Relationship between Mediator Release from Human Lung Mast Cells in vitro and in vivo

Abstract

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca⁺⁺-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H₁-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF_2α which could originate from mast cell-derived PGD₂. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma. These data suggest that release of inflammatory mediators are involved in the pathogenesis of the immediate airway response with antigen challenge, and that drugs used to treat asthma may have useful effects, both on the airways and on mediator-secreting cells. Since acquired bronchial hyperreactivity is related to airway inflammation and airway calibre, we propose that pharmacological control of mediator release in vivo represent...

Mast cells produce ENA-78, which can function as a potent neutrophil chemoattractant during allergic airway inflammation

“…In fact, the primary difference between allergic responses and other types of immune/inflammatory reactions appears to be mast cell degranulation events. Some of the most intriguing data on allergic responses indicated that degranulated mast cells release chemotactic factors specific for neutrophil and/or eosinophil accumulation [21,22]. Subsequent studies have identified nonspecific chemotactic factors, such as leukotrienes, etc., which are released by mast cells and contribute to the chemotactic responses.…”

Two types of human mast cells that have distinct neutral protease compositions.

“…Both types have high-affinity plasma membrane receptors for IgE and show coupled activation-secretion on cross-linkage of these receptors. An analogous heterogeneity has been suspected in humans based on the presence of formalin nonfixable and fixable mast cells in human gastrointestinal mucosa and submucosa, respectively (6)(7)(8), even though convincing histochemical, functional, or compositional differences between such mast cells is lacking (4,5,(9)(10)(11).…”

“…Both types are fixed better by Carnoy's fluid than by formalin. (4,5,(9)(10)(11).The presence of distinct chymotryptic neutral proteases in rat mucosal and connective tissue mast cells is a useful criterion for designation of a rat mast cell to a particular type (12, 13). For example, the finding of rat mucosal mast cell chymotryptic protease in a tumor cell line previously considered to be a rat basophil leukemia tumor (RBL-1) indicated that this tumor may be a rat mucosal mast cell leukemia tumor (14).…”

Effects of RS-601, a Novel Leukotriene D₄/Thromboxane A₂ Dual Receptor Antagonist, on Asthmatic Responses in Guinea Pigs

“…The major pathological processes involved in the airflow obstruction of asthma are mucosal edema due to increased vascular permeability, smooth muscle contraction, excessive mucus secretion, and airway inflammation [1][2][3]. Since approximately 90% of the subjects with asthma under the age of 30 years are atopic, allergic airway inflammation is thought to underline much of the altered airway physiology of asthma [4][5][6][7][8].…”