Project 4: Role of Extracellular Remodeling in Epithelial Defense Infectious agents, allergens and other noxious agents enter through exposed mucosal surfaces, such as the respiratory, gastrointestinal and genitourinary tracts. In response to these patholological agents inflammatory and immune cells are recruited and cross the epithelial barrier in response to a chemotactic gradient. To maintain their function as a barrier to infection, an adequate number of inflammatory cells must cross into the luminal spaces. In addition, if the mucosal epithelium is compromised, the defense against infection is lost. The epithelial barrier must therefore be restored as quickly as possible, to minimize the opportunity for entry of infectious agents. Matrix metalloproteinases (MMPs) are upregulated during lung injury, repair and inflammation. Transgenic mouse models with altered proteolytic potential present unique opportunities to elucidate important cellular and genetic pathways by which extracellular proteolysis participates in these epithelial defense mechanisms. The overall goal of this proposal is to identify the pathways impacting epithelial defense (inflammatory cell recruitment, epithelial repair) regulated by by these enzymes. We will address the characteristics and functional significance of MMP interactions by combined in vivo and in vitro approaches: allergic inflammation and infection and the attending epithelial damage. As a mucosal tissue, we will primarily focus on the lung, but, as needed, will also will interrogate other mucosal tissues. We propose to determine the role of these genes in regulating inflammatory cell behavior during transendothelial and transepithelial egress. We hypothesize that dysregulated airway MMP activity modifies the behavior of inflammatory cells by altering extracellular remodeling that impacts on synthesis or release of chemoattractants and/or antagonists of chemoattractant action, into the airspaces, and thus chemoattractant gradients needed to attract the cells out of the parenchymal space into the airspaces are not formed or maintained. Moreover we hypothesize that these enzymes regulate the processes of epithelial repair necessary as a consequence of inflammation. We will study this in vivo using micro-organisms or their products in models of infection (with Project 2) or allergic sensitization in mice that have genetic modifications in MMP expression or activity, or treat mice with MMP inhibitors. We will evaluate cell recruitment in the spaces. We will use optical imaging (with Core C) to study the reactions to microorganisms or their products in models of sterile inflammation, infection or allergic sensitization in vivo, ex vivo and in epithelial cell culture models. We will use mice that have genetic modifications in expression of these genes, concentrating on MMP2, MMP9 and MMP13. We will use mutant mice, specific inhibitors and normal as well as genetically modified epithelial cells in culture to collaborate with Projects 1, 2, 3 and Cores B and C, to investigate the role of of these genes in epithelial wound healing. The immediate implications of this work are in its applications to use of instilled chemoattractant agents and other molecules that modify epithelial defense and will provide proof-of-principle that these critical MMP substrates are potentially efficacious in intervention in epithelial defense mechanisms. Only a thorough understanding of the actions and effects of these enzymes and their major substrates will help mitigate the defense against infection so that recruitment of adequate numbers of inflammatory cells into the spaces beyond the epithelial barrier and the ability of the epithelial to repair itself can be accelerated.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-IPG-I)
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University of California San Francisco
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