LitCovid-sentences  

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T7 0-61 Sentence denotes Establishing a foundation for COVID-19 and vascular pathology
T8 63-82 Sentence denotes The vascular system
T9 83-316 Sentence denotes The vascular system also referred to as the circulatory system or vascular tree carries blood, oxygen and essential elements to all metabolically active tissues and organs of the body and carries waste materials and by-products away.
T10 317-528 Sentence denotes There are five distinct components of the circulatory system: arteries and arterioles (arterial system), veins and venules (venous system) and capillaries (microvascular system) that link arterioles and venules.
T11 529-669 Sentence denotes The dimensions of blood vessels vary by an order of several thousand-fold with capillaries as small as 10 µm to the aorta of 25 mm (Fig. 1).
T12 670-835 Sentence denotes Fig. 1 The circulatory system consists of the heart and large, medium and small arteries (arterioles), capillaries, small veins (venules, sinusoids) and large veins.
T13 836-1055 Sentence denotes Normal function depends on the flow of blood (and nutrients) to and from vital organs; however, the microvessels (arterioles, capillaries and venules) are responsible for vascular tone, homeostasis and tissue perfusion.
T14 1056-1060 Sentence denotes From
T15 1061-1137 Sentence denotes Endothelial cells respond to injury in several stages (reviewed in Abraham).
T16 1138-1526 Sentence denotes While there may be injurious agent-specific responses, in a majority of cases the initial event is triggered by infection (viral, bacterial), oxidative stress, hypoxia, turbulent blood flow and shear stress, environmental toxins and circulating elements that follow tissue injury with the release of cell-free nucleic acids, histones, chemokines, cytokines and damage-associated proteins.
T17 1527-1671 Sentence denotes The two-level response to endothelial cell injury includes an initial rapid response and a slower phenotypic response (reviewed in Abraham) [1].
T18 1672-1892 Sentence denotes Briefly, the initial response causes sudden changes in endothelial cell protective or integrity proteins, including nitric oxide, prostaglandins, endothelins, von Willebrand factor (VWF) and tissue plasminogen activator.
T19 1893-2056 Sentence denotes The slower phenotype response reflects structural changes of endothelial cell topography, cell orientation, basement membranes and surrounding smooth muscle cells.
T20 2057-2391 Sentence denotes In addition to the extent of initial injury, phenotypic changes follow a response to injury with release of endocrine and paracrine factors, primarily growth factors that provoke the deposition of extracellular matrix and the activation and proliferation of smooth muscle cells, pericytes and mesenchymal cells within the vessel wall.
T21 2392-2487 Sentence denotes Vessel remodeling can occur with changes in cellular architecture and function [2, 3] (Fig. 2).
T22 2488-2947 Sentence denotes Fig. 2 Pf4+-macrophages are the major resource to generate second wave of pro-inflammatory factors at late stage of IAV-driven pneumonia. a Heat-maps showing the normalized expression (Z-score) of the pro-inflammatory genes in the various cells of clusters with high ratios at day 7 p.i.. b The normalized expression (UMI counts) of some significant genes with high expression in different clusters at day 7 p.i.. c Pf4+ cells in the lung after IAV infection.
T23 2948-3050 Sentence denotes The tdtomato-Pf4 mice were uninfected or infected with 0.5 LD50 of influenza A/PR/8/34 (H1N1) viruses.
T24 3051-3114 Sentence denotes At day 7 p.i, the tdtomato-Pf4+ cells in the lung were scanned.
T25 3115-3194 Sentence denotes The nucleus was stained with DAPI (blue) and tomato-Pf4 (red) was shown in red.
T26 3195-3294 Sentence denotes Scale bars, 500 μm. d At day 0 and day 7 p.i., the tdtomato-Pf4+ cells in the lung were calculated.
T27 3295-3370 Sentence denotes At least 300 cells in each group from three independent assays were scored.
T28 3371-3481 Sentence denotes Data are shown as the mean ± SD. **, P < 0.01 (Student t test, n = 3). e The expression of Ccl2 in Pf4+ cells.
T29 3482-3570 Sentence denotes The tdTomato-Pf4 mice were infected with 0.5 LD50 of influenza A/PR/8/34 (H1N1) viruses.
T30 3571-3668 Sentence denotes At day 7 p.i, the tdTomato-Pf4+ cells in the lung were stained with anti-Ccl2 antibodies (green).
T31 3669-3750 Sentence denotes The nucleus was stained with DAPI (blue) and Pf4-tdTomato (red) was shown in red.
T32 3751-4129 Sentence denotes Scale bars, left, 200 μm; right, 50 μm. f Heatmap showing the scaled distances calculated based on Pearson correlations for relationships between the z-score normalized mean expression profiles in all the indicated cells. g PCA plot showing the relationships among the indicated cell clusters and the megakarycytes from lung and bone mellow described by others (SRP097794, NCBI)
T33 4130-4144 Sentence denotes (From Zhang J.
T34 4145-4175 Sentence denotes PLoS Pathol 2020;16: e1008334.
T35 4176-4192 Sentence denotes With permission)
T36 4194-4242 Sentence denotes The vascular endothelium: structure and function
T37 4244-4270 Sentence denotes Vascular endothelial cells
T38 4271-4435 Sentence denotes The complex structure–function relationship of vascular endothelial cells has fascinated pathologists, physiologists, protein chemists and scientists for centuries.
