Alexandra R Lucas

Alexandra R Lucas
University of Florida | UF · Division of Cardiovascular Medicine

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189
Publications
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Publications

Publications (189)
Article
Full-text available
Immune cell invasion after the transplantation of solid organs is directed by chemokines binding to glycosaminoglycans (GAGs), creating gradients that guide immune cell infiltration. Renal transplant is the preferred treatment for end stage renal failure, but organ supply is limited and allografts are often injured during transport, surgery or by c...
Article
Full-text available
The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study...
Article
Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX). Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and h...
Chapter
Serine protease inhibitors are ubiquitous regulators for a multitude of pathways in humans. The serpins represent an ancient pathway now known to be present in all kingdoms and often regulating central pathways for clotting, immunity, and even cancer in man. Serpins have been present from the time of the dinosaurs and can represent a large proporti...
Chapter
Biochemical fluorogenic and chromogenic assays facilitate real-time study of enzyme function. Based on the principle of enzymatic inhibition, these kinetic assays can be adapted to measure the function of serpins. Compared to traditional, electrophoretic study of serpin inhibitory complex formation, kinetic assays allow for finer temporal resolutio...
Chapter
Serine protease inhibitors, or serpins, function as central regulators for many vital processes in the mammalian body, maintaining homeostasis for clot formation and breakdown, immune responses, lung function, and hormone or central nervous system activity, among many others. When serine protease activity or serpin-mediated regulation becomes unbal...
Chapter
Serine protease inhibitors, serpins, can have profound effects on many systems in the body including immune defense systems. The microbiome, specifically the gut and lung bacterial microbiota, is now known, under some conditions, to alter immune defenses. DNA library preparation for microbiome studies is a procedure that prepares microbial genomic...
Chapter
Serpins have a wide range of functions in regulation of serine proteases in the thrombotic cascade and in immune responses, representing up to 2–10% of circulating proteins in the blood. Selected serpins also have cross-class inhibitory actions for cysteine proteases in inflammasome and apoptosis pathways. The arterial and venous systems transport...
Chapter
Serpins function as a trap for serine proteases, presenting the reactive center loop (RCL) as a target for individual proteases. When the protease cleaves the RCL, the serpin and protease become covalently linked leading to a loss of function of both the protease and the serpin; this suicide inhibition is often referred to as a “mouse trap.” When t...
Article
Full-text available
Early damage to transplanted organs initiates excess inflammation that can cause ongoing injury, a leading cause for late graft loss. The endothelial glycocalyx modulates immune reactions and chemokine-mediated haptotaxis, potentially driving graft loss. In prior work, conditional deficiency of the glycocalyx-modifying enzyme N-deacetylase-N-sulfot...
Article
Full-text available
The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a 'first-in-class' therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been de...
Article
Aims: Atrial fibrillation (AF) ablation is associated with increased circulating markers of inflammation. Innate immune, or inflammation, pathways up-regulate mononuclear cell responses and may increase risk for recurrent arrhythmia. Chemokines and serine protease coagulation pathways both activate innate immune responses. Here, we measured inflam...
Article
Full-text available
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium o...
Article
Full-text available
Serpins regulate coagulation and inflammation, binding serine proteases in suicide inhibitory complexes. Target proteases cleave the serpin reactive center loop (RCL) scissile P1-P1' bond resulting in serpin-protease suicide inhibitory complexes. This inhibition requires a near full-length serpin sequence. Myxomavirus Serp-1 inhibits thrombolytic a...
Article
Aim: Ser ine p rotease in hibitors ( Serpins ) regulate key clotting and inflammatory pathways. Two anti-inflammatory Serpins , neuroserpin (NSP) and Serp-1 markedly reduce arterial inflammation and plaque growth in a rodent aortic transplant vasculitis model after single dose infusion. NSP is a mammalian serpin that inhibits thrombolytic proteases...
Article
Introduction: Periodontal disease (PD) is a polymicrobial dysbiotic chronic inflammatory disease produced by a complex subgingival microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). American Heart Association supported the association between PD and ASVD but not causal association. Prior reports investigated...
Article
We report a rare case of left atrial myxoma with concomitant classical Hodgkin's lymphoma in a 36-year-old woman with a non-significant medical history and 4 months of progressively worsening palpitations, dyspnoea on exertion, chest discomfort and fatigue. Outpatient echocardiography revealed functional mitral valve stenosis as a result of a large...
Article
The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6(-/-) mouse to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and F...
Article
Full-text available
The American Heart Association supports an association between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) but does not as of yet support a causal relationship. Recently, we have shown that major periodontal pathogens Porphyromonas gingivalis and Treponema denticola are causally associated with acceleration of aortic athero...
Article
Full-text available
Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide rang...
