Various clinical syndromes have been shown to possess a common set of pathophysiologic events that appear to be driven in part by lipopolysaccharide activation of the immune/inflammatory system. These maladies may include: thermal injury, multiple trauma, and sepsis. In many of these cases, the lung is one of many target organs involved in the pathology induced by exaggerated host cell activation events. In order to elucidate factors that dictate the induction of these events, this proposal will examine the cellular production and mechanism that regulate gene expression by various macrophage populations. Interleukin-1 (IL-1), tumor necrosis factor (THF-alpha), and transforming growth factor-beta (TGF-beta) will be analyzed and examined for their production and regulation at the cellular and molecular levels. The modulation of these cell-to-cell communication signals by alveolar macrophages and Kupffer cells will be assessed at the antigenic, bioactive, and mRNA levels. The in vivo production of the above mediators will also be studied in the ascites fluid and serum of complete Freund's adjuvant immunized mice challenged with graded doses of LPS. In addition, the kinetics of mRNA accumulation and regulation by macrophages from treated animals will be examined. Initial in vivo studies will assess the ability of TNF-alpha, IL-1alpha, and IL-1beta to act alone or in concert with each other to mimic LPS-induced organ pathology. Techniques and methodologies employed throughout this proposal include: bioassays for IL-1, TNF, TGF-beta; immunohistochemical and Western blot analyses; Northern blot, nuclear transcription, mRNA stability studies and in situ hybridization analysis for the molecular biology studies; and histologic and permeability assessment of organ injury. Unique aspects of this proposal are the implementation of molecular approaches to study monokine production and regulatory mechanism of gene expression by macrophages during cell activation. These techniques will be used to monitor therapeutic approaches to aid our understanding and treatment of LPS-mediated disease processes. This study will provide important knowledge regarding 1) the molecular mechanisms of IL-, TGF-beta, and TNF production and regulation during macrophage activation; 2) cellular and molecular parameters which preface subsequent LPS-induced injury; and 3) mechanisms and efficacy for pharmacologic manipulations that may regulate LPS-mediated tissue injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Carson 4th, William F; Cavassani, Karen A; Soares, Elyara M et al. (2017) The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages. J Immunol 199:1865-1874
Carson 4th, William F; Salter-Green, Sarah E; Scola, Melissa M et al. (2017) Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6. Cell Immunol 314:63-72
Ito, Toshihiro; Itakura, Junya; Takahashi, Sakuma et al. (2016) Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain-Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia. Crit Care Med 44:e530-43
Kovach, Melissa A; Singer, Benjamin H; Newstead, Michael W et al. (2016) IL-36? is secreted in microparticles and exosomes by lung macrophages in response to bacteria and bacterial components. J Leukoc Biol 100:413-21
Podsiad, Amy; Standiford, Theodore J; Ballinger, Megan N et al. (2016) MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway. Am J Physiol Lung Cell Mol Physiol 310:L465-75
Kroetz, Danielle N; Allen, Ronald M; Schaller, Matthew A et al. (2015) Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection. PLoS Pathog 11:e1005338
Carson 4th, William F; Guernsey, Linda A; Singh, Anurag et al. (2015) Cbl-b Deficiency in Mice Results in Exacerbation of Acute and Chronic Stages of Allergic Asthma. Front Immunol 6:592
Dewyer, Nicholas A; El-Sayed, Osama M; Luke, Catherine E et al. (2015) Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury. Thromb Haemost 114:1028-37
Schaller, Matthew; Ito, Toshihiro; Allen, Ronald M et al. (2015) Epigenetic regulation of IL-12-dependent T cell proliferation. J Leukoc Biol 98:601-13
Kittan, Nicolai A; Allen, Ronald M; Dhaliwal, Abhay et al. (2013) Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes. PLoS One 8:e78045

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