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
United States
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Han, Hongwei; Ziegler, Steven F (2017) Intradermal administration of IL-33 induces allergic airway inflammation. Sci Rep 7:1706
Kang, Inkyung; Harten, Ingrid A; Chang, Mary Y et al. (2017) Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation. J Biol Chem 292:51-63
Wight, Thomas N (2017) Provisional matrix: A role for versican and hyaluronan. Matrix Biol 60-61:38-56
Sheih, A; Parks, W C; Ziegler, S F (2017) GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen. Mucosal Immunol 10:705-715
Wight, Thomas N; Frevert, Charles W; Debley, Jason S et al. (2017) Interplay of extracellular matrix and leukocytes in lung inflammation. Cell Immunol 312:1-14
Gaucherand, Léa; Falk, Ben A; Evanko, Stephen P et al. (2017) Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan-Enriched Extracellular Matrix Adhesive for Monocytes. J Cell Biochem 118:2118-2130
Han, H; Roan, F; Johnston, L K et al. (2017) IL-33 promotes gastrointestianl allergy in a TSLP-independent manner. Mucosal Immunol :
Secor, Patrick R; Michaels, Lia A; Smigiel, Kate S et al. (2017) Filamentous Bacteriophage Produced by Pseudomonas aeruginosa Alters the Inflammatory Response and Promotes Noninvasive Infection In Vivo. Infect Immun 85:
Han, Hongwei; Roan, Florence; Ziegler, Steven F (2017) The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev 278:116-130
Kashiwagi, Mariko; Hosoi, Junichi; Lai, Jen-Feng et al. (2017) Direct control of regulatory T cells by keratinocytes. Nat Immunol 18:334-343

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