Widespread Endothelial Damage Research Articles

COVID-19 enfeksiyonu geçiren hastada böbrek pelvis rüpürünün eşlik ettiği spontan ciddi retroperitoneal kanama: Olgu sunum

Spontaneous rupture of the renal pelvis is a rarely encountered urological event that causes extravasation of urine. It often occurs as a result of increased intrapelvic pressure secondary to obstructions developed in the urinary system. Similarly spontaneous retroperitoneal hematoma is retroperitoneal hemorrhage that occurs without trauma or an underlying pathology. In this study, we present a case of spontaneous rupture of the renal pelvis that developed secondary to compression of the hematoma that occurred spontaneously in the retroperitoneum in a 63-year-old female patient who received anticoagulant therapy with the diagnosis of Covid-19 infection. In the light of this case, we would like to emphasize that widespread endothelial cell damage associated with Covid-19 infection may cause spontaneous severe retroperitenal bleeding and accompanying renal pelvis rupture. In which both the rarely encountered spontaneous rupture of the renal pelvis and spontaneous retroperitoneal bleeding are seen simultaneously in the same patient, is reporting for the first time in the literature. Keywords: anticoagulant treatment, COVID-19, renal pelvis rupture, retroperitoneal hematoma, urinary obstruction

Síndromes hipertensivos del embarazo: pautas actualizadas para la conducta clínica

Hypertensive syndromes of pregnancy are a leading cause of maternal and perinatal morbidity and mortality worldwide.Their etiology is complex, multifactorial and not yet fully understood; however, there is recent evidence that the symptoms are attributable to an excessive inflammatory response causing widespread endothelial damage. During the last few years, our understanding of these entities has progressed, leading to modified definitions and diagnostic criteria for hypertensive syndromes of pregnancy. Although it is possible to control blood pressure with antihypertensive drugs and prevent seizures with magnesium sulfate, for the time being the only definitive treatment for preeclampsia and eclampsia remains scheduled, often premature, delivery. This study provides updated guidelines for early diagnosis and timely treatment of the different types of hypertensive syndromes of pregnancy.

Could COVID-19 Induced Endothelial Dysfunction Explain New Onset Peyronie's Disease?

IntroductionCoronavirus Disease 2019 (COVID-19) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV-2) which has been found to cause systemic inflammation in some patients. Many possible long-term sequelae of COVID-19 have yet to be identified. Since endothelial cells have both angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) receptors, and SARS-CoV-2 requires both receptors for cell entry, we hypothesized that widespread endothelial damage caused by COVID-19 infection leads to Peyronie's disease (PD).ObjectiveNew-onset PD after resolved COVID-19 infection was evaluated.MethodsThis study was performed after Institutional Review Board approval. After comprehensive history and physical exam, penile duplex was used to evaluate blood flow and characterize any plaques. International Index of Erectile Function (IIEF) was used to evaluate erectile function. Brachial artery flow-mediated dilation (FMD) and endothelial progenitor cell – colony forming units (EPC-CFU) assays were utilized as measures of endothelial function. Available data from two separate control groups were used for comparisons: “No PD” contains subjects with a history of cardiovascular disease and normal erectile function according to IIEF-EF score (n=27). This group was selected to serve as a negative control with endothelial dysfunction. A second control group “Healthy Controls” was selected as a positive control containing male participants who were free from any significant cardiovascular medical history (n=9).ResultsNew-onset PD after resolution of COVID-19 infection was identified in one patient. The penile duplex with erectogenic agents demonstrated normal vascular flow with presence of calcified plaques. The PD group median EPC-CFU levels were 0 as compared to 1.60 in the no PD (negative control) group and 20.00 in healthy (positive) controls. Similarly, median FMD% was impaired in the PD group (2.35%) and no PD group (3.88%) as compared to healthy controls (7.75%).ConclusionsThese findings reveal a novel mechanism for PD after resolution of COVID-19 infection. These findings have significant clinical and biological implications for males with PD and should be considered as a possible sequela of COVID-19 infection.DisclosureAny of the authors act as a consultant, employee or shareholder of an industry for: Acerus Pharmaceuticals, Boston Scientific, Coloplast, Endo Pharmaceuticals, Empower Pharmacy, Nestle Health, Olympus

Coagulation changes in COVID-19 infection and its implication in management

COVID-19 infection causes substantial changes in blood coagulation. Understanding this process helps management of the patient with least injury through therapeutic misadventurism. At the heart of the disease process, there is widespread endothelial and pulmonary alveolar epithelial cell damage related to the entry and proliferation of the virus and subsequent cellular response to virus invasion. The virus directly triggers fibrinolytic system which positively increase cellular viral load, cytokine generation, exudation in the alveoli, and both intravascular and extravascular blood coagulation and fibrinolysis. The major coagulation catastrophe comes from immunocoagulation and contribution by specific and non-specific cells (lymphocytes, monocytes, and neutrophils) augmenting the process. Hypoxia also contributes and plays an independent role. Platelet activation, complement activation, and vasculitis or vasculitis-mimics take part in the process. Some of these mechanisms are well established and some are yet to be worked out. COVID-19 infection unequivocally points out the great role of cellular activation and cytokines play in coagulation process; indicates classical anticoagulants, antiplatelets, statins, complement inhibitors, and steroids in managing this infection. The author concentrates on the pathobiology of blood coagulation with perspectives on how to manage each of these steps.

High value of mid-regional proadrenomedullin in COVID-19: A marker of widespread endothelial damage, disease severity, and mortality.

