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1.
Biochem Pharmacol ; 197: 114909, 2022 03.
Article in English | MEDLINE | ID: covidwho-1616378

ABSTRACT

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases.


Subject(s)
COVID-19/pathology , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Vascular Diseases/pathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/immunology , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Sepsis/drug therapy , Sepsis/etiology , Sepsis/immunology , Sepsis/pathology , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/immunology
3.
Clin Neurol Neurosurg ; 201: 106436, 2021 02.
Article in English | MEDLINE | ID: covidwho-1059739

ABSTRACT

BACKGROUND: To evaluate overall ischemic stroke volumes and rates, specific subtypes, and clinical presentation during the COVID-19 pandemic in a multicenter observational study from eight states across US. METHODS: We compared all ischemic strokes admitted between January 2019 and May 2020, grouped as; March-May 2020 (COVID-19 period) and March-May 2019 (seasonal pre-COVID-19 period). Primary outcome was stroke severity at admission measured by NIHSS stratified as mild (0-7), moderate [8-14], and severe (>14). Secondary outcomes were volume of large vessel occlusions (LVOs), stroke etiology, IV-tPA rates, and discharge disposition. RESULTS: Of the 7969 patients diagnosed with acute ischemic stroke during the study period, 933 (12 %) presented in the COVID-19 period while 1319 (17 %) presented in the seasonal pre-COVID-19 period. Significant decline was observed in the mean weekly volumes of newly diagnosed ischemic strokes (98 ± 3 vs 50 ± 20,p = 0.003), LVOs (16.5 ± 3.8 vs 8.3 ± 5.9,p = 0.008), and IV-tPA (10.9 ± 3.4 vs 5.3 ± 2.9,p = 0.0047), whereas the mean weekly proportion of LVOs (18 % ±5 vs 16 % ±7,p = 0.24) and IV-tPA (10.4 % ±4.5 vs. 9.9 % ±2.4,p = 0.66) remained the same, when compared to the seasonal pre-COVID-19 period. Additionally, an increased proportion of patients presented with a severe disease (NIHSS > 14) during the COVID-19 period (29.7 % vs 24.5 %,p < 0.025). The odds of being discharged to home were 26 % greater in the COVID-19 period when compared to seasonal pre-COVID-19 period (OR:1.26, 95 % CI:1.07-1.49,p = 0.016). CONCLUSIONS: During COVID-19 period there was a decrease in volume of newly diagnosed ischemic stroke cases and IV-tPA administration. Patients admitted to the hospital had severe neurological clinical presentation and were more likely to discharge home.


Subject(s)
COVID-19/epidemiology , Neurology/trends , Societies, Medical/trends , Stroke/drug therapy , Stroke/epidemiology , Thrombolytic Therapy/trends , Administration, Intravenous , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Cohort Studies , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies , Stroke/diagnosis , Tissue Plasminogen Activator/administration & dosage , United States/epidemiology , Vascular Diseases/drug therapy , Vascular Diseases/epidemiology
4.
Naunyn Schmiedebergs Arch Pharmacol ; 394(5): 1003-1007, 2021 05.
Article in English | MEDLINE | ID: covidwho-1028548

ABSTRACT

Since March 2020, the world has been fighting a global pandemic caused by a new coronavirus SARS-CoV-2 (COVID-19). SARS-CoV-2 is responsible for severe acute respiratory syndrome, an airway disease that can be severe and fatal in a percentage of cases. Patients with severe COVID-19 can develop extrapulmonary lesions, with renal, hepatic, cardiac, neurological, and tissue involvement that can cause further severe complications. On December 21, 2021, the European Medicines Agency (EMA) authorized the marketing of the first COVID-19 vaccine. However, several randomized trials are ongoing to find effective, safe, and widely available treatments. The most severe stages of COVID-19 infection are characterized by a multi-system inflammatory state induced by a cytokine storm causing multi-organ injury. Epidemiologic evidence has shown that glucocorticoids (GCs), particularly dexamethasone, are used in severe, hospitalized patients with COVID-19 with good therapeutic benefit. COVID-19 can also damage the endothelial system, causing microcirculatory disturbances and consequently leading to functional organ disorders. The combination of endothelial dysfunction with a generalized inflammatory state may contribute to the general pro-coagulative state described in patients with COVID-19 with increased risk of venous and arterial occlusions. The aim of this article is to describe the therapeutic utility of GCs in stabilizing the vascular endothelial barrier in COVID-19 infection. Indeed, we believe that the stabilization of the endothelial barrier and the anti-inflammatory effect of GCs could be the main effect underlying the therapeutic efficacy in COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Endothelium, Vascular/physiopathology , Glucocorticoids/therapeutic use , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Dexamethasone/therapeutic use , Humans , Randomized Controlled Trials as Topic
5.
Radiat Res ; 195(1): 1-24, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1021760

ABSTRACT

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.


Subject(s)
COVID-19/physiopathology , Pandemics , Radiation Injuries/physiopathology , SARS-CoV-2/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/physiopathology , Angiotensin-Converting Enzyme 2/deficiency , Angiotensin-Converting Enzyme 2/physiology , Animals , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , Clinical Trials as Topic , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Hematologic Diseases/etiology , Hematologic Diseases/physiopathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Intercellular Signaling Peptides and Proteins/therapeutic use , Mesenchymal Stem Cell Transplantation , Mice , Organ Specificity , Pyroptosis , Radiation Injuries/blood , Radiation Injuries/drug therapy , Radiation Injuries/immunology , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2/isolation & purification , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology
7.
Nat Rev Cardiol ; 18(3): 194-209, 2021 03.
Article in English | MEDLINE | ID: covidwho-936141

ABSTRACT

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.


Subject(s)
Blood Coagulation Disorders/blood , Blood Platelet Disorders/blood , COVID-19/blood , Endothelium, Vascular/physiopathology , Inflammation/blood , Thrombosis/blood , Administration, Inhalation , Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , Blood Platelet Disorders/drug therapy , Blood Platelet Disorders/etiology , Blood Platelet Disorders/physiopathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/physiopathology , Endothelium-Dependent Relaxing Factors/therapeutic use , Epoprostenol/therapeutic use , Heart Disease Risk Factors , Humans , Iloprost/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Nitric Oxide/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/etiology , Thrombosis/immunology , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/physiopathology , Vascular Diseases/blood , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology , Vasodilator Agents/therapeutic use , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/physiopathology
9.
Adv Drug Deliv Rev ; 157: 96-117, 2020.
Article in English | MEDLINE | ID: covidwho-610205

ABSTRACT

The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges.


Subject(s)
Drug Delivery Systems , Endothelium, Vascular/metabolism , Vascular Diseases/drug therapy , Animals , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Humans , Inflammation/drug therapy , Nanomedicine , Nanoparticles
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