Impact of thrombosis on pulmonary endothelial injury and repair following sepsis

The prevailing morbidity and mortality in sepsis are largely due to multiple organ dysfunction (MOD), most commonly lung injury, as well as renal and cardiac dysfunction. Despite recent advances in defining many aspects of the pathogenesis of sepsis-related MOD, including acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. Human and animal studies have shown that pulmonary thrombosis is common in sepsis-induced ARDS, and preclinical studies have shown that anticoagulation may improve outcome following sepsis challenge. The potential beneficial effect of anticoagulation on outcome is unconvincing in clinical studies, however, and these discrepancies may arise from the multiple and sometimes opposing actions of thrombosis on the pulmonary endothelium following sepsis. It has been suggested, for example, that mild pulmonary thrombosis prevents escape of bacterial infection into the circulation, while severe thrombosis causes hypoxia and results in pulmonary endothelial damage. Evidence from both human and animal studies has demonstrated the key role of microvascular leakage in determining the outcome of sepsis. In this review, we describe thrombosis-dependent mechanisms that regulate pulmonary endothelial injury and repair following sepsis, including activation of the coagulation cascade by tissue factor and stimulation of vascular repair by hypoxia-inducible factors. Targeting such mechanisms through anticoagulant, anti-inflammatory, and reparative methods may represent a novel approach for the treatment of septic patients.

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Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00249-8 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Eleni Gavriilaki ◽

Vincent T. Ho ◽

Wilhelm Schwaeble ◽

Thomas Dudler ◽

Mohamed Daha ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Endothelial Injury ◽

Coagulation Cascade ◽

Lectin Pathway ◽

Hematopoietic Stem

AbstractHematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins—collectively termed lectins—bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.

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The role of IL-1 in gout: from bench to bedside

Rheumatology ◽

10.1093/rheumatology/kex449 ◽

2017 ◽

Vol 57 (suppl_1) ◽

pp. i12-i19 ◽

Cited By ~ 10

Author(s):

Alexander So ◽

Alexandre Dumusc ◽

Sonia Nasi

Keyword(s):

Animal Studies ◽

Reactive Oxygen Species Generation ◽

Inflammasome Activation ◽

Acute Gout ◽

Oxygen Species ◽

Biological Responses ◽

Novel Approach ◽

The Subject

Abstract The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout.

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The pathophysiology of sepsis—2021 update: Part 1, immunology and coagulopathy leading to endothelial injury

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxab380 ◽

2021 ◽

Author(s):

Judith Jacobi

Keyword(s):

Treatment Options ◽

Endothelial Injury ◽

Coagulation Cascade ◽

Secondary Infections ◽

Sepsis And Septic Shock ◽

Risk And Benefit ◽

Insight Into ◽

Related Mortality

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose To provide an overview of current literature on the pathophysiology of sepsis, with a focus on mediators of endothelial injury and organ dysfunction. Summary Sepsis is a dysregulated response to infection that triggers cascades of interconnected systems. Sepsis has been a significant cause of mortality worldwide, and the recent viral pandemic that may produce severe sepsis and septic shock has been a major contributor to sepsis-related mortality. Understanding of the pathophysiology of sepsis has changed dramatically over the last several decades. Significant insight into the components of the inflammatory response that contribute to endothelial injury and trigger coagulation pathways has been achieved. Similarly, characterization of anti-inflammatory pathways that may lead to secondary infections and poor outcome has illustrated opportunities for improved therapies. Description of an increasing number of important mediators and pathways has occurred and may point the way to novel therapies to address immune dysregulation. Pharmacists will need a fundamental understanding of the overlapping pathways of the immune response to fully prepare for use of novel treatment options. While pharmacists typically understand coagulation cascade how to utilize anticoagulants, the issues in sepsis related coagulopathy and role of mediators such as cytokines and complement and role of activated platelets and neutrophils require a different perspective. Conclusion Pharmacists can benefit from understanding both the cellular and organ system issues in sepsis to facilitate assessment of potential therapies for risk and benefit.

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Hyperthrombotic Milieu in COVID-19 Patients

Cells ◽

10.3390/cells9112392 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2392

Author(s):

Mohamed Hassan Kamel ◽

Wenqing Yin ◽

Chris Zavaro ◽

Jean M. Francis ◽

Vipul C. Chitalia

Keyword(s):

