Jamie E. Meegan

• Doctor of Philosophy
• PostDoc Position at Vanderbilt University

Elevated circulating cell-free hemoglobin (Hb) is a pathological driver of endothelial injury and contributes to disease severity and organ dysfunction during several pathologies, including sickle cell disease, pulmonary hypertension, primary graft dysfunction after lung transplantation, and sepsis. However, the signaling mechanisms involved in Hb-...

Objectives/Goals: • To determine the impact of liraglutide on inflammation and organ injury during sepsis. • To investigate the protective effects of liraglutide on microvascular dysfunction in a clinically relevant model of sepsis. • To provide evidence for the potential therapeutic use of GLP-1 receptor agonists in endothelial dysfunction in seps...

Blood-brain barrier (BBB) dysfunction occurs in numerous central nervous system disorders. Unfortunately, a limited understanding of the mechanisms governing barrier function hinders the identification and assessment of BBB-targeted therapies. Previously, we found that non-muscle myosin light chain kinase (nmMLCK) negatively regulates the tight jun...

Background: Sepsis results in significant organ damage due in part to a breakdown in endothelial vascular function. Elevated levels of cell-free hemoglobin (CFH) drive endothelial dysfunction in the lungs. CFH generates reactive oxygen species (ROS) via the iron present in the heme moiety, which can be oxidized from ferrous (CFH2+) to ferric (CFH3+...

Introduction: Lung microvascular endothelial barrier disruption is a critical feature of acute lung injury during several pathologies, including sepsis. Plasma cell-free hemoglobin (CFH) is elevated in approximately 80% of patients with sepsis and is independently associated with development of acute respiratory distress syndrome (ARDS) and mortali...

Introduction: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection characterized by increased systemic inflammation and microvascular injury. Recently, commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have demonstrated unexpected anti-inflammatory effect...

Background: During sepsis, red blood cells lyse and release cell-free hemoglobin (CFH) into the circulation causing vascular dysfunction and ROS production. The heme moiety of CFH is normally in the CFH ²⁺ oxidative state but can be oxidized to CFH ³⁺ and CFH ⁴⁺ . Our knowledge of which oxidation state of CFH causes vascular injury remains unknown....

Introduction: Disruption of the microvascular endothelial barrier is a critical pathological feature of sepsis-induced acute lung injury. Plasma cell-free hemoglobin (CFH) is elevated in approximately 80% of patients with sepsis and is independently associated with development of acute respiratory distress syndrome (ARDS) and mortality. Oxidized CF...

Cell-free hemoglobin is a pathophysiological driver of endothelial injury during sepsis and acute respiratory distress syndrome (ARDS), but the precise mechanisms are not fully understood. We hypothesized that hemoglobin (Hb) increases leukocyte adhesion and endothelial activation in human lung microvascular endothelial cells (HLMVEC). We stimulate...

Circulating cell‐free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemo...

Sepsis is a devastating disease with high morbidity and mortality and no specific treatments. The pathophysiology of sepsis involves a hyperinflammatory response and release of damage-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), from activated and dying cells. Purinergic receptors activated by ATP have gained atten...

Sepsis is a critical problem in intensive care units globally, and accounts for 20% of all annual deaths. During septic shock, the highly inflammatory state leads to the release of cell-free hemoglobin (CFH) from lysed red blood cells. Once released into the vascular circulation, CFH can oxidize from the normal ferrous 2+ state to methemoglobin (3+...

Introduction: Sepsis, a dysregulated host response to infection with high morbidity and mortality, is characterized by a systemic inflammatory response and widespread vascular hyperpermeability leading to edema, organ dysfunction, and death with no specific treatments. Disruption of the microvascular endothelial barrier is a critical pathological...

Mouse models of acute lung injury (ALI) have been instrumental for studies of the biologic underpinnings of lung inflammation and permeability, but murine models of sepsis generate minimal lung injury. Our goal was to create a murine sepsis model of ALI that reflects the inflammation, lung edema, histologic abnormalities and physiologic dysfunction...

Circulating cell-free hemoglobin (CFH) contributes to endothelial injury in several inflammatory and hemolytic conditions. We and others have shown that CFH causes increased endothelial permeability, but the precise mechanisms of CFH-mediated endothelial barrier dysfunction are not fully understood. Based on our previous study in a mouse model of s...

Levels of circulating cell-free hemoglobin are elevated during hemolytic and inflammatory diseases and contribute to organ dysfunction and severity of illness. Though several studies have investigated the contribution of hemoglobin to tissue injury, the precise signaling mechanisms of hemoglobin-mediated endothelial dysfunction in the lung and othe...

Non-invasive sampling of the distal airspace in patients with Acute Respiratory Distress Syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from Heat Moisture Exchange filters (HME) closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to det...

Objectives We previously reported microvascular leakage resulting from fibrinogen-γ chain C-terminal products (γC) occurred via a RhoA-dependent mechanism. The objective of this study was to further elucidate the signaling mechanism by which γC induces endothelial hyperpermeability. Since it is known that γC binds and activates endothelial αvβ3, a...

Cell‐free hemoglobin is released into the circulation during conditions in which red blood cell lysis occurs such as hemolytic disorders and sepsis. In septic patients, increased levels of circulating cell‐free hemoglobin are independently associated with mortality and contribute to organ dysfunction, including acute respiratory distress syndrome (...

