Role of mast cells in airway remodeling

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The extent of airway remodeling correlates with severity of asthma. Persistent airway hyperresponsiveness (AHR) is associated with airway remodeling, but not with inflammation. The increase in ASM mass is recognized as one of the most important factors related to AHR and to the severity of asthma. The infiltration of ASM by mast cells (MCs) is associated with the disordered airway function. The mediators such as tryptase and cytokines from MCs can modulate ASM cell function and induce goblet cell hyperplasia. MCs were found to contribute to the development of multiple features of chronic asthma in MC-deficient mice. Therefore, MCs play an important role not only in immediate hypersensitivity and late phase inflammation but also in tissue remodeling in the airway.

Introduction

Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling. Airway remodeling is defined as the structural changes in the airways that may affect their functional properties. The structural changes include an increased airway smooth muscle (ASM) mass, mucus gland hypertrophy, deposition of extracellular matrix components, thickening of the reticular basement membrane, and angiogenesis [1]. Patients with asthma have accelerated loss of lung function over time, and some patients develop progressive fixed airflow obstruction. These features may reflect airway remodeling in severe and chronic asthma [1]. Although the relationship between remodeling and inflammation has not been fully understood, many reports suggested that airway remodeling might be a consequence of repeated injury and persistent inflammation [1]. However, remodeling processes begin early in the development of asthma and occur in parallel with the establishment of persistent inflammation [2]. Recent reports have demonstrated that persistence of AHR is dependent on airway remodeling and not on sustained inflammatory cell recruitment [3, 4, 5, 6••, 7••]. First, we will describe the new discoveries in regard to the relationship between AHR and the activation and resolution of inflammatory and remodeling events.

ASM hypertrophy and hyperplasia are now recognized as the most important factors related to AHR in vitro and in vivo and to the severity of asthma. Many inflammatory mediators and cytokines contribute to ASM proliferation [8], and ASM itself is a source of inflammatory mediators, suggesting autocrine proliferative responses and interaction with inflammatory cells.

Mast cells (MCs) are known to be the primary responders in allergic reactions, most of which are triggered by cross-linking of a high-affinity IgE receptor, FcɛRI. After activation, MCs exert their biological effects by releasing preformed and de novo-synthesized mediators, such as histamine, leukotrienes, and various cytokines/chemokines. Biogenic amines and lipid mediators cause rapid leakage of plasma from blood vessels, vasodilation, and bronchoconstriction. Cytokines mediate the late phase reaction characterized by an inflammatory infiltrate composed of eosinophils, basophils, neutrophils, and lymphocytes. Bronchial asthma is a manifestation of immediate hypersensitivity and late phase reactions in the lower respiratory tract. MCs have been reported to play an important role not only in immediate hypersensitivity and late phase reactions in the airway but also airway remodeling. In this paper, we will review the involvement of MCs and ASM cells in the pathogenesis of airway remodeling.

Section snippets

New discoveries regarding the relationship between AHR and the activation and resolution of inflammatory and airway remodeling events

AHR is an exaggerated narrowing of the airway in response to specific and nonspecific stimuli. It is a constant feature of asthma and can serve as an indicator of its severity [9]. Indeed, the clinical manifestations of asthma can be attributed to AHR. The mechanisms responsible for AHR are multiple. Induction and perpetuation of AHR may result from repeated inflammatory events involving a complex and coordinated response by multiple inflammatory and structural cells, mediators, connective

The immunological mechanisms of airway remodeling

ASM mass is increased in the asthma, particularly in severe asthma [15]. The increase in the ASM mass may be the result of hyperplasia [16] or hypertrophy [17], alone or together, or of ASM migration. The mechanisms that regulate ASM proliferation, hypertrophy, and migration have been the subject of numerous reviews [8, 18, 19]. Increased ASM mass has the potential to dominate the mechanical response of the remodeled asthmatic airway, and ASM dynamics play a crucial role in this process [20].

MC-derived mediator-induced airway remodeling

It has been reported that the infiltration of ASM by MCs is associated with the disordered airway function found in asthma [30]. Caroll et al. [31] studied the number of MCs and their degranulation in tissue obtained on postmortem examination from persons who had died from asthma, persons who had had asthma but had died from other causes, and non-asthmatic controls. They found that the largest proportion of MCs was in the ASM, and the number of degranulated MCs was greatest in the persons who

Conclusions

Persistent AHR is dependent on airway remodeling, but not on sustained inflammatory events. Therefore, regulation of airway remodeling is the most important issue for the treatment of chronic and severe asthmatics. Numerous cells and mediators including epithelial cells, cytokines and growth factors all appear to play a part in the remodeling process, but the precise roles of specific cells and mediators are yet to be defined clearly. However, it is clear that in addition to the early and late

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to acknowledge our finding from the Grants-in-Aid for Scientific Research (C) program of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Project No. 18604009, to YO), and the National Institute of Biomedical Innovation (Project ID05-24 to HS).

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