Medicine and Health Sciences Commons^™

Role Of Circular Rna Asph In Macrophage Polarization And Response In Sepsis, Tan Ze Wang

Electronic Thesis and Dissertation Repository

Circular RNAs (circRNAs), a novel non-coding RNA species generated by back-splicing, has been shown to participate in gene regulation of leukocytes. Our previous RNA sequencing results show circular RNA ASPH (circASPH) to be highly expressed in peripheral blood mononuclear cells of sepsis patients at the start of intensive care. Macrophages, as ubiquitous innate immune cells, are responsible for the recruitment of other immune cells at sepsis onset. This work investigates the role of circASPH in the regulation of macrophage polarization in sepsis. Using an in vitro THP-1 cell model, it was found that circASPH levels peaked after 24 h of …

Effects Of Annexin A5 On Endothelial Inflammation Induced By Lipopolysaccharide-Activated Platelets And Extracellular Vesicles, Brent Jeffrey Tschirhart

Electronic Thesis and Dissertation Repository

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets release membrane fragments called extracellular vesicles (EVs) with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated platelets and EVs in vascular …

Impact Of Graded Passive Cycling On Hemodynamics, Cerebral Blood Flow, And Heart Function In Healthy Adults And Septic Icu Patients, Jennifer Chen

Electronic Thesis and Dissertation Repository

Sepsis is a life-threatening dysregulation of host response to an infectious insult, which often leads to multi-organ failure. Sepsis survivors suffer from post-intensive care syndrome in part due to their prolonged bed rest and lack of mobility. Although early mobilization has been championed as a mechanism to counter the adverse effects associated with ICU immobility, due to sedation and mechanical ventilation, active early mobilization is not often administered in septic patients due to worries of hemodynamic instability and potential for inducing adverse events. Passive exercise is a mobilization modality that circumvents the need for patients to be conscious and participatory …

The Role Of Regulator Of G Protein Signaling 2 In Inflammatory Cytokine Release In Endotoxemia In Mice, Xin Tong Ma

Electronic Thesis and Dissertation Repository

In sepsis, lipopolysaccharide (LPS) activates toll-like receptor 4 to stimulate the release of inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNF-α), leading to cardiac dysfunction. Regulator of G protein signaling 2 (RGS2) limits G protein-coupled receptor signaling by increasing the rate of G protein deactivation or inhibiting G protein-effector interactions. We hypothesized that RGS2 deficiency would enhance proinflammatory responses in endotoxemia. Adult wild-type and RGS2^-/- C57BL/6 mice and neonatal cardiomyocytes were treated with LPS and assessed for inflammatory responses and cardiac function. Myocardial TNF-α expression was higher in RGS2^-/- mice during endotoxemia. Additionally, cardiac function was impaired in …

Effects Of Maternal Protein Restriction On The Pulmonary Surfactant System During The Early Life And Adulthood, Reza Khazaee

Electronic Thesis and Dissertation Repository

Fetal growth restriction (FGR) is defined by low birth weight and contributes to a variety of adult-onset diseases with different severities between males and females. However, the effects of FGR on the pulmonary surfactant are not fully elucidated. In this thesis, first, we investigated the FGR effects on the lung function and the surfactant system at the early postnatal life. It was hypothesized that FGR contributes to alterations of lung mechanics and the surfactant system during the neonatal period. Second, we assessed the FGR effects on the surfactant system in response to sepsis in adulthood. It was hypothesized that FGR …

Increased Mitochondrial Calpain-1 Is An Important Mechanism Contributing To Mitochondrial Ros Generation In Cardiac Diseases, Rui Ni

Electronic Thesis and Dissertation Repository

Both calpain activation and excessive mitochondrial reactive oxygen species (mtROS) have been implicated in the pathogenesis of cardiac diseases. We investigated whether and how calpain regulates mtROS generation in mediating cardiac diseases.

In mouse models of streptozotocin-induced type-1 diabetes and lipopolysaccharides- induced sepsis, we show that the protein levels of calpain-1 and calpain activities in mitochondria were significantly elevated in diabetic and septic hearts. The elevation of mitochondrial calpain-1 correlated with an increase in mtROS generation and oxidative damage. Importantly, cardiomyocyte-specific deletion of capns1 disrupted calpain-1 and calpain-2 in the heart and prevented mtROS generation in both septic and diabetic …

The Metalloproteinase-Dependent Role Of Timps In Regulation Of Pulmonary Microvascular Endothelial Cell Barrier Function During Sepsis, Marcello G. Masciantonio

Electronic Thesis and Dissertation Repository

Sepsis causes injury and dysfunction of pulmonary microvascular endothelial cells (PMVEC), leading to pulmonary edema. Metalloproteinases, are associated with inflammation and tissue damage, and their regulation by tissue inhibitors of metalloproteinases (TIMPs) may protect against septic PMVEC dysfunction. Thus, I hypothesize that murine septic PMVEC barrier dysfunction is due to disruption of the balance between metalloproteinases and TIMPs leading to increased metalloproteinase activity.

