The epithelium of the lung is one of the largest interfaces between the body and the environment and it is exposed daily to approximately 11,000 liters of air that is contaminated with bacteria, viruses, pathogens and allergens. The pulmonary host defense system must ignore harmless antigens but respond appropriately to harmful pathogens. One of local host defense system is pulmonary surfactant. Recent studies have identified two of the surfactant proteins, SP-A and SP-D, as members of the collectin family of collagen-like lectins that function in host defense. The overall hypothesis to be tested in this proposal is that SP-A and SP-D interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and pathogens while minimizing potentially harmful inflammatory consequences of an over exuberant immune response. Our findings that SP-A and SP-D have cell specific effects suggest that they modulate cellular response in a context specific manner. We propose to pursue three specific aims.
Aim 1 will define the roles of SP-A and SP-D and their receptors in regulating antigen uptake, intracellular targeting, and antigen presentation by bone marrow derived dendritic cells and mast cells. Blocking antibodies and receptor null mice will be used to test the hypothesis that dendritic and mast cell specific responses are modulated by different collectin receptors that target pathogens to different intracellular processing pathways for presentation via MHCI and MHCII.
Aim 2 will define the mechanism by which SP-A inhibits the maturation of dendritic cells. Studies will be performed with isolated cells, anti-receptor blocking antibodies, and with cells from receptor and cytokine null mice to test the hypothesis that SP-A interacts with specific receptors to alter production of cytokines or cytokine receptors that inhibit dendritic cell maturation.
Aim 3 will investigate SP-A and SP-D mediated regulation of Type II epithelial cell and lung dendritic cell immune functions in the normal and inflamed lung. Studies will be conducted in vitro with isolated cells and in vivo with collectin null mice using two models of lung inflammation, the LPS model and the ovalbumin model of allergic inflammation. These studies will provide new information about the role of SP-A and SP-D in regulating and coordinating the functions of cells of the innate and adaptive immune system and contribute to our understanding of the role of SP-A and SP-D in inflammatory lung diseases and to development of novel surfactant-containing therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Reynolds, Herbert Y
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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Foley, Joseph P; Lam, David; Jiang, Hongmei et al. (2012) Toll-like receptor 2 (TLR2), transforming growth factor-?, hyaluronan (HA), and receptor for HA-mediated motility (RHAMM) are required for surfactant protein A-stimulated macrophage chemotaxis. J Biol Chem 287:37406-19
Hsia, Bethany J; Pastva, Amy M; Giamberardino, Charles D et al. (2012) Increased Nitric Oxide Production Prevents Airway Hyperresponsiveness in Caveolin-1 Deficient Mice Following Endotoxin Exposure. J Allergy Ther Suppl 1:
Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph et al. (2012) Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation. J Immunol 188:957-67
Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph M et al. (2012) Surfactant protein A modulates induction of regulatory T cells via TGF-?. J Immunol 188:4376-84
Gowdy, Kymberly M; Cardona, Diana M; Nugent, Julia L et al. (2012) Novel role for surfactant protein A in gastrointestinal graft-versus-host disease. J Immunol 188:4897-905
Pastva, Amy M; Mukherjee, Sambuddho; Giamberardino, Charles et al. (2011) Lung effector memory and activated CD4+ T cells display enhanced proliferation in surfactant protein A-deficient mice during allergen-mediated inflammation. J Immunol 186:2842-9
Ledford, Julie G; Pastva, Amy M; Wright, Jo Rae (2010) Review: Collectins link innate and adaptive immunity in allergic airway disease. Innate Immun 16:183-90
Lo, Bernice; Hansen, Soren; Evans, Kathy et al. (2008) Alveolar epithelial type II cells induce T cell tolerance to specific antigen. J Immunol 180:881-8
Pastva, Amy M; Wright, Jo Rae; Williams, Kristi L (2007) Immunomodulatory roles of surfactant proteins A and D: implications in lung disease. Proc Am Thorac Soc 4:252-7
Hansen, Soren; Lo, Bernice; Evans, Kathy et al. (2007) Surfactant protein D augments bacterial association but attenuates major histocompatibility complex class II presentation of bacterial antigens. Am J Respir Cell Mol Biol 36:94-102

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