key: cord-1050686-guhvlfch
authors: Hattori, Yuichi; Hattori, Kohshi; Machida, Takuji; Matsuda, Naoyuki
title: Vascular endotheliitis associated with infections: its pathogenetic role and therapeutic implication
date: 2022-01-10
journal: Biochem Pharmacol
DOI: 10.1016/j.bcp.2022.114909
sha: 32061cde7c41264f9654e43c3bb8740aaa8ded3b
doc_id: 1050686
cord_uid: guhvlfch

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.

The endothelium, a single layer of squamous endothelial cells that lines the interior surface of blood vessels and lymphatics, not only serves as a physical barrier that restricts the flow of substances and fluid into and out of tissues, but also emerges as a key player in regulating the homeostasis of vascular tone by releasing vasodilatory factors, such as nitric oxide (NO) and prostacyclin, and vasoconstrictive factors, such as endothelin-1 and thromboxane A 2 (TXA 2 ) [1, 2] . The endothelium is also a source of a wide variety of factors that locally regulate permeability, cell growth and migration, platelet function, and inflammation [3] [4] [5] .

Since inflammation crucially involves adhesion, vascular leak, and infiltration of immune cells as well as activation of these infiltrated immune cells [6] , it becomes clear that endothelial cell activation can contribute to vascular and ultimately tissue inflammation, although the role of vascular adventitia and vasa vasorum in vascular inflammation has been described based on studies on atherosclerosis [7, 8] .

Endotheliitis (or endothelialitis) is recognized as inflammation of the endothelium lining the lumen of blood vessels in association with a direct consequence of infectious pathogen invasion and the host immune response. The term "endotheliitis" was [11] . However, no guidelines are currently established for dosage of treatment of viral endotheliitis [11] . Further understanding of molecular pathogenesis of corneal endotheliitis may be helpful to find out more effective treatment of this disorder.

In the liver, endotheliitis has been considered to be an important histologic feature involving apoptosis, and have asserted this state as endotheliitis with viral elements within endothelial cells and recruitment of inflammatory immune cells. Additionally, Smadja et al. [48] have revealed that angiopoietin-2, which is a maker of endothelial damage, is significantly elevated in critical COVID-19 patients. These findings strongly indicate that systemic endotheliitis, which can cause endothelial injury and dysfunction in blood vessels in principle organs, including lung, heart, kidney, and brain, plays a key role in the pathobiology of COVID-19, and thus protecting endothelial cells and reversing endotheliitis may be an essential therapeutic goal [49] .

Endotheliitis may be associated with thrombus formation in COVID-19. The levels of coagulation markers such as D-dimers have been shown to be elevated in blood from patients with severe COVID-19 [50] . Autopsy reports have revealed widespread microvascular thrombi in the lungs of deceased patients [14, 51] . Another study has also shown that the pattern of COVID-19 pneumonitis is predominantly a pauci-inflammatory septal capillary injury accompanied by significant deposits of membrane attack complex and complement lectin pathway activators in the microvasculature [52] , which is in accordance with the idea that severe COVID-19 may cause a catastrophic microvascular injury syndrome that includes activation of complement pathways, endotheliitis, and an associated procoagulant state. In severe COVID-19, furthermore, an atypical form of ARDS, which was named microvascular including dizziness, headache, disturbed consciousness, and paresthesia [65] . Patients with severe SARS-CoV-2 infection may represent ischemic stroke [66] and even fetal intracerebral hemorrhage [67] . Autopsy reports have shown brain tissue edema and partial neuronal degeneration in deceased patients [68] . Furthermore, the postmortem exam has found evidence for cerebral petechial hemorrhages and microthrombi in brain autopsies from SARS-CoV-2-infected patients [69] . This study has also reported intra-endothelial lymphocytic and monocytic inflammation with occasional apoptosis in the brain vasculature, consistent with the presence of intracerebral endotheliitis, in the patients diagnosed with SARS-CoV-2 infection [69] . Thus, cerebral endotheliitis may be responsible for the cerebrovascular pathology in COVID-19 and contribute to an increased risk of ischemic stroke and hemorrhagic encephalopathy. It is notable that higher ACE2 receptor expression in brain vasculature of COVID-19 patients with cerebral endotheliitis can be detected than in COVID-19 patients without cerebral endotheliitis or than in control patients [69] .

