Browsing by Author "Meier, Lee"

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    Defining Mechanisms of Inflammation and Fibrosis In Cardiac Valve Disease
    (2019-05) Meier, Lee
    Cardiovascular disease (CVD) has been the leading cause of death for over a century and it will continue to be for the foreseeable future. While it has long been hypothesized that inflammation and the immune system play contributory roles in CVD initiation and progression, only recently was confirmatory evidence acquired from a large-scale clinical trial in humans. Thus, despite the existence of significant scientific and clinical efforts invested in understanding immunopathology in CVD, only recently has definitive evidence in support of this line of reasoning been acquired. Despite numerous scientific advances in recent years, our understanding of CVD and the role of inflammation therein remains limited. To date, no FDA approved drugs exist that specifically target aspects of inflammation in CVD despite the breadth of scientific data that underlies its importance. As such, continued investigation of the cellular and molecular mechanisms that govern CVD initiation and progression are needed. In this dissertation I seek to expand the scientific and clinical community’s understanding of the role for inflammation in the development of cardiac valve disease, a subset of CVD and a significant contributor to morbidity and mortality worldwide. Firstly, Chapter 1 provides an overview of cardiovascular structure and normal physiology. Secondly, Chapter 2 provides a brief overview of various forms of acquired CVD including atherosclerotic CVD, with emphasis on valvular heart disease (VHD). Therein, I include an introductory discussion of the role of inflammation in acquired CVD development. Thirdly, Chapter 3 provides a discussion of the current understanding of antibodies with specificity to self-epitopes (i.e. autoantibodies) during the initiation and progression of CV inflammation and its downstream chronic consequences on CV function. Therein, I provide motivation for studying the role of autoantibodies in CVD initiation and progression and provide insight into the current understanding of how autoantibodies interface with elements of the circulatory system to further CVD progression. As our animal model of systemic inflammation and cardiac valve disease is driven by autoantibodies, the discussion in this review provides a framework for the experimental studies that follow in later chapters of this dissertation. Chapter 4 demonstrates that discrete population of mononuclear phagocytes (MNP) are critical for MV inflammation and fibrosis. Therein, I provide evidence that MNPs are necessary for disease initiation and progression and are critical orchestrators of MVD through cytokine secretion in response to activating FcγR signaling. Downstream of MNP cytokine production, activation of the MV interstitium drives recruitment of additional inflammatory cells. On a chronic timescale, MV fibrosis results. Finally, I provide evidence for upregulation of similar pathways in samples acquired from human inflammatory MVD. Chapter 5 expands on the observations set forth in Chapter 4, and provides additional mechanistic clarification of the role for MNPs during the initiation and progression of MV inflammation and fibrosis in K/B.g7 mice and in humans. Firstly, I demonstrate that type-2 inflammation is required for disease in K/B.g7 mice and acts through multiple levels to orchestrate both systemic inflammation and cardiac valve-localized inflammation and fibrosis. Within the context of MV disease, I provide evidence that IL-13 (and not IL-4) is an important aspect of valve fibrosis. Next, I demonstrate a role for apoptotic cell accumulation and expression of the ‘don’t eat me’ signal, CD47, during the initiation and progression MVD. I show that blockade of this immune checkpoint enhances phagocytic cell clearance, and decreases MNP production of TNF, IL-6, and IL-13. The MVD dampening effect is seen when CD47 blockade is conducted both preventatively and therapeutically, thereby underscoring the central role of this pathway in disease progression. Lastly, I provide evidence for upregulation of these pathways in human RHD samples, again providing evidence for the translational potential these results hold. Finally, Chapter 6 provides preliminary evidence that a hallmark of MV inflammation in K/B.g7 mice is induction of endothelial-mesenchymal transition (EndoMT). Therein, I show that MV endothelial cells upregulate CD47 during pathological EndoMT and that this process is attenuated in the setting of CD47 checkpoint blockade. Additional work is needed to better clarify the role for EndoMT in development of MV inflammation and fibrosis, however, it is tempting to speculate about a putative pro-fibrogenic role for endothelial-derived mesenchymal cells during the course of chronic MV inflammation and fibrosis. Collectively, the results presented here provide substantial mechanistic insight into the underlying cellular and molecular pathways that contribute to cardiac valve fibrosis in the setting of chronic, autoimmune inflammation. These studies were the first to definitively implicate myeloid cells in the fibrotic remodeling of the MV and, in doing so, identified nearly ten putative therapeutic targets for exploration in human disease. Future investigation will involve more definitive identification of specific cell population(s) that drive disease progression and their individual developmental origins.