Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen

Abstract

Eosinophil degranulation is thought to play a pivotal role in the pathogenesis of allergic disorders. Although mouse models of allergic disorders have been used extensively to identify the contribution of eosinophils to disease, ultrastructural evidence of active granule disassembly has not been reported. In this investigation, we characterized the degree of eosinophil activation in the bone marrow, blood, lung tissue, and airways lumen [bronchoalveolar lavage fluid (BALF)] of ovalbumin-sensitized and aero-challenged wild-type and interleukin-5 transgenic mice. Degranulation was most prominent in and primarily compartmentalized to the airways lumen. Eosinophils released granule proteins by the process of piecemeal degranulation (PMD). Accordingly, recruitment and activation of eosinophils in the lung correlated with the detection of cell-free eosinophil peroxidase in BALF and with the induction of airways hyper-reactivity. As in previous studies with human eosinophils, degranulation of isolated mouse cells did not occur until after adherence to extracellular matrix. However, higher concentrations of exogenous stimuli appear to be required to trigger adherence and degranulation (piecemeal) of mouse eosinophils when compared with values reported for studies of human eosinophils. Thus, mouse eosinophils undergo PMD during allergic inflammation, and in turn, this process may contribute to pathogenesis. However, the degranulation process in the allergic lung of mice is primarily compartmentalized to the airway lumen. Understanding the mechanism of eosinophil degranulation in the airway lumen may provide important insights into how this process occurs in human respiratory diseases.

Coexpression of IL-5 and Eotaxin-2 in Mice Creates an Eosinophil-Dependent Model of Respiratory Inflammation with Characteristics of Severe Asthma

“…In contrast, most reports suggest that mouse eosinophils display little to no degranulation (see for example, Refs. 5 and 40) and in the few studies describing this phenomenon, eosinophil degranulation was limited to cells in the airway lumen and to piecemeal release (36,41). Nonetheless, the apparent lack of extensive degranulation of mouse eosinophils may also, in part, reflect inadequacies of existing models for such studies.…”

Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation

“…In spite of the commonly held perspective proposing that eosinophil secondary granule proteins are significant contributors to histopathologies and lung dysfunction, the definition of the cellular and molecular events surrounding degranulation has been severely limited by the inability of established mouse models of aeroallergen challenge to display the extensive eosinophil degranulation found in human subjects with asthma (38,40,53). This lack of concordance has typically been explained as either a limitation of mouse models (reviewed in Reference 54), shortcomings linked with available allergens administered to mice (55), and/or the allergen challenge protocols themselves (56,57).…”

Airway hyperresponsiveness induced by cationic proteins in vivo: site of action

“…Also, MBP has been found on damaged epithelial surfaces and in mucus plugs in patients who died from status asthmaticus (16), showing that severe asthma is associated with a substantial presence of eosinophils and MPB within the airway lumen. Indeed, Clark et al (4) recently showed that the majority of eosinophil degranulation predominately occurs in the lumen of the airways. Furthermore, we have previously shown in an airway tube system that cationic proteins also disrupt epithelial function when present to the basolateral aspect of the tissue but do not affect airway responsiveness when presented to the outside of the airway (7).…”