Hypertension, diabetes, heart failure, coronary heart disease, smoking, and advanced age are known to be risk factors for severe COVID-19. Interestingly, they have a certain thing in common: their vascular endothelial function is significantly impaired [70] . If the patients with pre-existing endothelial dysfunction become infected with SARS-CoV-2, aggregation of endothelial dysfunction by COVID-19 endotheliitis may impair organ perfusion and cause a procoagulant state leading to macro-and microvascular thrombotic events. Recent reports have also revealed a robust and independent association of obesity with COVID-19 severity [71, 72] . In obesity, there exists low-grade chronic inflammation, and this status is conditioned by dysregulated endocrine and paracrine actions of adipocyte-derived factor, which could in turn disrupt vascular homeostasis and lead to endothelial dysfunction [73] .

Although the exact mechanisms by which COVID-19 can be exacerbated in obesity are not fully understood, it seems plausible that obese subjects with pre-existing endothelial dysfunction are vulnerable to a more severe disease course given the critical role of the endothelium in vascular homeostasis and tissue perfusion.

In summary, COVID-19 is not limited to a disease affecting the respiratory tract 

Sepsis and its sequalae are the leading cause of mortality in the critically ill patient population. It is fully accepted that sepsis represents a continuum of a syndrome encompassing multiple pathological processes, including systemic inflammation, coagulopathy, and systemic vascular collapse, and sepsis is now defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection [74] . Indeed, sepsis can affect major organs in the body, such as lung, liver, kidney, and heart, ultimately leading to their failure. The development of the failure of one or more organs poses a major threat to the survival of patients, and sepsis mortality is most often attributable to multiple organ dysfunction [75] .

The pathological process in the development of multiple organ dysfunction in sepsis is incompletely understood. Vascular endothelial activation and dysfunction are critical hallmarks of sepsis, which likely play a key role in the sepsis phenotype [76] [77] [78] [79] .

Endothelial activation per se is not harmful because it represents a physiological adaptation to different stimuli and can be considered a response to injury [80] .

However, endothelial activation is an early step in fueling endothelial damage. In sepsis, vascular endothelial cells become activated and dysfunctional, causing hemostatic disturbance, increased leukocyte trafficking, amplified inflammation, altered vasomotor tone, and loss of barrier function [79, 81, 82, 83] . Consequently, disturbed endothelial function could play an integral role in microvascular dysfunction which is characterized by heterogeneous perfusion of tissues due to the lack, or intermittent perfusion, of capillaries adjacent to those with normal perfusion [84] . The heterogeneity of microcirculation in sepsis can be considered to break down tissue oxygenation, leading to hypoxic areas even in the presence of preserved total blood flow to organs [85] . Microvascular failure would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Accordingly, vascular endothelial activation and dysfunction may be a primary cause of organ damage in sepsis [79] .

The interaction of endothelial cells with neutrophils or monocytes plays a crucial role in the pathogenesis of sepsis [78] . This interaction is transmitted by adhesion molecules to which leukocytes anchor themselves, allowing them to eventually stray into extravascular tissues. The surface expression of adhesion molecules, such as P-selectin, E-selectin, VCAM-1, and intracellular adhesion molecule-1 (ICAM-1), are strikingly up-regulated in endothelial cells when activated by bacterial products or pro-inflammatory cytokines [86] [87] [88] [89] . Selectins serve as a medium for sticking and rolling, while VCAM-1 and ICAM-1 are the key in mediating firm adhesion and act as a gatekeeper of leukocyte transendothelial migration. In such moments, leukocytes can release inflammatory mediators and reactive molecules to destroy pathogens, but at the same time their release would lead to endothelial damage. Alternatively, exposure to bacterial products or pro-inflammatory cytokines would result in the inflamed endothelium which may be referred to as endotheliitis.