T39 4436-4687 Sentence denotes The structural aspects of endothelial cells are themselves deceivingly simple and divided into three distinct surfaces: the luminal surface (non-thrombogenic), the cohesive junctional surface and an adhesive abluminal surface (reviewed in Tucker) [4].
T40 4688-4857 Sentence denotes The functional roles and broad-reaching intricacies of each surface are highly complex and, in many ways, distinguish normal physiology from pathological conditions [5].
T41 4858-5848 Sentence denotes The vascular endothelium’s functional role is separated into distinct parts: (1) barrier function—highly selective and regulates inflammatory and immune responses, (2) transport function—responsible for cell–cell signaling and pinocytosis (i.e. particles in extracellular fluid enter the cell through invaginations or clefts in the cell membrane), (3) vascular repair function-restores structural and functional normalcy, (4) angiogenesis function-reparative and adaptive to injurious conditions, (5) thromboregulation function- supports physiological blood flow and prevents unwanted (or needed) blood clotting, (6) vasoregulation function—responds to local conditions and signals vasodilation or vasoconstriction, (7) metabolic function—responsible for a highly regulated synthesis of growth factors, adhesion molecules and receptors; and (8) immune function-responds to a variety of immune cells, expresses histocompatibility antigens and regulates antigen presenting cells [6] (Fig. 3).
T42 5849-6100 Sentence denotes Fig. 3 Endothelial cells exhibit a broad range of functions that include physical barrier, endocrine, paracrine and autocrine, vascular remodeling and repair, regulation of thrombosis, regulation of inflammation, cell migration and cellular signaling.
T43 6101-6396 Sentence denotes Endothelial cell (EC), nitric oxide (NO), prostacyclin (PGI2), endothelin (ET), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI)-1, inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, platelet/endothelial cell adhesion molecule (PECAM)-1
T44 6397-6485 Sentence denotes The vascular endothelium constitutes an inner lining of arteries, veins and capillaries.
T45 6486-6606 Sentence denotes Accordingly, it is in direct communication with circulating blood components and tissues (reviewed in Krüger-Genge) [7].
T46 6607-6739 Sentence denotes In addition to its fundamental substrate delivery capabilities, the vascular endothelium is an active endocrine and paracrine organ.
T47 6740-6850 Sentence denotes Moreover, it is tissue-specific, carrying out specialized functions as needed under highly dynamic conditions.
T48 6851-7045 Sentence denotes Even a brief summary of vascular endothelium structure and function underscores its critical role in human health and disease, and the potential consequences of injury and resulting dysfunction.
T49 7046-7225 Sentence denotes These include, but are not limited to, vascular integrity, permeability, cellular/tissue cross talk, and the regulation of vasomotor activity, coagulation and inflammation [7, 8].
T50 7227-7258 Sentence denotes Microvascular endothelial cells
T51 7259-7420 Sentence denotes The microcirculation is represented by blood vessels of the smallest diameter (terminal arterioles, capillaries, and venules), but overall greatest surface area.
T52 7421-7530 Sentence denotes In addition, the microcirculation plays a critical role in tissue perfusion and exchange of vital substrates.
T53 7531-7811 Sentence denotes While smooth muscle cells are present within the walls of microvessels, specialized cells known as pericytes embedded in the basement membrane also play an important role in regulating tone, maintaining vascular integrity and phagocytosing cellular debris [9] (reviewed in Lee L.)
T54 7813-7844 Sentence denotes Vascular endothelial glycocalyx
T55 7845-8077 Sentence denotes The luminal surface of endothelial cells within arteries, veins and microvessels is coated with a thin (~ 500 nm) glycocalyx layer of plasma proteins, sulfated proteoglycans, glycoproteins and hyaluronan (reviewed in Weinbaum) [10].
T56 8078-8252 Sentence denotes Endothelial cell glycocalyx has several recognized functions, including maintaining vascular integrity, permeability, shear stress, mechanosensing and inflammatory responses.
T57 8253-8331 Sentence denotes Leukocytes traversing a small-caliber capillary actually crush the glycocalyx.
T58 8332-8451 Sentence denotes The transient deformation quickly corrects due to the elasticity of core proteins that behave like elastic fibers [11].
T59 8452-8545 Sentence denotes The properties of vascular endothelial glycocalyx layer change under inflammatory conditions.
T60 8546-8677 Sentence denotes Cytokine-mediated activation of proteases partially degrade the layer permitting leukocyte rolling, tethering and recruitment [12].
T61 8678-8775 Sentence denotes An intact glycocalyx can regulate the degree of leukocyte capture, recruitment and extravasation.
T62 8776-8970 Sentence denotes Endothelial glycocalyx degradation occurs in chronic disease states like diabetes mellitus [13], significantly impacting responses to acute infectious and metabolic conditions [14, 15] (Fig. 4).
T63 8971-9581 Sentence denotes Fig. 4 Structure of the endothelial glycocalyx/endothelial surface layer. a Endothelial glycocalyx thickness is larger than the endothelial cell itself, as demonstrated by electron microscopy of ruthenium-red labeled rat myocardial capillaries. In vivo, the glycocalyx forms an even more substantial ESL, with thickness > 1 µm. b Pathological degradation of the glycocalyx/ESL during critical illnesses (such as sepsis) causes not only local endothelial injury, but also releases biologically active heparan sulfate fragments into the circulation that may influence signaling processes in an endocrine fashion.