Article
Tannerella forsythia is a Gram-negative anaerobic organism that inhabits the subgingival cavity and initiates connective tissue destruction and alveolar bone resorption in periodontal disease (PD). PD is a chronic immunoinflammatory disease and has been linked to several systemic diseases including atherosclerosis. This study evaluated the effects...
Chapter
Full-text available
Serine protease inhibitors, termed serpins, regulate myriad physiological processes in the mammalian body from thrombotic and thrombolytic pathways to inflammation, angiogenesis, hormone transport, and hypertension. The large percentage of serpins among the plasma proteins in the circulating blood as in the case of plasminogen activators, the funct...
Conference Paper
Full-text available
A 65-year-old man presented with long-standing rheumatoid arthritis (RA), severe fatigue and mild arthritis of metacarpophalaneal joints. Physical examination revealed S3, II/IV decrescendo diastolic murmur and 2+ LL oedema. Anticyclic citrullinated peptide antibodies were >250 units. Echocardiogram showed an 8 cm pericardial mass with no atrial or...
Article
Full-text available
Inflammation of the retina is a contributing factor in ocular diseases such as uveitis, diabetic retinopathy, and age related macular degeneration (AMD). The M013 immunomodulatory protein from myxoma virus has been shown to interfere with the pro-inflammatory signaling pathways involving both the NLRP3 inflammasome and NF-κB. We have developed and...
Article
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Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase reste...
Conference Paper
The host recognizes periodontal pathogens by activation of the innate immune system pattern recognition receptors (PRRs). Toll-like receptor 2 (TLR2) is a PRR that is strongly activated by periodontal pathogens, and implicated in periodontal disease (PD) and atherosclerosis. Atherosclerosis has a strong inflammatory component, in which TLR2 signali...
Article
Many viruses encode virulence factors to facilitate their own survival by modulating a host's inflammatory response. One of these factors, secreted from cells infected with myxoma virus, is the serine proteinase inhibitor (serpin) Serp-1. Because Serp-1 had demonstrated anti-inflammatory properties in arterial injury models and viral infections, it...
Article
Full-text available
Atherosclerotic vascular disease is a leading cause of myocardial infarction and cerebrovascular accident, and independent associations with periodontal disease (PD) are reported. PD is caused by polymicrobial infections and aggressive immune responses. Genomic DNA of Porphyromonas gingivalis, the best-studied bacterial pathogen associated with sev...
Conference Paper
Background: Cryoballoon ablation (CB) for atrial fibrillation (AF) activates inflammation that may lead to increased atrial fibrosis, thrombosis, and recurrent arrhythmia. Two viral anti-inflammatory proteins, M-T7 (a chemokine/glycosaminoglycan inhibitor) and Serp-1 (a serine protease inhibitor) have proven anti-inflammatory activity in animal mod...
Conference Paper
Background: Activation of innate immune responses after atrial fibrillation (AF) ablation may lead to collateral atrial myocardial damage, fibrosis, and recurrent arrhythmia. The extent of the inflammatory response to cryoballoon ablation (CB) is not yet well defined. Non-specific inflammation suppression with corticosteroids has had a varied clini...
Conference Paper
Complex subgingival bacteria synergistically mediate periodontal disease (PD) progression. Innate immune recognition by toll-like receptors (TLRs) plays a primordial role in recognition of bacteria and TLR4 expression seen in gingival epithelium-connective tissue interface of patients with PD. The role of active chronic Polymicrobial periodontal in...
Article
Full-text available
Treponema denticola is a predominantly subgingival oral spirochete closely associated with periodontal disease and has been detected in atherosclerosis. This study was designed to evaluate causative links between periodontal disease induced by chronic oral T. denticola infection and atherosclerosis in hyperlipidemic ApoE−/− mice. ApoE−/− mice (n =...
Article
Full-text available
Abdominal aortic aneurysms are often fatal due to atherosclerosis, thromboembolism, rupture, and hemorrhage, however, treatment is limited to expectant monitoring and surgical intervention. Inflammation is detected in aneurysms and in plaque with associated increased apoptosis, chemokines, cytokines, hemorrhage, and thrombosis. We compared treatmen...
Article
Viral chemokine modulating proteins provide new and extensive sources for therapeutics. Purified M-T7, a poxvirus-derived secreted immunomodulatory protein, reduces mononuclear cell invasion and atheroma in rodent models of angioplasty injury as well as aortic and renal transplant, improving renal allograft survival. M-T7 is a rabbit species-specif...
Conference Paper
Background Lethal viral infections produce widespread inflammation with vascular leakage, clotting and bleeding (DIC), and high mortality, up to 40–70% in disseminated viral infections. Treatment for sepsis and DIC remains very limited. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by a cyto...
Article
Full-text available
Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migr...
Article
Serpins in the mammalian body are highly potent serine protease inhibitors which modulate both thrombotic and thrombolytic pathway activation, with direct and indirect crosstalk with immune and inflammatory pathways. In this review, we discuss mammalian and viral serpins as regulators of coagulation and inflammation. We focus first on the thromboti...
