronchitis and normal controls for both the anti-IL-4 mAb 3H4 (2.4, 0, 0, respectively; P=0.001) and anti-IL-4 mAb 4D9 (1.6, 0, 0, respectively; P=0.02). There were no group differences in the number of IL-5+ cells (P=0.31). In six subjects with asthma, IL-13 expression by cells within the airway smooth muscle was studied. The median (range) of IL-13+cells was 2 (0.9-2.7). Ninety-four percent of the cells expressing IL-4 (3H4), 92% of those expressing IL-4 (4D9) and 100% expressing IL-13 in the airway smooth muscle were mast cells. Fifty-five percent of the mast cells within the airway smooth muscle co-localized to IL-4 (3H4), 29% to IL-4 (4D9) and 17% to IL-13. CONCLUSIONS: In asthma, IL-4+ and IL-13+ cells were present within the airway smooth muscle and were expressed predominantly by mast cells, suggesting that IL-4 and IL-13 may play an important role in mast cell-airway smooth muscle interactions.     

Seasonal allergic conjunctivitis is accompanied by increased mast cell numbers in the absence of leucocyte infiltration

Background Seasonal allergic conjunctivitis (SAC) is the most common allergic disease to affect the eye. occurring alone or in association with allergic rhinitis. Infiltration with mast cells and eosinophils is characteristic of the chronic forms of allergic conjunctivitis such as vernal and atopic keratoconjunctivitis. and these cell types also contribute significantly to allergic inflammation in the skin. Indirect evidence for a similar pattern of cellular events in SAC comes from studies which demonstrate raised eosinophil and neutrophil numbers in conjunctival scrapings and elevated levels of mast cell tryptase in tears following allergen challenge. Objective To directly characterize the inflammatory cell infiltrate in SAC and to determine its clinical relevance. Methods We employed specific immunohistochemical staining to count masi cells, eosinophiis and neutrophiis in the conjunctival epithelium and lamina propria of eight atopic patients with SAC in, and 12 SAC patients out of the hay fever season. Sixteen patients with no history of ocular allergy were used as control subjects. Results Mast cells were absent from normal epithelium. During the pollen season median mast cell numbers in the lamina propria were found to be increased by 6I'J(in patients with SAC compared with normals (P= 0.012). Eosinophils were found in the lamina propria in less than half of the symptomatic patients with SAC and in only three patients were eosinophils present in the epithelium. The neutrophil numbers in the lamina propria of patients with SAC tended to be higher than normals but these changes did not reach statistical significance. Conclusion Conclusion These data based on the direct assessment of conjunctival tissue provide evidence that symptoms occur in SAC in the absence of detectable recruitment of eosinophils or neutrophils. This suggests that this disorder is related to mast cell-mediated changes.     

Remodelling of airway smooth muscle in asthma: what sort do you have?

BACKGROUND: Shortening of smooth muscle around airways is the basis of symptoms and abnormal lung function in asthma. The airway wall is increased in thickness in small and large airways asthma, in relation to the clinical severity of asthma and the airway smooth muscle layer is the main contributor to this thickening. The relative contributions of more airway smooth muscle cells, bigger cells or more extracellular matrix to the increased thickness of the smooth muscle layer in asthma is not clear and has been examined in only a small number of cases, Studies of the natural history of asthma suggest that the clinical severity of asthma is relatively constant over time, deficits in lung function compared with nonasthmatic subjects occur early in the course of the disease and the decline in lung function with age is increased in asthma. HYPOTHESIS: The observations from studies of the quantitative pathology and the natural history of asthma might be combined in the hypothesis that the severity of asthma is determined early (in its natural history) and is related mainly to increased volume density of airways smooth muscle cells (hyperplasia) and that later deposition of extracellular matrix from larger, hypertrophic smooth muscle cells results in fixed and increasing deficits in lung function. SPECULATION: The relative contribution of more smooth muscle cells, bigger cells and extracellular matrix will be determined by unbiased stereological measurements in many cases of asthma of varying severity. The outcomes of such studies will be methods of monitoring and of treatment that will be tailored to the sort of smooth muscle modelling that is present in individual cases.