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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McMahan, Ryan S; Birkland, Timothy P; Smigiel, Kate S et al. (2016) Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation. J Immunol 197:899-909
Valladao, Andrea C; Frevert, Charles W; Koch, Lisa K et al. (2016) STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata. J Immunol 197:4541-4551
Stolley, J Michael; Campbell, Daniel J (2016) A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2-Dependent Regulatory T Cells in the Spleen. J Immunol 197:2635-45
Reeves, Stephen R; Kaber, Gernot; Sheih, Alyssa et al. (2016) Subepithelial Accumulation of Versican in a Cockroach Antigen-Induced Murine Model of Allergic Asthma. J Histochem Cytochem 64:364-80
Merrilees, Mervyn J; Zuo, Ning; Evanko, Stephen P et al. (2016) G1 Domain of Versican Regulates Hyaluronan Organization and the Phenotype of Cultured Human Dermal Fibroblasts. J Histochem Cytochem 64:353-63
Wight, Thomas N (2016) Provisional matrix: A role for versican and hyaluronan. Matrix Biol :
Keire, Paul A; Bressler, Steven L; Mulvihill, Eileen R et al. (2016) Inhibition of versican expression by siRNA facilitates tropoelastin synthesis and elastic fiber formation by human SK-LMS-1 leiomyosarcoma smooth muscle cells in vitro and in vivo. Matrix Biol 50:67-81
Vandivort, Tyler C; An, Dowon; Parks, William C (2016) An Improved Method for Rapid Intubation of the Trachea in Mice. J Vis Exp :53771
Piliponsky, Adrian M; Lahiri, Asha; Truong, Phuong et al. (2016) Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis. Am J Respir Cell Mol Biol 55:264-74
Sheih, A; Parks, W C; Ziegler, S F (2016) GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen. Mucosal Immunol :

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