Role of Heparan Sulfate NDST-1 in Allergic Inflammation and Airway Remodeling

University Of California, San Diego, La Jolla CA

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Abstract

Allergic asthma is a chronic inflammatory disorder of the airways. There is good evidence that many of the[unreadable] features of asthma, including airway remodeling (AR) are largely due to inappropriate activation of T cells[unreadable] and consequent imbalance of Th1/Th2 cytokines and the recruitment if inflammatory cells including[unreadable] macrophages to the airway. However, the role of heparan sulfates (HS) in the modulation of airway allergic[unreadable] responses and airway remodeling are poorly understood. Heparin and HS interact with various components[unreadable] of the inflammatory cascade in vitro, such as P- and L-selectins, inflammatory mediators, proteoglycans,[unreadable] growth factors cytokines and chemokines to mediate leukocyte migration, endothelial proliferation and tissue[unreadable] remodeling. However the role of endothelial and leukocyte expressed HS in allergic inflammation and AR[unreadable] has never been determined. To study the significance of HS in AR, glucosaminyl N-deacetylase/N-sulfotransferase-[unreadable] 1 (NDST1) was knocked out in endothelial cells (EC) and leukocytes using the Cre-loxP[unreadable] system. The NDST-1-deficient mice (NDST1f/fTie2Cre+) showed impaired inflammatory responses in multiple[unreadable] types of assays in vitro and in vivo. Based on our preliminary observations that lack of NDST-1 in allergenchallenged[unreadable] mice leads to altered leukocyte trafficking, impaired macrophage but not eosinophil recruitment in[unreadable] the airways, reduced expression of the Th2 cytokine IL-5, TGF-beta1 and AHR, along with diminished EC[unreadable] proliferation, we postulate that the targeted deficiency of NDST-1 will result in abrogation of the inflammatory[unreadable] conditions associated with allergen-induced inflammation and AR. To examine this, two specific aims are[unreadable] proposed. In the first specific aim we will assess the role of HS biosynthetic enzyme NDST-1 in the[unreadable] expression of Th2 cytokines, generation and recruitment of macrophages and macrophage progenitor cells[unreadable] to the airways and trafficking of mononuclear cells within the pulmonary vascular bed in the remodeled[unreadable] airways of allergen mice. In this aim the ability of bone marrow derived CD34+ progenitors cells to interact[unreadable] with murine lung EC in the context of HS expression will be examined in NDST1f/fTie2Cre+ mutant and[unreadable] NDST1f/fTie2Cre- wild type mice. In the second specific aim we will delineate the role of HS/NDST-1 in[unreadable] allergen-mediated AR and pulmonary angiogenesis associated with repetitive allergen challenge.[unreadable] Specifically, we will examine the role of HS/NDST-1 on the release of TGF-beta1, MMP-9, FGF-2 and VEGF by macrophages and other inflammatory cells and their effect on the cellular features of airway remodeling. We[unreadable] will also examine the role of NDST-1 and HS to modulate trafficking of inflammatory leukocytes with[unreadable] angiogenic blood vessels of the NDST-1 deficient and wild type mice exposed to repetitive allergen[unreadable] challgenge. Overall we will attempt to delineate the functional importance of EC vs. leukocyte expressed HS[unreadable] by NDST-1 in airway remodeling and airway allergic inflammation.