T64 9582-9724 Sentence denotes For simplicity, chondroitin sulfate and hyaluronic acid are not shown. α4 and β4 refer to glycosidic bonds connecting constituent saccharides.
T65 9725-9868 Sentence denotes Inset: structure of a heparan sulfate octasaccharide fragment, demonstrating potential sites of sulfation within constituent disaccharide units
T66 9869-9884 Sentence denotes (From Oshima K.
T67 9885-9915 Sentence denotes Pulmonary Circulation 2017; 8:
T68 9916-9921 Sentence denotes 1–10.
T69 9922-9938 Sentence denotes With permission)
T70 9940-9953 Sentence denotes Baroreceptors
T71 9954-10077 Sentence denotes The arterial baroreceptor system is intimately involved with maintaining vascular tone and blood pressure homeostasis [16].
T72 10078-10307 Sentence denotes Arterial baroreceptors (stretch receptors located in the carotid sinuses and aortic arch) provide continuous feedback on blood pressure to the central nervous system, which responds with physiological efferent autonomic activity.
T73 10308-10534 Sentence denotes Activation of arterial baroreceptors in response to increased blood pressure causes activation of vagal cardio-inhibitory neurons and a decrease of sympathetic neuron discharges to the heart and peripheral resistance bed [17].
T74 10535-10651 Sentence denotes The end-result is a decrease in heart rate, cardiac contractility, peripheral vascular resistance and venous return.
T75 10652-10819 Sentence denotes By contrast, a decrease in sympathetic activity and vagal inhibition, leads to tachycardia and heightened cardiac contractility, vascular resistance and venous return.
T76 10820-10943 Sentence denotes Baroreflex activity responds to the influence of many factors, including respiratory, behavioral and environmental factors.
T77 10944-11178 Sentence denotes Common cardiovascular diseases, ranging from coronary artery disease, myocardial infarction, essential hypertension and heart failure are associated with baroreceptor reflex abnormalities, primarily chronic adrenergic activation [18].
T78 11179-11323 Sentence denotes Whether or not COVID-19 associated vascular injury causes baroreceptor reflex abnormalities is a question under investigation in our laboratory.
T79 11325-11372 Sentence denotes How do endothelial cells regulate inflammation?
T80 11373-11526 Sentence denotes The anti-inflammatory properties that characterize normal vascular endothelium are governed by a variety of external signals and intracellular mediators.
T81 11527-11710 Sentence denotes The operative external signals include anti-inflammatory cytokines, transforming growth factor β, interleukin (IL)-10, IL-1 receptor agonist, and high-density lipoprotein cholesterol.
T82 11711-11844 Sentence denotes Laminar shear stress, through the generation of nitric oxide, is of particular importance in maintaining inflammoresistance [19, 20].
T83 11846-11891 Sentence denotes How do endothelial cells regulate thrombosis?
T84 11892-12077 Sentence denotes The normal vascular endothelium contains natural anticoagulants, platelet inhibitors, and fibrinolytic proteins that function in an integrated fashion to maintain vital organ perfusion.
T85 12078-12379 Sentence denotes Because tissue factor, expressed locally at sites of vessel wall injury and from circulating monocytes [21] plays a pivotal role in the thrombotic phenotype of coronary atherosclerosis, an important surface protein antagonist, tissue factor pathway inhibitor (TFPI), has gained considerable attention.
T86 12380-12640 Sentence denotes A variety of other surface proteins, including protein C, protein S, protein Z, nitric oxide, glycosaminoglycans, β2-glycoprotein 1, tissue plasminogen activator, urokinase-like plasminogen activator and thrombomodulin among others play critical roles [22–24].
T87 12642-12685 Sentence denotes How do endothelial cells facilitate repair?
T88 12686-12859 Sentence denotes Angiopoietin-1 tyrosine protein kinase receptor related Tie-2 signaling in endothelial cells plays a pivotal role in wound healing, vascular integrity and angiogenesis [25].
T89 12860-13055 Sentence denotes Individually, angiopoietin (ANG)-1 is essential for blood vessel growth and maturation, and ANG-2 acts in combination with vascular endothelial cell growth factor (VEGF) to initiate angiogenesis.
T90 13056-13142 Sentence denotes In conditions like cancer, there is an upregulation and over-expression of ANG-2 [25].
T91 13143-13248 Sentence denotes ANG-1 is chemotactic for endothelial cells, but neither ANG-1 nor ANG-2 exert proliferative effects [26].
T92 13249-13287 Sentence denotes ANG-2 is a natural inhibitor of ANG-1.
T93 13288-13409 Sentence denotes Endothelial cells express ANG-2 mRNA and protein, supporting the potential for autocrine activation of angiopoietin/Tie2.
T94 13410-13488 Sentence denotes ANG-1 and Tie-2 are highly expressed in both arteries and veins [27] (Fig. 5).
T95 13489-13607 Sentence denotes Fig. 5 Schematic representation of the Ang2 effect on the vascular bed in normal conditions, inflammation, and cancer.
T96 13608-13718 Sentence denotes Under normal physiological conditions, Ang2 levels are low, but are upregulated during inflammation or cancer.
