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

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.

Pathophysiology of Cardiac Injury in COVID-19 Patients with Acute Ischaemic Stroke: What Do We Know So Far?—A Review of the Current Literature

With the onset of the COVID-19 pandemic, it became apparent that, in addition to pulmonary infection, extrapulmonary manifestations such as cardiac injury and acute cerebrovascular events are frequent in patients infected with SARS-CoV-2, worsening clinical outcome. We reviewed the current literature on the pathophysiology of cardiac injury and its association with acute ischaemic stroke. Several hypotheses on heart and brain axis pathology in the context of stroke related to COVID-19 were identified. Taken together, a combination of disease-related coagulopathy and systemic inflammation might cause endothelial damage and microvascular thrombosis, which in turn leads to structural myocardial damage. Cardiac complications of this damage such as tachyarrhythmia, myocardial infarction or cardiomyopathy, together with changes in hemodynamics and the coagulation system, may play a causal role in the increased stroke risk observed in COVID-19 patients. These hypotheses are supported by a growing body of evidence, but further research is necessary to fully understand the underlying pathophysiology and allow for the design of cardioprotective and neuroprotective strategies in this at risk population.

СУЧАСНІ АСПЕКТИ РОЗВИТКУ КОАГУЛОПАТІЇ У ПАЦІЄНТІВ ПРИ COVID‑19 ІНФЕКЦІЇ: ОГЛЯД ЛІТЕРАТУРИ

This review summarizes current knowledge about coagulation disorders associated with COVID-19 infection. Despite a significant amount of research, it is currently unclear whether COVID-19 is the direct cause of coagulopathic disorders or they occur as the infectious process progresses. Different authors have proposed several pathogenetic mechanisms for the development of coagulopathy in this disease. However, the most important is the release of a large number of cytokines that provoke interstitial inflammation, endothelial damage and activation of coagulation, in the pathogenesis of which the tissue factor plays a key role. Hyperinflammatory reactions lead to tissue damage, disruption of the endothelial barrier and uncontrolled activation of coagulation. In the lungs and, possibly, in other organs, under the influence of the virus, local damage to the vascular endothelium occurs, which leads to angiopathy, activation and aggregation of platelets with the formation of blood clots and concomitant consumption of platelets. Systemic hypercoagulation and hyperfibrinogenemia significantly increase the likelihood of large vessel thrombosis and thromboembolic complications, which are detected in 20–30% of patients in the intensive care units. Along with an increase in the level of cytokines in the blood, their content also increases in the lungs and in the bronchoalveolar lavage fluid. Cytokine storm leads to systemic intravascular coagulation, multiple organ failure and death. The review also provides the rationale for the principles of managing patients with coagulopathy based on the known mechanisms of unique disorders inherent in COVID-19. It has been shown that the problem of the pathogenesis of the development of blood clotting disorders in COVID-19 infection remains relevant.

Placental Pathology in Maternal Ornithine Transcarbamylase Deficiency

Introduction Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, inherited in an X-linked manner. Males are severely affected. Female phenotypes vary from asymptomatic to severe, and symptoms may be triggered by high metabolic states like childbirth. Literature on OTC deficiency in pregnancy and placental pathology is limited. Methods Pathology records were searched at a single referral center from 2000–2020 and identified three placental cases from two mothers heterozygous for OTC deficiency. Placental pathology and maternal and neonatal history were reviewed in detail. Results The placenta from one symptomatic mother carrying an affected male fetus showed widespread high-grade fetal vascular malperfusion (FVM) lesions of varying age. These lesions were not seen in the two placentas from the asymptomatic mother. Discussion In cases of symptomatic maternal OTC deficiency, our findings highlight the need for placental examination. Since thrombotic events in the placenta have the potential to associate with fetal and neonatal endothelial damage, a high index of suspicion for neonatal thrombosis may be warranted.

Preeclampsia: From Etiopathology to Organ Dysfunction

Preeclampsia is a hypertensive disorder of pregnancy affecting 6–12% of the population. There are various risk factors for the development of preeclampsia, ranging from advanced maternal age to genetics. The proposed etiologies for preeclampsia are abnormal placentation, immunological intolerance, endothelial damage, and genetic inheritance. The pathogenesis includes endothelial activation and dysfunction leading to vasospasm. Preeclampsia is divided into two stages: asymptomatic and symptomatic stages. Preeclampsia causes multiple organ involvement, namely central nervous system, respiratory, cardiovascular, hematological dysfunction, HELLP (hemolysis elevated liver enzymes, low platelets) syndrome, endocrine, renal, hepatic, and uteroplacental dysfunction. These organ dysfunctions increase morbidity and mortality in preeclamptic pregnant patients.