During sepsis, circulating levels of cell‐free hemoglobin (CFH) are often elevated due to the lysis of red blood cells, and higher concentrations are associated with worse clinical outcomes. Sepsis is caused by a widespread inflammation response, which leads to the release of pro‐inflammatory molecules and cytokines into the circulation. These comp...

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular...

Aims: Microvesicles (MVs) conduct intercellular communication and impact diverse biological processes by transferring bioactive cargos to other cells. We investigated whether and how endothelial production of MVs contribute to vascular dysfunction during inflammation. Methods and results: We measured the levels and molecular properties of endoth...

Objective The endothelial glycocalyx constitutes part of the endothelial barrier but its degradation leaves endothelial cells exposed to transmigrating cells and circulating mediators that can damage the barrier or promote intercellular gaps. Syndecan proteins are key components of the endothelial glycocalyx and are shed during disease states where...

The microvascular endothelium serves as the major barrier that controls the transport of blood constituents across the vessel wall. Barrier leakage occurs during infection or sterile inflammation, allowing plasma fluid and cells to extravasate and accumulate in surrounding tissues, an important pathology underlying a variety of infectious diseases...

Inflammation-induced blood–brain barrier (BBB) dysfunction and microvascular leakage are associated with a host of neurological disorders. The tight junction protein claudin-5 (CLDN5) is a crucial protein necessary for BBB integrity and maintenance. CLDN5 is negatively regulated by the transcriptional repressor FOXO1, whose activity increases durin...

Endothelial surface glycocalyx composed of glycosaminoglycans, proteoglycans and glycoproteins plays an important role in regulating vascular barrier integrity. A disintegrin metalloprotease 15 (ADAM15) is a membrane‐associated sheddase which has recently been characterized as a mediator of endothelial hyperpermeability during inflammation. This st...

The endothelial glycocalyx (GCX) is a complex matrix of glycosaminoglycans and proteoglycans such as syndecans (SDCs), which form a protective layer on the vascular luminal surface contributing to the endothelial barrier function. Ectodomain shedding of transmembrane proteoglycans or degradation of GCX components can damage barrier integrity. The o...

Aims: Endothelial hyperpermeability exacerbates multiple organ damage during inflammation or infection. The endothelial glycocalyx, a protective matrix covering the luminal surface of endothelial cells (ECs), undergoes enzymatic shedding during inflammation, contributing to barrier hyperpermeability. A disintegrin and metalloproteinase 15 (ADAM15)...

Disruption of vascular endothelial barrier results in excessive accumulation of plasma proteins and fluid within the interstitial space, exacerbating tissue injury caused by infection or sepsis. There is an urgent need to explore effective strategies to restore vascular barrier integrity in patients with sepsis. Glycocalyx, an endothelial surface c...

Circulating extracellular histones are known to contribute to tissue injury in systemic inflammatory responses to infection, trauma, and burns. The mechanisms of histone modifications and their effects on inflammation are currently being investigated. One such modification, namely citrullination of histone 3, is catalyzed by the peptidylarginine de...

The endothelial glycocalyx (eGCX) is a protective barrier on the luminal surface of endothelial cells. The syndecan family of proteoglycans constitute integral components of the eGCX and can act as receptors for many cell signaling pathways. Under inflammatory conditions, the eGCX can be cleaved and shed by proteases such as matrix metalloproteinas...

Microparticles (MPs) are small membrane vesicles released by activated cells in response to physical or biological stimulation. They mediate cell‐cell communication by transferring a cargo of cell surface receptors, mRNAs, and microRNAs to target cells. Recent studies have shown an altered MP production in the circulation during inflammation or sep...

Neutrophil extracellular traps (NETs) are DNA‐webs containing histones and granular enzymes produced by neutrophils during host defense against infection. It is becoming increasingly apparent that circulating NETs exacerbate tissue injury associated with inflammation. The purpose of this study was to determine the effects of NETs on endothelial bar...

Neutrophils play an essential role in host defense against infection or injury. While neutrophil activation is necessary for pathogen clearance and tissue repair, a hyperactive response can lead to tissue damage and microcirculatory disorders, a process involving complex neutrophil-endothelium crosstalk. This review highlights recent research findi...

Endothelial dysfunction is a hallmark of systemic inflammatory response underlying multiple organ failure. Here we report a novel function of DHHC-containing palmitoyl acyltransferases (PATs) in mediating endothelial inflammation. Pharmacological inhibition of PATs attenuates barrier leakage and leucocyte adhesion induced by endothelial junction hy...

Supplementary Figures 1-5 and Supplementary Tables 1-7.

Neutrophil extracellular traps (NETs) participate in host defense against infection. Increased levels of NETs have been detected in patients with systemic inflammatory response syndrome (SIRS). Furthermore, several animal models of SIRS have shown that circulating NETs exacerbate vascular injury in inflammation. The purpose of this study was to det...

Blood-brain barrier (BBB) dysfunction is a hallmark of neuroinflammation brought on by pathologies such as stroke and amyloid angiopathy. Inflammatory cytokines that act directly on cerebral endothelium can impair tight junction (TJ) stability. We previously identified a mechanism for IL-1β-mediated dysfunction involving inactivation of the PI3K/Ak...

Blood-brain barrier (BBB) dysfunction is a hallmark of neuroinflammation brought on by pathologies such as stroke and amyloid angiopathy. Inflammatory cytokines that act directly on cerebral endothelium can impair tight junction (TJ) stability. We previously identified a mechanism for IL-1β-mediated dysfunction involving inactivation of the PI3K/Ak...