T97 13719-13997 Sentence denotes Ang2 acts on endothelial cells, increasing endothelial permeability and also on the pericytes, causing pericyte detachment from the basement membrane, further inducing vascular leakiness, immune or/and cancer cell trans-endothelial migration, and deterioration of the condition.
T98 13998-14060 Sentence denotes Ang2 has been proposed as a marker for inflammatory conditions
T99 14061-14076 Sentence denotes (From Akwii RG.
T100 14077-14095 Sentence denotes Cells 2019; 8:471.
T101 14096-14112 Sentence denotes With permission)
T102 14113-14209 Sentence denotes The tyrosine kinase family of cell surface proteins plays an important role in vascular biology.
T103 14210-14420 Sentence denotes In response to a variety of conditions/environment-specific signals, tyrosine kinases engage in proliferation, migration, differentiation and morphologic organization that aligns with surroundings tissues [28].
T104 14421-14607 Sentence denotes Tyrosine kinases are commonly distinguished from one-another according to structural and sequence characteristics e.g. vascular endothelial growth factors (VEGF-R1, VEGF-R2 and VEGF-R3).
T105 14608-14676 Sentence denotes Each plays an essential role in maintaining vascular integrity [29].
T106 14677-14901 Sentence denotes The Tie [tyrosine kinase with immunoglobulin and epidermal growth factor (EGF) homology domains] receptor family represent a second sub-family of endothelial cell receptor tyrosine kinases identified as Tie-1 and Tie-2 [30].
T107 14902-15090 Sentence denotes Tie-1 and Tie-2 are vital to maintain growth and integrity of the vasculature, including endothelial cell-smooth muscle cell communication in vascular morphogenesis (see discussion above).
T108 15091-15169 Sentence denotes Infectious diseases affecting the lungs cause varying degrees of inflammation.
T109 15170-15279 Sentence denotes Dysregulated inflammation is particularly deleterious and often associated with endothelial cell dysfunction.
T110 15280-15480 Sentence denotes Trent et al. [31] reported dysregulated pulmonary inflammation and Tie-2-related endothelial dysfunction contributing to lung damage and mortality in a murine model of Orienta Tsutsugamushi infection.
T111 15481-15731 Sentence denotes Tissue findings included a high level of Ang-2 proteins in pulmonary endothelial cells, a progressive loss of endothelial cell quiescent and junction proteins, and a substantial decrease in Tie-2 receptor at the transcriptional and functional levels.
T112 15732-15816 Sentence denotes In-vitro infection of primary human endothelial cells demonstrated similar findings.
T113 15817-15941 Sentence denotes Tie-1 is upregulated by oscillating shear stress and differentially expressed in a dynamic pattern with disturbed flow [32].
T114 15942-16104 Sentence denotes Tie-1 deletion in mice causes abnormal extracellular matrix deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content.
T115 16105-16220 Sentence denotes The findings suggest that abnormal blood flow is a stimulus for endothelial cell Tie1-mediated paracrine signaling.
T116 16222-16292 Sentence denotes The contribution of platelets to vascular integrity, growth and repair
T117 16293-16384 Sentence denotes The interactions between platelets and the vascular endothelium are a tightly orchestrated.
T118 16385-16535 Sentence denotes In response to inflammatory stimuli, P-selectin rapidly translocates from membranes of storage granules (Weibel-Palade bodies) to the plasma membrane.
T119 16536-16615 Sentence denotes GPIbα present on platelets recognizes and binds to endothelial cell P-selectin.
T120 16616-16792 Sentence denotes Firm adhesion of platelets to intact endothelial cells depends on platelet integrin αIIbβ3 bridging to endothelial receptors such as αVβ3 and intercellular adhesion molecule-1.
T121 16793-16884 Sentence denotes Ligands for bridging include fibrinogen, fibronectin, and von Willebrand factor (VWF) [33].
T122 16885-16934 Sentence denotes Inflammatory cytokines augment platelet adhesion.
T123 16935-17082 Sentence denotes Platelets are essential for maintaining vascular integrity [34] and endothelial barrier function, particularly in the setting of inflammation [35].
T124 17083-17216 Sentence denotes In addition to physical interactions, platelets promote vascular integrity through synthesis and release of bioactive mediators [36].
T125 17218-17265 Sentence denotes Vascular endothelial cell pathology in COVID-19
T126 17266-17335 Sentence denotes The vascular pathology of COVID-19 is a topic of great interest [37].
T127 17336-17531 Sentence denotes Briefly, necropsy and post-mortem biopsies of decedents with COVID-19 reveal macro and microvascular thrombosis involving arteries, veins, arterioles, capillaries and venules in all major organs.
T128 17532-17635 Sentence denotes Varga and colleagues describe endothelial cell involvement and endotheliitis across vascular beds [38].
T129 17636-17831 Sentence denotes Accumulation of inflammatory cells and viral inclusions by histology and electron microscopy, respectively, occurred within the vascular endothelium of the heart, small bowel, kidneys, and lungs.
T130 17832-17930 Sentence denotes In autopsy and surgical tissues, there was diffuse lymphocytic endotheliitis and apoptotic bodies.
T131 17931-18120 Sentence denotes It is important to consider that apoptosis may not require host cell viral entry, but rather binding to the cell surface and subsequent proinflammatory and apoptotic pathway signaling [39].