PMVEC were isolated from wild type (WT) and Timp3^-/- mice. Timp and metalloproteinase mRNA expression was altered under septic conditions and this was associated with increased metalloproteinase activity. Global metalloproteinase inhibitors BB-94 and TAPI-2 reduced albumin …

Basic Science To Clinical Research: Segmentation Of Ultrasound And Modelling In Clinical Informatics, Ali K. Hamou

Electronic Thesis and Dissertation Repository

The world of basic science is a world of minutia; it boils down to improving even a fraction of a percent over the baseline standard. It is a domain of peer reviewed fractions of seconds and the world of squeezing every last ounce of efficiency from a processor, a storage medium, or an algorithm. The field of health data is based on extracting knowledge from segments of data that may improve some clinical process or practice guideline to improve the time and quality of care. Clinical informatics and knowledge translation provide this information in order to reveal insights to …

Analysis Of Invariant Natural Killer T Cells In Intra-Abdominal Sepsis, Ram Venkatesh Anantha

Electronic Thesis and Dissertation Repository

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNKT) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of circulating iNKT cells in their peripheral blood, as compared to non-septic patients. We therefore investigated iNKT cells in mice with intra-abdominal sepsis (IAS). Our data show that iNKT cells are …

Effect Of Ascorbate On Coagulation And Fibrinolytic Factors In The Septic Microvasculature, Scott Swarbreck

Electronic Thesis and Dissertation Repository

Sepsis, a systemic inflammatory response to an infection, is a significant cause of morbidity and mortality worldwide. The microcirculation during sepsis fails, in part, due to microthrombosis and the resulting plugging of capillaries, precipitating organ failure. Intravenous injection of ascorbate has been shown to reduce capillary plugging, however the mechanism of this protective effect is unclear. We hypothesized that ascorbate-mediated destabilization of the microthrombi through promoting fibrinolysis could contribute to this protection.

We showed that streptokinase, a pro-fibrinolytic agent, reduced the capillary plugging to a similar degree as ascorbate. This similarity provided the impetus for studying the effect of ascorbate …

Development Of A Translational Animal Model Of Sepsis, Nathaniel E. Hayward

Electronic Thesis and Dissertation Repository

Sepsis is an excessive inflammatory response to infection that leads to multiple organ failure. The high mortality rates in the intensive care unit have remained stagnant, which can be attributed to the disconnect between the bench and the bedside. There is a global need for an animal model of sepsis that is more relevant to the clinical scenario. We developed an in vivo rat model of sepsis, with a high level of instrumentation, to monitor macrovascular and microvascular changes over the course of a feces-induced peritonitis (FIP) .

In addition, early fluid resuscitation of septic patients is associated with better …

Involvement Of Interleukin-33/St2 In Myocardial Dysfunction In Murine Model Of Sepsis, Yoonmi Choe

Electronic Thesis and Dissertation Repository

The disruption of myocardial extracellular matrix (ECM) has been implicated in myocardial dysfunction during sepsis. However, the underlying mechanism(s) are not clear. Interleukin-33 (IL-33) is a cytokine which regulates collagen synthesis in various cardiac pathologies. The purpose of the present study is to test whether IL-33 contributes to sepsis-induced myocardial dysfunction through regulation of matrix metalloproteinase-9 (MMP-9). The in vivo, feces-induced peritonitis (FIP) in mice and in vitro lipopolysaccharide (LPS) treatments to isolated cardiomyocytes were used. In FIP mice, myocardial IL-33 and MMP-9 expression were increased and myocardial contractility was decreased. Myocardial function in FIP mice was improved when treated …

Modeling Oxygen Transport In Three-Dimensional Capillary Networks, Graham M. Fraser

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to examine how the use of real 3-dimensional (3D) capillary network geometries affect models of oxygen transport to tissue. Software was developed to reconstruct microvascular geometry in 3D from intravital video. Characterization of 3D reconstructions demonstrated that capillary density, length and capillary diameter were consistent with previous findings. Using reconstructed capillary networks a strategy was devised that utilized red blood cell (RBC) supply rate (SR) as a metric for flow modeling. Applying the RBC SR based flow model on baseline and perturbed flow conditions demonstrated that RBC SR is a major determinant of oxygen …