Vascular endothelial cells express and synthesize the molecules that are vital in regulating hemostasis, including von Willebrand factor (vWF), tissue factor (TF), and plasminogen activator inhibitor type 1 (PAI-1) [78] . When the inflammatory host response to infection become exaggerated in association with the severity of sepsis, excessive inflammation drives hemestasis toward a prothrombotic and antifibrolytic state, leading to disseminated microvascular thrombosis, organ ischemia, and ultimately multiple organ dysfunction syndrome [78, 90] . The blood clotting protein vWF can be considered as a marker of inflammation and endothelial activation, and accelerates platelet adhesion to the damaged vessel wall and thrombus formation on a collagen surface under flow condition [91, 92] . In sepsis, the procoagulant glycoprotein TF can be highly released not only by mononuclear phagocytes such as monocytes and macrophages but also by endothelial cells [93] . Meanwhile, TF pathway inhibitor, which is predominantly expressed by endothelial cells, is both consumed and degraded in sepsis, abetting a procoagulant state [94] . Although activated protein C is a potent anticoagulant that also displays profibrinolytic and anti-inflammatory properties, the protein C system is significantly impaired in sepsis possibly due to accentuated consumption and limited activation of protein C resulting from the down-regulation of endothelial expression of thrombomodulin and endothelial protein C receptors [95] . In severe sepsis, furthermore, the synthesis of the serine protease antithrombin, a natural antagonist to thrombin that is activated several fold by circulating heparin-like substances, is down-regulated and its consumption is markedly increased due to ongoing thrombin formation [96] , which would accelerate a procoagulant state. In addition, the fibrinolytic pathway in sepsis is suppressed by the increase in the release of PAI-1 from activated endothelial cells and platelets. Such a series of imbalances can ultimately lead to the dissemination of fibrin-rich microvascular thrombi which is observed as the development of overt disseminated intravascular coagulation (DIC) in septic patients [78] .

Vascular endothelial cell apoptosis may play a contributory role in the development of endothelial dysfunction in sepsis, producing multiorgan failure.

Apoptosis has been considered to be a second prominent feature of sepsis [97] [98] [99] .

Over the last a few decades, abundant in vitro studies have shown that endothelial cell apoptosis can occur in response to bacterial products or pro-inflammatory cytokines [99] [100] [101] . Endothelial apoptosis has been also revealed in in vivo rodent models of sepsis [102] [103] [104] . Furthermore, an increase in circulating endothelial cells has been identified in septic patients [105] , suggesting that vascular endothelial cell apoptosis may occur in human sepsis. Indeed, evidence for vascular endothelial cell apoptosis has been reported in postmortem biopsies obtained from patients who had died of sepsis-related ARDS [106] . Interestingly, it has been demonstrated that the prevention of vascular endothelial apoptosis by in vivo systemic delivery of siRNAs targeting caspase-8/caspase-3 or Fas-associated death domain (FADD) can confer a survival advantage in mice with microbial sepsis [107, 108] . However, we need to take into account that the survival benefit of caspase-8/caspase-3 or FADD siRNAs may arise from the preventive effect on apoptotic death of not only vascular endothelial cells but also of other cell types, such as lymphocytes and parenchymal cells.

Evidence is emerging to suggest that vascular endotheliitis appears to be a contributory factor to vasculopathy and coagulopathy in sepsis. On a background of endothelial dysfunction, systemic endotheliitis likely plays a pivotal role in the pathogenesis of sepsis leading to multiorgan failure syndrome. Further understanding of the pathogenic role of endotheliitis in sepsis would be imperative to delineating clinical implications for adverse outcome prevention and potential therapeutic interventions.