T132 18122-18179 Sentence denotes Endothelial cells are a target for inflammatory mediators
T133 18180-18305 Sentence denotes Metabolic abnormalities, oxidative stress, chemokines, cytokines and by products of DAMPs cause endothelial cell injury [40].
T134 18306-18450 Sentence denotes While the toxic effect(s) can be direct, impaired epi-genetic regulation and activation of resident neutrophils and macrophages also contribute.
T135 18451-18611 Sentence denotes Products of vascular injury recruit neutrophils through several signaling pathways, including PI3K/AKt/eNOS/NF-Kβ and ERK1/2/P38 MAPK-activated protein kinases.
T136 18612-18743 Sentence denotes Recruited neutrophils subsets promote inflammation and further injury by releasing TNF-α, IL-1 and IL-8, and forming NETs [41, 42].
T137 18744-18904 Sentence denotes Endothelial cells produce macrovesicles in response to inflammatory conditions and inflammatory mediators, including cytokines, thrombin and complement 5a [43].
T138 18905-19021 Sentence denotes In turn, the endothelial cell  macrovesicles impair adherans junctions, promote neutrophil binding and release NETs.
T139 19022-19341 Sentence denotes Released during periods of cell death and immune activation, histone, nucleosomes and NETs induce cytotoxicity by altering cell membrane permeability to calcium ions, activating TLRs on innate immune cells, stimulating NLRP3 inflammasome and complement systems, resulting in a sterile pro-inflammatory environment [44].
T140 19343-19381 Sentence denotes Histones cause endothelial cell injury
T141 19382-19448 Sentence denotes Five major families of histones exist: H1/H5, H2A, H2B, H3 and H4.
T142 19449-19568 Sentence denotes Histones H2A, H2B, H3 and H4 are known as the core histones, while histones H1 and H5 are known as the linker histones.
T143 19569-19665 Sentence denotes The core histones are dimers and all possess the histone fold domain (reviewed in Simpson) [45].
T144 19666-19756 Sentence denotes Extracellular histones are cytoxic and cause endothelial cell injury and dysfunction [46].
T145 19757-19878 Sentence denotes The cytotoxicity primarily occurs within the microcirculatory system, and causes ultrastructural changes and dysfunction.
T146 19879-20183 Sentence denotes Altered flow dynamics cause further endothelial cell damage and glycocalyx shedding [47] Inflammatory conditions with high concentrations of extracellular histones and cytokines damage the endothelial glycocalyx accompanied by its degradation shedding of syndecan-1, heparan sulfate, and hyaluronan [47].
T147 20184-20285 Sentence denotes Cytokine-induced endothelial cell injury occurs in a variety of conditions including acute infection.
T148 20286-20347 Sentence denotes Tumor necrosis factor (TNF)-α is particularly cytotoxic [48].
T149 20348-20510 Sentence denotes The mechanism(s) for injury include recruitment and binding of monocytes, up-regulation of caspase-1, IL-1β and expression of pyroptosis-related factors (Fig. 6).
T150 20511-20553 Sentence denotes Fig. 6 Mechanisms of Sterile Organ Injury.
T151 20554-20753 Sentence denotes Toxic insults initiate both controlled and uncontrolled cell death in endothelial cells leading to apoptotic/necrotic tissue and release of intracellular cell components into the extracellular space.
T152 20754-20949 Sentence denotes These include immunogenic compounds such as RNA and DAMPs (HMGB1, ATP and Histone) which bind to and activate specific TLRs, driving the NFkB-mediated transcription of pro-inflammatory cytokines.
T153 20950-21011 Sentence denotes Platelets adhere to the endothelium via ICAM-1 and Kindlin-3.
T154 21012-21105 Sentence denotes Activated platelets release Poly P, which activates Factor XII, and subsequently, complement.
T155 21106-21211 Sentence denotes This results in activation of the coagulation pathways and further tissue injury, edema and inflammation.
T156 21212-21299 Sentence denotes Activated T cells release pro-inflammatory mediators and can cause direct cytotoxicity.
T157 21300-21491 Sentence denotes High mobility group box (HMGB)-1, damage associated molecular patterns (DAMPS), toll-like receptors (TLR), reactive oxygen species (ROS), polyphosphates (Poly-P), adenosine triphosphate (ATP)
T158 21492-21511 Sentence denotes (From Silk E et al.
T159 21512-21546 Sentence denotes Cell Death Disease 2017; 8: e2812.
T160 21547-21563 Sentence denotes With permission)
T161 21565-21617 Sentence denotes Neutrophil activation causes endothelial cell injury
T162 21618-21728 Sentence denotes Neutrophil activation and neutrophil extracellular traps (NETs) cause endothelial cell glycocalyx injury [49].
T163 21729-21888 Sentence denotes The concentration of circulating histones is directly proportional to the degree of inflammation and end organ dysfunction in trauma or sepsis-like conditions.
T164 21889-21997 Sentence denotes Exposure of endothelial cells to histones causes decreased vasodilation and cell death in 25% of cells [50].
T165 21998-22169 Sentence denotes Citrullinated histones 3 (H3CiT) can directly contribute to NET-associated inflammatory responses and opens cell–cell adherans junctions impairing vascular integrity [51].
T166 22170-22400 Sentence denotes The bioactive proteins released from NETs that cause tissue injury include myeloperoxidase (MPO), neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, high-mobility group box (HMGB)-1, proteinase (PTN)-3 and properdin [52].
