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Up-Regulation and Activation of Eosinophil Integrins in Blood and Airway after Segmental Lung Antigen Challenge¹

Mats W. Johansson^2,*, Elizabeth A. B. Kelly, William W. Busse, Nizar N. Jarjour and Deane F. Mosher^*,

^* Department of Biomolecular Chemistry and Department of Medicine, University of Wisconsin, Madison, WI 53706

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 _D and the N29 epitope of activated β₁ integrins on blood eosinophils and of _M, 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 _M 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 _Dβ₂ surface expression is low. After Ag challenge, circulating eosinophils adopt a phenotype with activated β₁ integrins and up-regulated _Dβ₂, 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 _Mβ₂ and activation of β₂ integrins.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Specialized Center of Research Grant HL56396, Program Project Grant HL88594, and General Clinical Research Center Grant M01 RR03186 from the National Institutes of Health.

² Address correspondence to Dr. Mats W. Johansson, Department of Biomolecular Chemistry, University of Wisconsin, 4285A Medical Sciences Center, 1300 University Avenue, Madison, WI 53706. E-mail address: mwjohansson{at}wisc.edu

³ Abbreviations used in this paper: BAL, bronchoalveolar lavage; AgPD₂₀, provocative dose of Ag producing a 20% fall in FEV₁; FEV₁, forced expiratory volume in 1 s; gMCF, geometric mean channel fluorescence.

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