Clinical and neurophysiological correlations in post-Covid‑19 patients and rationale for pathogenetic therapy

Clinical and neurological, neurophysiological, and neuropsychological examination of 50 patients aged 50–65 y. o. with an experience of COVID‑19 infection within the last 3 to 6 months, revealed pathological changes in the central nervous system in the form of cerebrastenic and autonomic disorders, motor disorders, vestibulopathy symptoms, which occurred in various combinations, with astheno-vegetative syndrome as obligate. Cognitive impairments were detected in 26% of patients; the mental fatigability index was 1.055 ± 0.124; a high level of situational anxiety was noted in 35% of patients, and a high level of personal anxiety in 50 % of patients with the experience of COVID‑19. The study of brain biopotentials revealed moderate diffuse changes (18%) and irritative disorders on the part of hypothalamic (69 %) and diencephalic structures (20%). All of the above may indicate that, regardless of the form of coronavirus infection occurred in humans, i. e., latent, mild, moderate or severe, one of the targets of the pathological impact of COVID‑19 virus is the median structures of the brain responsible for autonomic and cognitive functions. Nevertheless, in our opinion, these disorders are associated not with a direct pathological effect, but are mediated mainly by circulatory disorders in the microcirculatory bed due to endothelial damage and are rather functional disorders on the part of the central nervous system. This provides the grounds for the selection of pathogenetic therapy aimed at stabilizing the functional state of neurons, and one of the drugs of choice may be citicoline (Noocyl), the action of which is associated with reinforcing the cell membrane of the neuron and normalizing bioelectric processes.

Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies

Systemic Sclerosis (SSc) is an autoimmune disease marked by dysregulation of the immune system, tissue fibrosis and dysfunction of the vasculature. Vascular damage, remodeling and inadequate endothelial repair are hallmarks of the disease. Since early stages of SSc, damage and apoptosis of endothelial cells (ECs) can lead to perivascular inflammation, oxidative stress and tissue hypoxia, resulting in multiple clinical manifestations. Raynaud's phenomenon, edematous puffy hands, digital ulcers, pulmonary artery hypertension, erectile dysfunction, scleroderma renal crisis and heart involvement severely affect quality of life and survival. Understanding pathogenic aspects and biomarkers that reflect endothelial damage in SSc is essential to guide therapeutic interventions. Treatment approaches described for SSc-associated vasculopathy include pharmacological options to improve blood flow and tissue perfusion and, more recently, cellular therapy to enhance endothelial repair, promote angiogenesis and heal injuries. This mini-review examines the current knowledge on cellular and molecular aspects of SSc vasculopathy, as well as established and developing therapeutic approaches for improving the vascular compartment.

Coronavirus disease 2019-induced hypercoagulability and its clinical implications

Coronavirus disease 2019 is the disease produced by severe acute respiratory syndrome-coronavirus-2, which is introduced into the host’s cell thanks to the angiotensin-converting enzyme 2 receptor. Once there, it uses the cell’s machinery to multiply itself. In this process, it generates an immune response that stimulates the lymphocytes to produce cytokines and reactive oxygen species that begin to deteriorate the endothelial cell. Complement activation, through the complement attack complex and C5a, contributes to this endothelial damage. The different mediators further promote the expression of adhesion molecules on the endothelial surface, which encourages all blood cells to adhere to the endothelial surface to form small conglomerates, called clots, which obstruct the lumen of the small blood vessels. Furthermore, the mediators of clot lysis are inhibited. All this promotes a prothrombotic environment within the pulmonary capillaries that is reflected in the elevation of D-dimer. The only solution for this cascade of events seems to be the implementation of an effective anticoagulation protocol that early counteracts the changes induced by thrombi in the pulmonary circulation and reflected in the functioning of the right ventricle.

Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage and repair, together with the preservation of endothelial integrity, is of crucial importance for the homeostasis of endothelium. Endothelial Progenitor Cells (EPCs) represent a heterogenous cell population, characterized by the ability to differentiate into mature endothelial cells (ECs), which contribute to vascular homeostasis, neovascularization and endothelial repair. A modification of the number and function of EPCs has been described in numerous chronic inflammatory and auto-immune conditions; however, reports that focus on the number and functions of EPCs in RA are characterized by conflicting results, and discrepancies exist among different studies. In the present review, the authors describe EPCs’ role and response to RA-related endothelial modification, with the aim of illustrating current evidence regarding the level of EPCs and their function in this disease, to summarize EPCs’ role as a biomarker in cardiovascular comorbidities related to RA, and finally, to discuss the modulation of EPCs secondary to RA therapy.