T167 22402-22424 Sentence denotes Vasculitis in COVID-19
T168 22425-22519 Sentence denotes Endothelial cell inflammation, apoptosis and dysfunction occur in patients with COVID-19 [37].
T169 22520-22595 Sentence denotes The interface of endothelial cells and viruses is of longstanding interest.
T170 22596-22680 Sentence denotes For example, a major viral attachment and entry site for viruses is heparan sulfate.
T171 22681-22870 Sentence denotes This is found on the endothelial surface and consists of repeating disaccharide unites of glucosamine and uronic acid with interspaced sulfate group attachments (reviewed in Agelidis) [53].
T172 22871-22992 Sentence denotes The highly sulfated state results in a negative density and binding capacity for a variety of positively charged ligands.
T173 22993-23094 Sentence denotes A partial but representative summary of individual sites of vasculitis is provided (Table 1) [54–69].
T174 23095-23122 Sentence denotes Table 1 COVID-19 vasculitis
T175 23123-23232 Sentence denotes Patient (n) Age (Y) Sex Country Organ system Signs and symptoms Diagnostic test Treatment Outcomes References
T176 23233-23265 Sentence denotes 1 69 M Brazil CNS (VBS) Trochlea
T177 23266-23281 Sentence denotes Nerve palsy MRI
T178 23282-23326 Sentence denotes MR IV Methyl-prednisone Resolved De Oliveira
T179 23327-23386 Sentence denotes 1 NR NR NR CNS Corpus Callosum infarct MRI NR NR Varatharaj
T180 23387-23397 Sentence denotes 7 11–17 4M
T181 23398-23424 Sentence denotes 3F Spanish Skin Chilblains
T182 23425-23465 Sentence denotes “COVID-Toes” Biopsy Observation Resolved
T183 23466-23483 Sentence denotes 8 weeks Colmenero
T184 23484-23496 Sentence denotes 17 15–63 11M
T185 23497-23522 Sentence denotes 6F France Skin Chilblains
T186 23523-23565 Sentence denotes Toes, heels, fingers Biopsy N NR Kanitakis
T187 23566-23578 Sentence denotes 19 11–17 14M
T188 23579-23603 Sentence denotes 5F Italy Skin Chilblains
T189 23604-23643 Sentence denotes Toes, heels, soles Biopsy NR Resolution
T190 23644-23661 Sentence denotes >30days El-Hachem
T191 23662-23705 Sentence denotes 1 65 M France CNS Altered mental status MRA
T192 23706-23730 Sentence denotes MRI Supportive NR Hanafi
T193 23731-23749 Sentence denotes 1 50 M Asia Kidney
T194 23750-23755 Sentence denotes Liver
T195 23756-23767 Sentence denotes Lung Sepsis
T196 23768-23784 Sentence denotes Hypoxia Necropsy
T197 23785-23814 Sentence denotes Biopsy Supportive Deceased Xu
T198 23815-23881 Sentence denotes 1 NR NR NR GI Tract Diarrhea Biopsy Supportive Recovered Carnevale
T199 23882-23892 Sentence denotes 10 5–16 7M
T200 23893-23910 Sentence denotes 3F Italy Coronary
T201 23911-23925 Sentence denotes Arteries Fever
T202 23926-23935 Sentence denotes Skin rash
T203 23936-23944 Sentence denotes Diarrhea
T204 23945-23965 Sentence denotes Hypotension Clinical
T205 23966-23987 Sentence denotes Echocardiography IVIG
T206 23988-24013 Sentence denotes Aspirin Recovered Verdoni
T207 24014-24048 Sentence denotes 1 > 53 NR Switzerland Lung Dyspnea
T208 24049-24082 Sentence denotes Fever Necropsy NR Deceased Menter
T209 24083-24093 Sentence denotes 4 50–76 3M
T210 24094-24119 Sentence denotes 1F Spain Aorta Acute Limb
T211 24120-24128 Sentence denotes Ischemia
T212 24129-24152 Sentence denotes Stroke CTA Thrombectomy
T213 24153-24181 Sentence denotes Anticoagulation 3 discharged
T214 24182-24209 Sentence denotes 1 deceased Gomez Arbelaez -
T215 24210-24313 Sentence denotes 1 67 M Italy Aortic Prosthetic graft Respiratory failure Arterial Duplex Supportive Deceased Giacomelli
T216 24314-24337 Sentence denotes 2 60, 75 M UK Mesentery
T217 24338-24363 Sentence denotes Aorta Acute Limb ischemia
T218 24364-24382 Sentence denotes Abdominal pain CTA
T219 24383-24399 Sentence denotes CTA Thrombectomy
T220 24400-24436 Sentence denotes Bowel Resection Discharged Villliany
T221 24437-24487 Sentence denotes 5 57–71 3M 2F France Aorta Acute limb ischemia CTA
T222 24488-24511 Sentence denotes Arterial Duplex Surgery
T223 24512-24544 Sentence denotes Anticoagulation Amputation Kashi
T224 24545-24639 Sentence denotes 1 NR NR Spain Retinal Artery No symptoms Fundoscopy Observation No symptoms Quintana-Castanedo
T225 24640-24772 Sentence denotes VBS vertebrobasilar system, NR not reported, IVIG intravenous immunoglobulin, CTA Computed Tomography Angiography, UK United Kingdom
T226 24773-24839 Sentence denotes Urticarial vasculitis occurred in two patients with COVID-19 [70].
