CD14, Surfactant Proteins, and Vascular Inflammation

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

The central hypothesis of this project is that vascular wall endothelial and smooth muscle cells (SMC) are[unreadable] part of a complex and highly regulated innate immune system that modulates inflammatory signaling in[unreadable] atherosclerosis. We have discovered that human coronary artery SMC (HCASMC) express membranebound[unreadable] CD14, a pattern recognition receptor that plays a central role in transducing innate immune[unreadable] responses to endotoxin and other bacterial products in inflammatory cells. We have also detected[unreadable] expression in vascular cells of surfactant protein D (SP-D), a member of the collectin family of proteins[unreadable] that binds to endotoxin and CD14 to modulate innate immune responses in the lung. Using a combination[unreadable] of pharmacological, molecular, and gene-based approaches, we propose to: 1. Test the hypothesis that[unreadable] CD14 in SMC plays a central role in transducing immune responses to multiple inflammatory mediators. We[unreadable] will identify CD14 ligands in HCASMC, and we will examine regulation of CD14 expression in HCASMC and[unreadable] human coronary artery endothelial cells by oxidative stress and activation of PPAR-gamma. We will also[unreadable] determine whether CD14 ligation modulates expression and function of scavenger receptors in SMC. 2L[unreadable] Test the hypothesis that SP-D modulates CD14-mediated pro-inflammatory signaling in vascular cells.[unreadable] We propose to examine mechanisms whereby SP-D blocks pro-inflammatory signaling in vascular cells,[unreadable] focusing on the role of binding of SP-D to endotoxin and cell signaling proteins. We will also determine[unreadable] whether SP-D expression is regulated by inflammatory mediators and/or oxidative stress. 3. Test the[unreadable] hypothesis that CD14 and SP-D modulate atherosclerosis in apoE-/- mice. Using CD14-/- and SP-DV-/- mice[unreadable] cross-bred with apoE-/- mice to create double knockout mice, we will examine the extent of[unreadable] atherosclerosis, vascular inflammation, and endothelial dysfunction in the absence and presence of[unreadable] recurrent challenges with low-level endotoxin to stimulate the innate immune system. Together, the proposed[unreadable] studies will provide novel insight into the potentially critical role of CD14 in vascular inflammation, and[unreadable] modulation of CD14 expression in the vascular wall by oxidant stress and PPAR-gamma. Further, the proposed[unreadable] studies will be the first to investigate the potential immunomodulatory role of SP-D in the vascular wall.[unreadable] These studies will help to elucidate mechanisms whereby vascular wall cells contribute to inflammation[unreadable] now known to be an important cause of atherosclerosis. Further, our findings may lead to new[unreadable] approaches to treating the inflammatory component of atherosclerosis.