Vascular endotheliitis could be attributed to adhesion molecules, pro-inflammatory cytokines, and pro-inflammatory chemokines, which would be released by activated endothelial cells or leukocytes (Fig. 2) . Endothelial cells may be activated by bacterial products, pro-inflammatory cytokines, or direct viral infection of endothelial cells. In activated endothelial cells, expression on endothelial surfaces of adhesion molecules, such as P-selectin, E-selectin, VCAM-1, and ICAM-1, is promoted [86] [87] [88] [89] . The signal transduction pathways for these adhesion molecules in vascular endothelial cells appear to include the transcription of NF-κB [86, 109] . This can be supported by the finding that the inhibition of NF-κB by the use of a truncated IκBɑ 

A number of medicinal drugs with endotheliitis-targeted therapeutic properties may be an ideal potential therapeutic candidate for prevention and treatment of the development of multiorgan dysfunction in infection-associated inflammatory diseases.

Numerous clinical trials have been conducted and are underway to assess the therapeutic potential of these drugs. Here we offer potential therapeutic interventions that could target vascular endotheliitis with a central focus on treatment of COVID-19 (Table 1) .

Statins, which are widely prescribed for treatment of lipid disorders, may be a progenitor cells could play a role in their protective profile [129] . We have shown that fluvastatin improves impaired endothelial function in endotoxemic rabbits [130] , suggesting that statins may be helpful in inflammatory conditions characterized by endothelial injury and dysfunction. Interestingly, in a retrospective cohort study, statin use has been found to be associated with lower mortality when compared with non-use in COVID-19 [131] . A small observation study in elderly nursing home subjects has also revealed a higher chance of a symptom-free COVID-19 in statin-users vs. 

The anti-malaria drugs chloroquine and hydroxychloroquine have been used as an anti-inflammatory agent to treat rheumatoid arthritis and systemic lupus erythematosus stress [145] , suggesting that endothelial cell injury may account for the failure of chloroquine and hydroxychloroquine as a medication for treating COVID-19.

Glucocorticoids are widely used for anti-inflammatory therapy in chronic inflammatory diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. Glucocorticoids are known to suppress inflammation through several molecular mechanisms [146] [147] [148] . Glucocorticoids bind to cytosolic glucocorticoid receptors (GRs) which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids can increase the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1, IL-10, IL-1 receptor antagonist, and neutral endopeptidase, but this is unlikely to account for all of the broad-spectrum anti-inflammatory actions of glucocorticoids.

The most striking effect of glucocorticoids is to repress the expression of multiple inflammatory genes, such as pro-inflammatory cytokines, enzymes, receptors, and adhesion molecules. This cannot be due to a direct interaction between GRs and GRE, as these binding sites are absent from the promoter regions of most inflammatory genes. It is more likely to be due to a direct inhibitory interaction between activated GRs and activated transcription factors, such as AP-1 and NF-κB, which regulate the inflammatory gene expression.

In the vascular system, GRs are expressed not only by vascular smooth muscle cells but also by endothelial cells [149] . 

Defibrotide is a sodium salt complex mixture of single-stranded phosphodiester oligodeoxyribonucleotides derived from porcine intestinal mucosal DNA by controlled depolymerisation [156] [157] [158] . Defibrotide is approved for treatment of hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome, which mainly occurs following high-dose chemotherapy in the setting of allogeneic hematopoietic stem cell transplantation [157, 159] . The mode of action of defibrotide remains largely unknown but it has been reported to have multiple antithrombotic, anti-ischemic, anti-inflammatory, anti-adhesive and pro-fibrinolytic, and anticoagulant properties [156] [157] [158] . In vitro studies using endothelial cell lines have revealed that defibrotide can suppress the up-regulation of VCAM-1, ICAM-1, VE-cadherin, and vWF in response to acute graft-vs.-host disease sera [160] . Furthermore, defibrotide has been found to inhibit leukocyte-endothelial interactions by down-regulating expression of endothelial adhesion molecules in a fully major histocompatibility complex-mismatched murine model of allogeneic hematopoietic stem cell transplantation [161] . Moreover, it is suggested that defibrotide may restore thrombotic-fibrinolytic balance at the endothelial level and protect endothelial cells [158] . The multi-target and endothelial-based pleiotropic properties of defibrotide make it an attractive candidate for the treatment of the advanced stage of COVID-19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality [49, 162] . In this regard, there is a recent report showing complete resolution and no attributable toxicity in two critically ill pediatric patients who received defibrotide for a SARS-CoV-2-associated multisystem inflammatory syndrome [163] . In the ongoing 

