This project will focus on the role of leukocyte integrins in the development of airway inflammation and hyperresponsiveness. Integrins were originally identified because of their ability to mediate cell adhesion, but it is now clear that they also play major roles in determining how a cell responds to its environment. Systemic or aerosol administration of anti-integrin antibodies inhibits airway inflammation and hyperresponsiveness in several animal models. In many cases, these effects cannot be accounted for by a direct blockade of integrin-mediated recruitment of leukocytes from the blood into the airways. In vitro evidence obtained using purified blood leukocytes and cultured cell lines strongly suggests that many in vivo effects of anti-integrin antibodies are instead accounted for by alterations in integrin-mediated signaling pathways involved in the regulation of leukocyte activation, cytokine production, and mediator release. The goal of this project is to analyze the importance of these mechanisms in the ovalbumin-allergic mouse model using both in vitro and in vivo approaches. Preliminary experiments conducted in collaboration with other SCOR investigators have analyzed leukocyte recruitment, integrin and integrin ligand expression, cytokine production, mediator release, and airway responsiveness in this model. The results indicate that the model resembles asthma in several important respects. The project has three specific aims: (A) To analyze how beta-2 and alpha-4 integrins modulate the activation of pulmonary T cells, eosinophils, and macrophages in vitro; (B) To analyze the effects of anti- integrin and anti-ligand antibodies on mediator and cytokine release from lung fragments; and (C) To analyze the effects of in vivo administration of anti-integrin and anti-ligand antibodies on inflammation, cytokine production, mediator release, and airway hyperresponsiveness. These studies address fundamental questions about the role of leukocyte integrins in the development and persistence of airway inflammation and hyperresponsiveness, and will help to provide a rational basis for the development of systemic or inhaled integrin antagonists for the treatment of asthma.
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