Up-Regulation and Activation of Eosinophil Integrins in Blood and Airway after Segmental Lung Antigen Challenge

Abstract

We hypothesized that there are clinically relevant differences in eosinophil integrin expression and activation in patients with asthma. To evaluate this, surface densities and activation states of integrins on eosinophils in blood and bronchoalveolar lavage (BAL) of 19 asthmatic subjects were studied before and 48 h after segmental Ag challenge. At 48 h, there was increased expression of αD and the N29 epitope of activated β1 integrins on blood eosinophils and of αM, β2, and the mAb24 epitope of activated β2 integrins on airway eosinophils. Changes correlated with the late-phase fall in forced expiratory volume in 1 s (FEV1) after whole-lung inhalation of the Ag that was subsequently used in segmental challenge and were greater in subjects defined as dual responders. Increased surface densities of αM and β2 and activation of β2 on airway eosinophils correlated with the concentration of IL-5 in BAL fluid. Activation of β1 and β2 on airway eosinophils correlated with eosinophil percentage in BAL. Thus, eosinophils respond to an allergic stimulus by activation of integrins in a sequence that likely promotes eosinophilic inflammation of the airway. Before challenge, β1 and β2 integrins of circulating eosinophils are in low-activation conformations and αDβ2 surface expression is low. After Ag challenge, circulating eosinophils adopt a phenotype with activated β1 integrins and up-regulated αDβ2, changes that are predicted to facilitate eosinophil arrest on VCAM-1 in bronchial vessels. Finally, eosinophils present in IL-5-rich airway fluid have a hyperadhesive phenotype associated with increased surface expression of αMβ2 and activation of β2 integrins.

IL-5 Induces Suspended Eosinophils to Undergo Unique Global Reorganization Associated with Priming

“…Consistently, eosinophils from switchassociated protein-70-deficient mice, which are defective in formation of structures identified as uropods, adhere poorly to inflamed vessels in intravital experiments (32). Thus, we consider the rapid polarization and nucleopod formation by suspended eosinophils in response to the concentrations (ng/ml) of IL-5 that can be found, for example, in bronchoalveolar lavage after segmental antigen challenge (33), as a model of the changes that occur as eosinophils encounter such stimulation and stably arrest in and extravasate from vessels of, for instance, the bronchi of subjects with asthma.…”

Regulation of Arachidonate Remodeling Enzymes Impacts Eosinophil Survival during Allergic Asthma

“…Primed peripheral blood eosinophils have been reported in other studies from subjects with asthma, including up-regulated surface receptors (32), up-regulated intergrins (33), primed responses to chemoattractants (34), and increased transepithelial migration (35), as well as primed superoxide gerneration (36) and leukotriene production (37). These primed features are further augmented in eosinophils in the airway fluid obtained by BAL, where activated eosinophilic cationic protein (38), lipid body formation with increased AA and eicosanoid generation (39), and hyperadhesive phenotypes (33) have been reported. The inflammatory signals responsible for the activation of asthmatic eosinophils remain to be identified, and may be either direct allergens or secondary products of allergen stimulation of airway cells.…”

A pathophysiological role of PDE3 in allergic airway inflammation

“…Elevated levels of CD11b in neutrophils and eosinophils were seen in affected lung tissue when compared with blood levels (61). Segmental lung antigen challenge upregulates and activates eosinophil integrins in blood and airways of asthmatics (62). From studies in the 1990s it is known that PDE4 inhibition and theophylline can rapidly reduce the expression of CD11b in neutrophils and eosinophils (63,64).…”