Cell Damage ◽

Anticoagulation Therapy ◽

Endothelial Damage ◽

Coagulation Cascade ◽

Thromboembolic Events ◽

Coronary Syndrome ◽

Venous Thromboembolic Events ◽

Venous Thromboembolic ◽

Systemic Manifestations

COVID-19 infection has protean systemic manifestations. Experience from previous coronavirus outbreaks, including the current SARS-CoV-2, has shown an augmented risk of thrombosis of both macrovasculature and microvasculature. The former involves both arterial and venous beds manifesting as stroke, acute coronary syndrome and venous thromboembolic events. The microvascular thrombosis is an underappreciated complication of SARS-CoV-2 infection with profound implications on the development of multisystem organ failure. The telltale signs of perpetual on-going coagulation and fibrinolytic cascades underscore the presence of diffuse endothelial damage in the patients with COVID-19. These parameters serve as strong predictors of mortality. While summarizing the alterations of various components of thrombosis in patients with COVID-19, this review points to the emerging evidence that implicates the prominent role of the extrinsic coagulation cascade in COVID-19-related coagulopathy. These mechanisms are triggered by widespread endothelial cell damage (endotheliopathy), the dominant driver of macro- and micro-vascular thrombosis in these patients. We also summarize other mediators of thrombosis, clinically relevant nuances such as the occurrence of thromboembolic events despite thromboprophylaxis (breakthrough thrombosis), current understanding of systemic anticoagulation therapy and its risk–benefit ratio. We conclude by emphasizing a need to probe COVID-19-specific mechanisms of thrombosis to develop better risk markers and safer therapeutic targets.

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Helicobacter pylori and Cardiovascular Diseases

The Korean Journal of Helicobacter and Upper Gastrointestinal Research ◽

10.7704/kjhugr.2019.0048 ◽

2020 ◽

Vol 20 (1) ◽

pp. 4-10

Author(s):

Ju Yup Lee

Keyword(s):

Helicobacter Pylori ◽

Cardiovascular Diseases ◽

Vascular Diseases ◽

Cerebrovascular Diseases ◽

Endothelial Damage ◽

Coagulation Cascade ◽

Indirect Association ◽

Chronic Activation ◽

H Pylori

Since its discovery, Helicobacter pylori (H. pylori) has played a central role in the pathogenesis of gastroduodenal diseases. Additionally, there have been many studies that demonstrated the role of H. pylori infection in extragastric diseases. Many research studies have confirmed an indirect association between the prevalence of H. pylori infection and the occurrence of cardiovascular diseases (CVDs); however, the results are still conflicting. Most studies found that the involvement of H. pylori in this process was related to the chronic inflammation. This inflammation may facilitate the development of CVD-related atherosclerotic pathologies such as endothelial damage and chronic activation of coagulation cascade, etc. Furthermore, H. pylori infection is known to be associated with other vascular diseases such as cerebrovascular diseases and cardiac arrhythmias, especially atrial fibrillation. This review summarized the literature on the association of cardiovascular manifestations and H. pylori infection and provided information about the pathogenesis of this association.

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The Role of Granulocytes in Endotoxin-induced Vascular Injury

Blood ◽

10.1182/blood.v41.6.797.797 ◽

1973 ◽

Vol 41 (6) ◽

pp. 797-808 ◽

Cited By ~ 42

Author(s):

Evelyn Gaynor

Keyword(s):

Vascular Injury ◽

Nitrogen Mustard ◽

Endothelial Damage ◽

Endothelial Injury ◽

Sublethal Dose ◽

Blood Samples ◽

Intimal Injury

Abstract This study examines the role of neutrophils (PMN) in the pathogenesis of the endothelial lesion induced by a single sublethal dose of endotoxin. It is intended to clarify whether the margination of PMN on endothelium after endotoxin causes intimal injury or is a response to it. Neutropenic rabbits had mean PMN counts of 33/cu mm 72 hr after nitrogen mustard (HN2). They were heparinized and given either intravenous endotoxin or saline and were sacrificed 30-60 min later. Preterminal blood samples were positive for the presence of endothelium in 77% of endotoxin-treated neutropenic rabbits, in 87% of endotoxin-treated normal rabbits, and in only 12% of neutropenic rabbits given saline. Sections of aorta revealed marked abnormalities of endothelium in rabbits receiving endotoxin, whether neutropenic (90% had lesions) or normal (85% had lesions). Endothelial abnormalities included vacuolation and lysis, marked subendothelial edema, and desquamation. Similar lesions in control neutropenic rabbits were not found, and mild abnormalities were seen only rarely. These data indicate that neutropenia does not protect rabbits from endothelial injury due to endotoxin. They further suggest that HN2 may cause endothelial damage either directly or secondary to the effects of neutropenia.

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DEVELOPMENT OF A LATTICE BOLTZMANN FRAMEWORK FOR NUMERICAL SIMULATION OF THROMBOSIS

International Journal of Modern Physics C ◽

10.1142/s0129183107010711 ◽

2007 ◽

Vol 18 (04) ◽

pp. 483-491

Author(s):

S. E. HARRISON ◽

J. BERNSDORF ◽

D. R. HOSE ◽

P. V. LAWFORD

Keyword(s):

Lattice Boltzmann ◽

Blood Chemistry ◽

Endothelial Damage ◽

Coagulation Cascade ◽

Comprehensive Model ◽

Flow Solver ◽

Vein Thrombosis ◽

Complex Phenomena ◽

Deep Vein

The interacting factors relating to thrombogenesis were defined by Virchow in 1856 to be abnormalities of blood chemistry, the vessel wall and haemodynamics. Together, these factors are known as Virchow's triad. Many attempts have been made to simulate numerically certain aspects of the complex phenomena of thrombosis, but a comprehensive model, which includes the biochemical and physical aspects of Virchow's triad, and is capable of predicting thrombus development within physiological geometries has not yet been developed. Such a model would consider the role of platelets and the coagulation cascade along with the properties of the flow in the chosen vessel. A lattice Boltzmann thrombosis framework has been developed, on top of an existing flow solver, to model the formation of thrombi resulting from platelet activation and initiation of the coagulation cascade by one or more of the strands of Virchow's triad. Both processes then act in parallel, to restore homeostasis as the deposited thrombus disturbs the flow. Results are presented in a model of deep vein thrombosis (DVT), resulting from hypoxia and associated endothelial damage.