IL-6 is produced in response to infections and tissue injuries and contributes to host defense through the regulation of the immune reaction, the acute-phase response, hematopoiesis, and inflammation [165] . IL-6 exerts its biological activities via two molecules: IL-6 receptors (IL-6Rs) and gp130 [166] . Tocilizumab and sarilumab are monoclonal antibodies directed against IL-6Rs and are used to treat inflammatory conditions, such as rheumatoid arthritis. Sarilumab is a fully human monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6Rs, and inhibits IL-6-mediated signaling through these receptors, while tocilizumab is a recombinant humanized monoclonal antibody also directed against IL-6Rs.

In addition to immune-mediated cells, endothelial cells are also involved in the production of IL-6 in response to various stimuli [165] . IL-6Rs are expressed on the surface of human vascular endothelial cells [167] . Then, IL-6 directly affects vascular endothelial cells and could be the cause of endothelial cell dysregulation, characterized by hyperinflammation, abnormal coagulation, and vascular leakage. Since IL-6 promotes endothelial dysfunction, it has been suggested that this cytokine may play a role in the vascular endothelial dysfunction associated with COVID-19 [168] . In a recent work, moreover, the crucial role of IL-6 signaling in endothelial dysregulation during bacterial infection, sepsis, and COVID-19 has been noted [169] . The signal transduction of IL-6 involves activation of Janus kinase (JAK), then leading to activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) [170] . Systemic delivery of STAT3 decoy oligodeoxynucleotides has been found to minimize major end-organ injury and improve mortality in mice with cecal ligation and puncture-induced sepsis [171] . The clinical usefulness of tocilizumab and sarilumab for COVID-19 has been sequentially reported [172] [173] [174] . In addition, when tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial have been evaluated, it has been demonstrated that their treatment can improve outcomes, including survival, in critically ill patients with COVID-19 receiving organ support in intensive care units [175] , although it should be kept in mind that a number of randomized, controlled trials to date have largely negative [176] [177] [178] [179] [180] [181] .

Endotheliitis can lead to the formation of microthrombi, which may be responsible for the development of multiorgan damage. Aspirin, also called acetylsalicylic acid (ASA), which irreversibly inhibits cyclooxygenase-1 and results in preventing platelet aggregation by blocking the formation and release of TXA 2 , is well-established medication for the secondary prevention of cardiovascular and cerebrovascular events [182] . In patients with mild to moderate COVID-19, Frorêncio et al. [183] have reported that ASA treatment could offer relief of symptoms without hemorrhagic complications or other adverse effects. Although this is only a case series, with no control group and a low number of patients, they assume that ASA may useful as a secondary prophylaxis of thrombotic events in COVID-19 patients with multisystemic endotheliitis. The possible benefit of the prophylactic anticoagulation has been indicated by the use of heparin in moderate to severe COVID-19 [184] .

Furthermore, the anticoagulation agent dipyridamole has been found to markedly improve clinical outcomes in severely ill patients with COVID-19 [185] . Despite the plausible theoretical rationale, however, the role of empiric therapeutic anticoagulation in COVID-19 remains elusive with an urging call for further clinical study.

The vascular endothelium, which is a dynamic endocrine, paracrine, and autocrine organ, plays a vital role in regulating vascular tone and homeostasis.

Endotheliitis, hyperinflammation of the blood vessel endothelium, is actually associated with vascular endothelial dysfunction, thrombus formation, and hyperpermeability, and CRediT statements appear above the acknowledgement section of this revised paper. 

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