Although the modes of granule protein release and disappearance of eosinophils from the airway mucosa may determine the role of these granulocytes, they have not been extensively examined in vivo. For example, it would be of interest to learn more about potential connections between mucosal eosinophils and those eosinophils that may abound in tracheobronchial lymph nodes in allergy and asthma (32, 37). Several question also remain about such established in vivo fates of eosinophils as their entry into the airway lumen. Traversing the epithelium may be important in 'first line' airway defense, but may also be a clearance route whereby eosinophils could leave the mucosal tissue without causing inflammation. Perhaps mucosal inflammation can in part be resolved by efficiently inducing the luminal entry of airway tissue granulocytes. Eosinophils in the airway lumen, like eosinophils in culture are readily available for investigation. It is attractive, but not always possible, to translate appearances and biologic features of cells removed from tissue to diseased tissues in vivo. Thus, for example, although a classical from of eosinophil degranulation, exocytosis (Table 1), clearly occurs in vitro, it may remain to be demonstrated in airway tissues in vivo. Moreover, it cannot be excluded that apoptosis as a fate may be more valid for eosinophils of culture and airway luminal phenotype than for eosinophil in diseased airway tissues, whether or not the latter are treated with steriods. On the other hand, important phenomena may exist, such as eosinophil cytolysis, that do not fall within current avenues of min vivo research, but which may nevertheless may play significant roles in vivo. This latter possibility underscores the continued utility of disease like in vivo test systems involving classical clinical approaches (physiology, clinical pharmacodynamics, and histopathology) in original biomedical research (35, 36, 127). As a further point, PMD may exemplify an acknowledged but little investigated mechanism that is common both in vitro and in vivo. Growing evidence suggests that eosinophil cytolysis, producing Cfegs as protein-laden free granules in diseased airway pulmonary tissues, constitutes a major mode of activation of tissue eosinophils in vivo. This mode of degranulation is distinct from classical exocytosis and the common PMD (Figures 1 and 4). The extracellular eosinophil granules, appearing as Cfegs, are not doomed to phagocytosis, but appear to release their potent granule proteins close to target cells in diseased airway mucosa. The biologic regulation of eosinophil cytolysis (including the mode of protein release from free granule) emerges as a promising area of investigation to further the understanding of leukocyte activation and fate, and potentially to find novel treatments for eosinophilic conditions.