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Coupling of endothelial injury and repair: an analysis using an in vivo experimental model

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00466.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. H708-H713 ◽

Cited By ~ 17

Author(s):

Sonia Nogueras ◽

Ana Merino ◽

Raquel Ojeda ◽

Julia Carracedo ◽

Mariano Rodriguez ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Damage ◽

Endothelial Injury ◽

Circulating Angiogenic Cells ◽

Endothelial Apoptosis ◽

Threefold Increase ◽

Endothelial Repair ◽

Circulating Angiogenic Cell ◽

Injury And Repair

The repair of the endothelium after inflammatory injury is essential to maintaining homeostasis. The link between inflammation-induced endothelial damage and repair has not been fully characterized in vivo. We have developed a rat model to evaluate the coupling of lipopolysaccharide (LPS)-induced endothelial injury and repair. Aortic endothelium injury was analyzed by both inmunohistochemistry and flow cytometry to quantify the number of endothelial cells and the percentage of apoptotic endothelial cells. We have also identified the percentage of circulating angiogenic cells capable of repairing the damaged endothelium. Erythropoietin was administered to inhibit LPS-induced endothelial apoptosis. Loss of the normal endothelial structure was observed in the aorta of the animals treated with LPS. Eight hours after LPS administration, the number of endothelial cells decreased by 40%, returning to normal after 24 h. There was a threefold increase in the percentage of circulating angiogenic cells, which did not return to normal levels until 48 h after LPS administration. Circulating angiogenic cell levels did not change when LPS-induced endothelial damage was prevented by erythropoietin. The endothelial injury caused by inflammation activates the mobilization of circulating angiogenic cells, thus completing endothelial repair. Inflammation without endothelial injury does not trigger the mobilization of circulating angiogenic cells.

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Two subsets of circulating Ly6Clo monocytes distinguished by CD138 (syndecan-1) expression and Nr4a1 dependence in pristane-treated mice

10.1101/2022.01.09.475578 ◽

2022 ◽

Author(s):

Shuhong Han ◽

Haoyang Zhuang ◽

Rawad Daniel Arja ◽

Westley H Reeves

Keyword(s):

Lung Injury ◽

Disease Onset ◽

Endothelial Damage ◽

Diffuse Alveolar Hemorrhage ◽

Endothelial Injury ◽

Vascular Integrity ◽

The Face ◽

Pulmonary Capillaritis ◽

Patrolling Monocytes

Chronic peritoneal inflammation following pristane injection induces lupus with diffuse alveolar hemorrhage (DAH) and pulmonary capillaritis in C57BL/6 mice. The pathogenesis involves pristane-induced microvascular lung injury. BALB/c mice are resistant to endothelial injury and DAH. Lung disease in C57BL/6 mice is abolished by depleting monocytes/macrophages. The objective of this study was to define the role of myeloid subsets in DAH. Hemorrhage and vasculitis were abolished in Ccr2-/- mice, indicating involvement of bone marrow-derived monocytes/macrophages. Along with Ly6Chi monocytes, we found two subsets of circulating Ly6Clo monocytes: one CD138- and a novel CD138+ subset. Nr4a1-dependent patrolling Ly6Clo monocytes maintain vascular integrity after endothelial injury. Circulating Ly6CloCD138+ monocytes were associated with DAH and were absent in mice without DAH. They also were absent in Nr4a1-/- mice, whereas Ly6CloCD138- monocytes were unaffected. However, Nr4a1-/- mice were susceptible to pristane-induced DAH and lung vasculitis, suggesting that disease onset does not require Ly6CloCD138- monocytes. Peritoneal Ly6CloCD138+ M? were unchanged in Nr4a1-/- mice, indicating that they are not derived from Ly6CloCD138+ monocytes. We conclude that pristane-induced lung microvascular lung injury stimulates a wave of Nr4h1-dependent Ly6CloCD138+ patrolling monocytes in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage.

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Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614532 ◽

1999 ◽

Vol 81 (04) ◽

pp. 601-604 ◽

Cited By ~ 55

Author(s):

Hiroyuki Matsuno ◽

Osamu Kozawa ◽

Masayuki Niwa ◽

Shigeru Ueshima ◽

Osamu Matsuo ◽

...

Keyword(s):

Plasminogen Activator ◽

Thrombus Formation ◽

Endothelial Injury ◽

Fibrinolytic System ◽

Tissue Type ◽

Clot Lysis ◽

Wild Type ◽

Type Plasminogen Activator ◽

Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

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