Mechanisms of asthma and allergic inflammation
The role of the mast cell in the pathophysiology of asthma

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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.

Section snippets

Mast cells in the pathophysiology of asthma: a historical perspective

Mast cells secrete the autacoid mediators histamine, prostaglandin (PG) D2, and leukotriene (LT) C4, which are capable of inducing bronchoconstriction, mucus secretion, and mucosal edema, all features of asthma. This is particularly evident during experimental allergen challenge, in which blockade of these mediators attenuates the early fall in lung function (see review3). However, mast cells also synthesize and secrete a large number of proinflammatory cytokines (including IL-4, IL-5, and

Mast cells in the pathophysiology of asthma: recent advances

Although, in general, total mast cell numbers appear not to be increased in the bronchial mucosa of subjects with asthma compared with normal subjects, this inadequately describes the complexity, because it is evident that they localize to 3 key sites: the airway smooth muscle (ASM), the airway mucous glands, and the bronchial epithelium.

Conclusion

The mast cell has emerged as a pivotal cell in the pathogenesis of asthma. The poor efficacy of several so-called “mast cell stabilizing drugs” to improve asthma control is a result of the fact that these compounds are ineffective at inhibiting mast cell activation in chronic asthma. For example, disodium cromoglycate is only a weak inhibitor of IgE-dependent HLMC secretion, with maximal inhibition of histamine release in vitro of 10% to 20% when used in the high micromolar range,49 and it also

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    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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