T227 24840-25072 Sentence denotes While several skin manifestations of COVID-19 occur, including varicella-like exanthemas, dengue-like petechial rashes and urticaria, urticarial vasculitis is a form of leukocytoclastic vasculitis with deposition of immunocomplexes.
T228 25073-25229 Sentence denotes Pinot et al. [71] reported a case of central nervous system vasculopathy with antimyelin oligodendrocyte glycoprotein antibodies in a patient with COVID-19.
T229 25230-25304 Sentence denotes There was rapid clinical improvement following immunomodulating treatment.
T230 25305-25384 Sentence denotes Autoimmune disorders, such as Giullain–Barre’ syndrome have been reported [72].
T231 25385-25493 Sentence denotes A lymphocytic vasculitis presenting with skin lesions on the toes, feet, heals and hands occurs in COVID-19.
T232 25494-25568 Sentence denotes Most cases have been in children and adolescents, but not solely [56, 73].
T233 25569-25682 Sentence denotes Histopathology of biopsy-derived material show dermatitis and vascular degeneration of the basal epidermal layer.
T234 25683-25840 Sentence denotes Endotheliitis within lymphocytic infiltration of the dermal vesicles and arterioles, and microthrombosis of papillary dermal capillaries are common findings.
T235 25841-25983 Sentence denotes Immunohistochemistry reveals an inflammatory infiltrate predominately comprised of mature T cells with a predominance of helper t lymphocytes.
T236 25984-26163 Sentence denotes Cytoplasmic granular positivity for SARS–CoV-2 spike protein is present in endothelial cells of the capillary and post-capillary vesicles and in epithelial cells of eccrine units.
T237 26164-26229 Sentence denotes Coronavirus-like particles are detectable on electron microscopy.
T238 26230-26410 Sentence denotes Digital video capillaroscopy of patients with dermal lesions, including erythema nodosum shows pericapillary edema, dilated and abnormal appearing capillaries and microhemorrhages.
T239 26411-26640 Sentence denotes In children with chilblain lesions, IgA antibodies to SARS–CoV-2 spike protein S1 domain are observed, suggesting that their immune response represents mucosal protection that lessens the likelihood of triggering an IgG response.
T240 26641-26838 Sentence denotes Acro-ischemia with accompanying skin lesions (bulla, cyanosis) and dry gangrene is likely a combination of arterial vasculitis and coagulopathy compromising perfusion to the fingers, toes and legs.
T241 26839-26958 Sentence denotes While thrombosis commonly accompanies vasculitis, obliterating arteriolitis can also be a cause for tissue injury [62].
T242 26960-26976 Sentence denotes Kawasaki Disease
T243 26977-27078 Sentence denotes Kawasaki Disease is a systemic vasculitis that predominantly affects small and medium-sized arteries.
T244 27079-27261 Sentence denotes It si associated with the development of coronary artery aneurysms in up to one-third of untreated patients, and both systemic and cerebral artery aneurysms in 1–2% of patients [74].
T245 27262-27503 Sentence denotes The cause of KD has not been determined, but a framework for making the diagnosis is as follows [75]: a genetic predisposition to KD, immunomodulation related to habitual exposures and environmental factors and contact with disease triggers.
T246 27505-27526 Sentence denotes Kawasaki-like disease
T247 27527-27609 Sentence denotes Kawasaki Disease (KD) follows an excess innate immune response to viral pathogens.
T248 27610-27779 Sentence denotes Several investigators have proposed involvement of the stimulator of interferon genes (STING) pathway inhibited upstream by aspirin and intravenous immunoglobulins [76].
T249 27780-27891 Sentence denotes The same mechanism may operate in COVID-19 where SARS–COV-2 binding to ACE2 increases STING pathway activation.
T250 27892-28137 Sentence denotes In most instances, activation occurs during the second phase of illness with immune hyper-responses, decreased lymphocyte counts, increased monocyte populations that secrete cytotoxic cytokines and heightened B and T cell responses as well [77].
T251 28138-28374 Sentence denotes Kawasaki-like disease with accompanying toxic shock syndrome or multi-systemic inflammatory disease has been reported in children with COVID-19 [78, 79]-moderate coronary dilations were present in 25% of patients (age range 3–17 years).
T252 28375-28405 Sentence denotes Myocarditis is also seen [80].
T253 28406-28547 Sentence denotes Cardiac MRI showed diffuse myocardial edema on T2-STIR sequences and Native-T1 mapping, with no evidence of late gadolinium enhancement [81].
T254 28548-28720 Sentence denotes The pediatric inflammatory multisystem syndrome (PIMS) and KD-like disease described in COVID-19 shares similarities with traditional KD, but there are several differences.
T255 28721-28876 Sentence denotes PIMS occurs in older children (age 9 years or greater), children of African American, Caribbean, European and Hispanic ancestry rather than Asian ancestry.
T256 28877-28984 Sentence denotes Gastrointestinal symptoms and a lack of mucocutaneous and lymphatic signs are also differentiating factors.
T257 28985-29096 Sentence denotes Myocarditis is a distinguishing feature of PIMS as well at times requiring mechanical circulatory support [82].