Article
Full-text available
Serine protease inhibitors (Serpins) play an important role in regulating a wide array of diverse biological activities, representing up to 2-10% of circulating plasma proteins. The serpin suicide inhibitors regulate coagulation (thrombosis and thrombolysis), neurotrophic factors, hormone transport, complement and inflammation, angiogenesis, hormon...
Article
Full-text available
Lethal viral infections produce widespread inflammation with vascular leak, clotting and bleeding (disseminated intravascular coagulation, termed DIC), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce syste...
Article
Aim Atherosclerosis is characterized by chronic inflammation and cell death (apoptosis). Serine protease inhibitors, or serpins, regulate inflammatory, thrombotic and apoptotic pathways. Poxviruses encode cross-class serpins that prevent host cell apoptosis. Serp-2, from Myxoma, reduces plaque, inflammation and apoptosis in animal models; CrmA, fro...
Article
Background Glucocorticoids are a principal treatment for giant cell arteritis (GCA), with some studies reporting predominate effect on T helper17 (Th17) cell activity in GCA, with lesser effects on other inflammatory cells. Serp-1 is a 55kDa myxomaviral serpin that modifies macrophage, Th1, and Th17 responses in aortic transplants in animal models....
Article
Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with a critical role in tumor invasion, growth, angiogenesis, and metastasis. Increased serine proteases in the thrombolytic cascade, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory c...
Article
Background Lethal viral infections produce widespread inflammation with vascular leaking, clotting and bleeding (DIC), and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by a cytokine storm and also induce systemic inflammation. Normal host ser ine p roteases in hibitor ( serp...
Conference Paper
Objective: Periodontal disease (PD) and Atherosclerotic Vascular Disease (ASVD), are chronic, multifactorial, and polymicrobial in nature. PD has been associated as a contributing factor to multiple systemic diseases, including ASVD, diabetes, rheumatoid arthritis, and Alzheimer’s disease. Recently, the American Heart Association supported the asso...
Conference Paper
Objective: Periodontal disease (PD) is caused by chronic infection with polymicrobial subgingival pathogens (Porphyromonas gingivalis (P.gingivalis), Treponema denticola (T.denticola), Tannerella forsythia (T.forsythia) and Fusobacterium nucleatum (F.nucleatum)). PD is now recognized as a risk factor for atherosclerotic vascular disease (ASVD). Num...
Article
Full-text available
Periodontal disease (PD) and atherosclerosis are both polymicrobial and multifactorial and although observational studies supported the association, the causative relationship between these two diseases is not yet established. Polymicrobial infection-induced periodontal disease is postulated to accelerate atherosclerotic plaque growth by enhancing...
Article
Full-text available
Many patients suffering from angina pectoris are treated with percutaneous coronary intervention (PCI) and quickly develop angiographic renarrowing, or restenosis, at the site of PCI treatment. Restenosis is thought to arise from the combinatorial activation of thrombotic and inflammatory responses. The inflammatory response responsible for resteno...
Article
Full-text available
Poxviruses express highly active inhibitors, including serine proteinase inhibitors (serpins), designed to target host immune defense pathways. Recent work has demonstrated clinical efficacy for a secreted, myxomaviral serpin, Serp-1, which targets the thrombotic and thrombolytic proteases, suggesting that other viral serpins may have therapeutic a...
Data
Viral cross-class serpins alter Staurosporine-induced apoptotic responses in T cells and monocytes, in vitro. Apoptotic responses were induced in T cells and monocytes using staurosporine. The ability of Serp-2, CrmA, or Serp-2 mutants to counteract this induction was measured by granzyme B and caspase 8 activity by IEPDase activity. Serp-2, but no...
Conference Paper
Objective: Periodontal diseases are among the most common chronic infections of mankind and are caused by polymicrobial subgingival pathogens (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia). A number of studies have demonstrated an association between periodontal disease and an increased risk for cardiovascular disease and...
Article
Inflammatory responses now have a defined central role in cancer cell growth, invasion, and metastases. Anti-inflammatory proteins from viruses target key stages in immune response pathways and have potential as novel therapeutics for cancer, including highly potent virus-derived inhibitors of protease, chemokine, cytokine, and apoptotic cascades t...
Article
Viruses express an arsenal of anti-inflammatory proteins that are being developed as immunotherapeutic drugs to treat cardiovascular disease. M-T7, a myxoma viral protein, has been shown to significantly block cell invasion and plaque growth after balloon angioplasty injury and transplantation. The binding target of M-T7 during a myxoma infection i...
Article
Vasculitic syndromes cause devastating arterial occlusion with associated end organ ischemia and significant morbidity. Treatment for vasculitic syndromes remains very limited. Gamma 68 herpesvirus (g68HV) infection in interferon gamma receptor deficient (IFNγR -/- ) mice provides a good working model of artery inflammation, inducing early death wi...