Little is currently known about anti-inflammatory pathways in asthma. Our novel studies have identified potent anti-inflammatory activities for ADAMS in allergic airway inflammation (AAI) in mice. The goal of this project is investigate the mechanisms by which ADAMS limits AAI and AHR in mice. In the long term, this research may lead to novel treatments for patients with asthma. ADAMs are transmembrane proteinases with a disintegrin and a metalloproteinase domain. ADAMs have the potential to regulate inflammatory processes in the lung because they shed and thereby regulate the biologic activites of cytokines, growth factors, and apoptosis ligands, and receptors for these molecules from cell surfaces. ADAMs also bind to integrins to regulate cell adhesion and migration. Little is known about the roles of ADAMs in asthma. Our preliminary studies show that ADAMS-/- mice with AAI have increased airway macrophage accumulation and increased airway hyper-responsiveness (AHR) to methacholine challenges compared to WT mice with AAI. This indicates that ADAMS has an anti-inflammatory role in AAI. We will investigate the mechanisms involved by pursuing the following Specific Aims:
Specific Aim 1 : Test the hypothesis that ADAMS reduces AAI and AHR in the pure BALB/c murine strain and fully characterize the phenotype of ADAMS-/- mice in this strain. We will compare the following in ovalbumin- or PBS-treated BALB/c ADAMS-/- versus BALB/c WT littermate control mice: 1) AAI in bronchoalveolar lavage (BAL) samples and lung sections;Th1, Th2, and anti-inflammatory cytokines in BAL fluid samples;and airway goblet cell metaplasia;and 2) AHR to methacholine challenges using FlexiventTM analysis.
Specific Aim 2 : We will test the hypothesisthat ADAMS reduces macrophage accumulation in the lungs of BALB/c mice with AAI by: 1) increasing apoptosis of airway macrophages during AAI;and/or 2) reducing monocyte transendothelial migration during AAI;and/or 3) proteolytically inactivating monocyte chemokines in the lung during AAI.
Specific Aim 3 : We will test the hypothesis that ADAMS limits AHR in BALB/c mice with AAI by reducing macrophage accumulation in murine airways. We will test whether depleting macrophages in ADAM8-/- mice with AAI reduces AHR to methacholine challenges in these mice. Relevance to public health: Asthma is a common disease which affected 15.7 million Americans in 2005. Current therapies are sometimes ineffective or have undesirable side-effects. Thus, there is a great need to new and improved treatments to the high limit morbidity and mortality associated with asthma.
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