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Philip W. Askenase explains why naturally occurring exosomes are better for drug discovery.

Exocytosis dependent on calcium and metabolic energy has been established as the mechanism for the release of membrane-bound secretory products from various exocrine, endocrine and neural cells1. This has also been shown to be the case in mast cells, which have been used increasingly as a model secretory system2. The secretory granules of mast cells contain several mediators3, some of which, such as histamine, are known to participate in many immune reactions and allergic diseases4,5. Because of mast cell involvement in these clinical syndromes, as well as the role of histamine in gastric acid secretion6and possibly in brain pathophysiology7, there has been great interest in the pharmacological modulation of histamine release from mast cells8. Serotonin is also stored in mast cell granules of several species but much less is known about its secretion. Because histamine and serotonin may have divergent functions in delayed hypersensitivity4,9, we hypothesized that these amines could undergo differential release. We now report that the tricyclic antidepressant drug amitriptyline (Elavil) inhibits histamine release from stimulated mast cells while permitting the release of serotonin. In these conditions, exocytosis of secretory granules is largely prevented, but serotonin is released by an unknown process which still requires calcium and metabolic energy. The ability to secrete differentially expands the physiological potential of the mast cell, and suggests that release of serotonin may not always indicate mast cell secretion via exocytosis of secretory granules.

Slow reacting substances (SRS) are potent bronchoconstrictors that are thought to be important in the pathophysiology of asthma1. Human2–5and animal6,7lung fragments release SRS when sensitized by IgE antibody and challenged with specific antigen. SRS have been shown recently to be a family of peptidolipids called leukotrienes (LTC4, LTD4and LTE4) that are derived from arachidonic acid8–11and are potent bronchoconstrictors in vivo and in vitro12,14. It is not known which cell(s) is responsible for releasing SRS but two recent observations have directed our attention to alveolar macrophages. First, Capron and co-workers demonstrated that serum IgE antibody from rats immune to Schistosoma mansoni parasites could cause rat peritoneal macrophages to be cytotoxic for schistosomules in vitro15. This is a result of the interaction of IgE with macrophage IgE Fc receptors16. Similar receptors are also present on rat alveolar macrophages17. Second, Bach and Brashler18–21established that rat peritoneal macrophages could release a mixture of LTC4and LTD4when stimulated by the calcium ionophore A23187. We now show that rat alveolar macrophages can be activated by calcium ionophore to release SRS and, when challenged with IgE antibody and specific antigen, release LTC4.