Cellular Inflammation in Asthma: Neutral Proteases of Mast Cells

Abstract

Atopy is a major risk factor for the development of asthma, and mast cells are the major effector cells of the immediate phase of allergic reactions. A variety of observations support the involvement of mast cells in asthma (table I). High numbers ofmast cells normally reside in the bronchial and alveolar walls, a few of which appear in the lumen (I). In asthmatic subjects, portions of the bronchial epithelium are shed, perhaps accounting for the modest increase in the numbers of luminal mast cells reported. Pulmonary mast cells respond to allergen in vivo as evidenced by increased concentrations of mast cell mediators in bronchoalveolar lavage fluid after inhalation of allergen by atopic subjects (2, 3). Furthermore, those atopic subjects with asthma show evidence for mast cell activation at baseline, when the only obvious pulmonary function abnormality is bronchial hyperreactivity (2). Finally, the hyperresponsiveness of atopic asthmatics to inhaled adenosine most likely occurs by the augmented release of preformed mediators from mast cells being activated concomitantly by other means (4-7). Whether this apparent state of mast cell activation in atopic asthma occurs through a classical IgE-allergen pathway or through other factors such as an imbalance in the ratio of histamine release factors and inhibiting factors is not known. The possibility of a more pervasive involvement of this cell type in asthma seems likely. Mast cells, when activated by allergen, release preformed mediators stored in secretory granules, which is typically accompanied by the synthesis and secretion 0 f lipid mediators and, possibly, eytokines (8). The predominant components that reside in the secretory granules of human mast cells include histamine, proteoglycan, either heparin or chondroitin sulfates, and neutral proteases. The neutral proteases include tryptase, chymase, carboxypeptidase (9), and a cathepsin-G-like enzyme (10). Tryptase resides in the secretory granules of all mast cells from the time granules first begin to form (11), whereas the others dwell in the granules of a subpopulation of mast cells. Those mast cells with tryptase alone are called MCT cells; those with all of the enzymes are called MCTe cells (12). Recently, five different cDNA molecules for human tryptase have been cloned and sequenced (13-15), and two genes for tryptase have been localized to chromosome 16. Whether more than one form of the catalytic enzyme exists and whether the cDNA products are distributed differently in different mast cell types are unknown at present. The possibility of additional forms of human chymase, analogous to the situation in rodents, also needs to be considered. The fact that these enzymes are selectively concentrated in mast cell secretory granules 518 should permit them to serve as indicators of mast cell activation and as markers of different types of mast cells. Also, their catalytic activities provide a mechanism for amplification of the phlogistic events observed in atopic disease. This discussion will focus on the neutral proteases of human mast cells as related to asthma.