This Program Project Grant application will test the hypothesis that communication between the stroma tissue-resident cells and infiltrating leukocytes is key to directing lung-specific inflammatory and antiinflammatory responses to infection or injury. We believe that the interplay between these cell populations, mediated by alterations in specific extracellular matrix components, is a critical aspect in the development of the response to challenge. Our overall hypothesis is that changes in local pericellular environments, such as deposition of specific extracellular matrix components or the elaboration of effector molecules, as a consequence of the host response to airway epithelial insults, provide spatial signals for recruitment and activation of leukocytes that ultimately shape the qualitative and quantitative patterns of both the innate and adaptive immune responses. An important, unifying, and novel concept that will be explored in this Program is that the progression from innate to adaptive immunity in the lung is fluid and mechanistically linked. Once recruited, infiltrated leukocytes induce further changes in local environments, escalating the inflammatory response. The individual projects in this proposal will probe different, yet complementary and sequential processes of this proposed inflammatory cascade. These aspects include: (1) the role of the interstitial matrix components versican and hyaluronan in regulating and shaping the innate response to lung infection (Wight), (2) the role ofthe epithelial-derived cytokine TSLP (thymic stromal lymphopoietin) in coordinating innate and adaptive responses in the lung (Ziegler), (3) the role of stromelysin-2 (MMP-10) in controlling macrophage activation during acute infection and later T cell responses (Parks), and (4) the role of the adaptive immune system, particularly regulatory T cells, in controlling chronic infection in the lung (Campbell). Each of these projects shares the common theme of how effectors molecules made by one cell type control the activity of specific leukocytes and overall this Program will provide an integrated approach for examining pulmonary inflammation.

Public Health Relevance

This scientific Program has great potential for improving the health of critically ill patients in the U.S. and abroad. We will generate information on the mechanisms by which interactions between infiltrating cells and resident lung cells leads to the development of pulmonary inflammation. This novel approach to study pulmonary disease will not only lead to important insights into disease development and progression, it may also Identify new therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Eu, Jerry Pc
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Benaroya Research Institute at Virginia Mason
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Wilson, S S; Tocchi, A; Holly, M K et al. (2015) A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol 8:352-61
Giannandrea, Matthew; Parks, William C (2014) Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 7:193-203
Chang, Mary Y; Tanino, Yoshinori; Vidova, Veronika et al. (2014) A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. Matrix Biol 34:1-12
Smigiel, Kate S; Richards, Elizabeth; Srivastava, Shivani et al. (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121-36
Srivastava, Shivani; Koch, Meghan A; Pepper, Marion et al. (2014) Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 211:961-74
Srivastava, Shivani; Koch, Lisa K; Campbell, Daniel J (2014) IFN?R signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. J Immunol 193:2733-42
Gharib, Sina A; Johnston, Laura K; Huizar, Isham et al. (2014) MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol 95:9-18
Smigiel, Kate S; Srivastava, Shivani; Stolley, J Michael et al. (2014) Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol Rev 259:40-59
Chang, Mary Y; Tanino, Yoshinori; Vidova, Veronika et al. (2014) Reprint of: A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. Matrix Biol 35:162-73
Kang, Inkyung; Yoon, Dong Won; Braun, Kathleen R et al. (2014) Expression of versican V3 by arterial smooth muscle cells alters tumor growth factor ? (TGF?)-, epidermal growth factor (EGF)-, and nuclear factor ?B (NF?B)-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion. J Biol Chem 289:15393-404

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