T258 29097-29233 Sentence denotes Adult-onset Kawasaki Disease Shock Syndrome complicated by coronary aneurysms occurred in a 20-year-old man of East Asian ancestry [83].
T259 29234-29293 Sentence denotes He received corticosteroids and intravenous immunoglobulin.
T260 29294-29474 Sentence denotes Securing a diagnosis is critical as early treatment (≤ 4 days) reduces the development of coronary arterial aneurysms and with shock syndrome improves left ventricular performance.
T261 29476-29509 Sentence denotes COVID-19 and vascular dysfunction
T262 29510-29630 Sentence denotes There is a proclivity for SARS–CoV-2 binding to endothelial cells with resulting inflammation (reviewed in Becker) [37].
T263 29631-29854 Sentence denotes Moreover, many of the predisposing comorbid conditions for COVID-19, including advanced age, diabetes mellitus, hypertension and obesity are associated with vascular dysfunction and altered endothelial cell metabolism [84].
T264 29856-29920 Sentence denotes Distinguishing vascular inflammation and dysfunction in COVID-19
T265 29921-30007 Sentence denotes Vascular disease has many distinct phenotypes and associated functional abnormalities.
T266 30008-30238 Sentence denotes While systemic conditions, ranging from metabolic to inflammatory and degenerative diseases often determine the location and make-up of accompanying vascular abnormalities, some conditions display a predominant vascular phenotype.
T267 30239-30348 Sentence denotes A discussion of vascular disease should distinguish causal, pathological, structural and functional elements.
T268 30349-30500 Sentence denotes The term “vasculopathy” represents any abnormality within a blood vessel- small, medium and large caliber, veins or arteries (reviewed in Seshan) [85].
T269 30501-30668 Sentence denotes Degenerative, metabolic and inflammatory conditions, embolic diseases and coagulation disorders are responsible for acute, subacute or chronic endothelial cell injury.
T270 30669-30796 Sentence denotes In many cases, non-inflammatory (necrotizing) vascular injury causes accumulation of immune complexes within the vessel’s wall.
T271 30797-30990 Sentence denotes A thickened intima with immunoglobulin and complement deposition, without inflammatory lymphocyte infiltration or atherosclerotic change are typical features of an autoimmune vasculopathy [86].
T272 30991-31166 Sentence denotes The pathological features are distinct and include endothelial cell swelling, vessel wall fragmentation, vessel wall fragmentation, endothelial cell pyknosis and karyorrhexis.
T273 31167-31280 Sentence denotes Pyknosis is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis.
T274 31281-31371 Sentence denotes Karyorrhexis, or fragmentation of the nucleus can follow if injury is severe or sustained.
T275 31372-31511 Sentence denotes Vasculitis displays classic histological findings of predominantly neutrophilic infiltrates affecting small and medium-sized blood vessels.
T276 31512-31557 Sentence denotes Large vessel vasculitis occurs in some cases.
T277 31558-31645 Sentence denotes Fibrinoid deposits, endothelial edema, and extravasation of red blood cells are common.
T278 31646-31732 Sentence denotes A mixed inflammatory infiltrate occurs, particularly in subacute stages older lesions.
T279 31733-31985 Sentence denotes The functional and phenotypic heterogeneity of the vascular endothelial lining, which is the primary target of injury, dictates different types of vascular lesions in the various organs, variability in clinical presentation, prognosis and therapy [85].
T280 31987-32043 Sentence denotes Clinical trials targeting vascular pathology in COVID-19
T281 32044-32186 Sentence denotes The ubiquitous involvement of EC in the phenotypic expression and natural history of COVID-19 establishes a firm basis for targeted therapies.
T282 32187-32368 Sentence denotes Ongoing studies target one or more vascular-specific proteins and signaling pathways, including angiopoietin-2 (NCT04342897), VEGF (NCT 04344782, NCT04275414, and NCT04305106) [87].
T283 32369-32492 Sentence denotes Endothelial cell markers of injury and function are included in several of the trials as surrogate or exploratory outcomes.
T284 32493-32661 Sentence denotes The biomarkers include vascular endothelial growth factor A, vascular endothelial growth factor receptor type 1, Syndecan-1 (marker of glycocalyx degradation), and VWF.
T285 32663-32696 Sentence denotes Conclusions and future directions
T286 32697-32793 Sentence denotes COVID-19 is a SARS–CoV-2 syndrome that can involve all organs, including the circulatory system.
T287 32794-33069 Sentence denotes Endothelial cell inflammation occurs within arteries, arterioles, capillaries, venules and veins and contributes to pathological events; including tissue hypoperfusion, injury, thrombosis and vascular dysfunction in the acute, subacute and possibly chronic stages of disease.
T288 33070-33295 Sentence denotes Beyond re-writing the textbooks that hence will include SARS–CoV-2 as a causal pathogen for multi-bed vasculitis, the data will show that it is a new category of systemic vasculitis forever captured in the annals of medicine.
T289 33296-33417 Sentence denotes As clinicians and scientists, we have but to understand, prevent, treat, document and inform at every step along the way.
T290 33418-33439 Sentence denotes “Yes we can, we must”
T291 33440-33461 Sentence denotes Mildred Jefferson, MD
T292 33462-33495 Sentence denotes Caroline Still Wiley Anderson, MD
T293 33496-33513 Sentence denotes Patricia Bath, MD