The widespread endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may lead to a disruption of the adrenomedullin (ADM) system responsible for vascular leakage, increased inflammatory status, and microvascular alteration with multi‐organs dysfunction. The aim of this study was to evaluate the role of mid‐regional proadrenomedullin (MR‐proADM) as a marker of SARS‐CoV2 related widespread endothelial damage, clinically identified by organs damage, disease severity and mortality. Patients with SARS‐CoV‐2 infection has been prospectively enrolled and demographic characteristic, clinical and laboratory data has been evaluated. In the overall population, 58% developed acute respiratory distress syndrome (ARDS), 23.3% of patients died, 6.5% acute cardiac injury, 1.4% of patients developed acute ischemic stroke, 21.2% acute kidney injury, 11.8% acute liver damage, and 5.4% septic shock. The best MR‐proADM cut‐off values for ARDS development and mortality prediction were 3.04 and 2 nmol/L, respectively. Patients presenting with MR‐proADM values ≥2 nmol/L showed a significantly higher mortality risk. In conclusion, MR‐proADM values ≥2 nmol/L identify those patients with high mortality risk related to a multiorgan dysfunction syndrome. These patients must be carefully evaluated and considered for an intensive therapeutic approach.

COVID-19 and the Kidney: Should Nephrologists Care about COVID-19 rather than Maintaining Their Focus on Renal Patients?

Clinical BackgroundThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread globally from late 2019, reaching pandemic proportions.EpidemiologyThe related disease, COVID-19, exacerbates and progresses due to patients' abnormal inflammatory/immune responses, widespread endothelial damage, and complement-induced blood clotting with microangiopathy. COVID-19 manifests mainly as a respiratory illness. In cases of severe viral pneumonia, it may lead to acute respiratory distress syndrome, respiratory failure, and death.ChallengesMany extrapulmonary manifestations commonly occur, and a substantial proportion of patients with severe COVID-19 exhibit signs of kidney damage. Clinically, kidney involvement ranges from mild/moderate proteinuria and hematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT). The pathophysiologic mechanisms of kidney damage and AKI in patients with COVID-19 remain unclear but are known to be multifactorial. Current knowledge implies direct SARS-CoV-2-dependent effects on kidney cells (tubular epithelial cells and podocytes) and indirect mechanisms through the systemic effect of viral infection secondary to the critical pulmonary illness and its management.Prevention and TreatmentStandard-of-care strategies apply, as there is no specific evidence to suggest that COVID-19 AKI should be managed differently from other types in severely ill patients. If conservative management fails, RRT should be considered. The choice of RRT approaches and sequential extracorporeal therapies depends on local availability, resources, and expertise. The focus should now be on the long-term follow-up of COVID-19 patients, especially those who developed kidney injury and dysfunction. This represents an opportunity for integrated multidisciplinary research to clarify the natural history of COVID-19 renal sequelae and the best therapeutic interventions to mitigate them.

Hyperthrombotic Milieu in COVID-19 Patients.

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.

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19.

In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.

Preliminary Post-Mortem COVID-19 Evidence of Endothelial Injury and Factor VIII Hyperexpression

(1) Background: The current outbreak of COVID-19 infection is an ongoing challenge and a major threat to public health that requires surveillance, prompt diagnosis, as well as research efforts to understand the viral pathogenesis. Despite this, to date, very few studies have been performed concerning autoptic specimens. Therefore, this study aimed: (i) to reiterate the importance of the autoptic examination, the only method able to precisely define the cause of death; (ii) to provide a complete post-mortem histological and immunohistochemical investigation pattern capable of diagnosing death from COVID-19 infection. (2) Methods: In this paper, the lung examination of two subjects who died from COVID-19 are discussed, comparing the obtained data with those of the control, a newborn who died from pneumonia in the same pandemic period. (3) Results: The results of the present study suggest that COVID-19 infection can cause different forms of acute respiratory distress syndrome (ARDS), due to diffuse alveolar damage and diffuse endothelial damage. Nevertheless, different patterns of cellular and cytokine expression are associated with anti-COVID-19 antibody positivity, compared to the control case. Moreover, in both case studies, it is interesting to note that COVID-19, ACE2 and FVIII positivity was detected in the same fields. (4) Conclusions: COVID-19 infection has been initially classified as exclusively interstitial pneumonia with varying degrees of severity. Subsequently, vascular biomarkers showed that it can also be considered a vascular disease. The data on Factor VIII discussed in this paper, although preliminary and limited in number, seem to suggest that the thrombogenicity of Sars-CoV2 infection might be linked to widespread endothelial damage. In this way, it would be very important to investigate the pro-coagulative substrate both in all subjects who died and in COVID-19 survivors. This is because it may be hypothesized that the different patterns with which the pathology is expressed could depend on different individual susceptibility to infection or a different personal genetic-clinical background. In light of these findings, it would be important to perform more post-mortem investigations in order to clarify all aspects of the vascular hypothesis in the COVID-19 infection.

Maternal variants within the apolipoprotein L1 gene are associated with preeclampsia in a South African cohort of African ancestry

ObjectivePreeclampsia (PE) is a complex pregnancy-specific medical disorder arising from an ischaemic placenta releasing factors causing widespread endothelial damage involving multiple organs systems, such as the renal system. Two variant alleles, termed G1 and G2, of the APOL1 gene are strongly associated with progressive renal disease and preeclampsia in the recessive or compound heterozygous state. Hence, we investigated the role of maternal APOL1 genotype in the pathogenesis of preeclampsia in South African women of African ancestry. Study designThis case-control study comprised three groups of South African pregnant women of African ancestry attending a regional hospital in Durban, South Africa: mothers experiencing normotensive pregnancies, early onset preeclampsia and late onset preeclampsia underwent APOL1 genotyping. Differences in G1 and G2 allele and genotype frequencies were analysed for the three groups. ResultsOur study revealed a significant association between the maternal APOL1 G1 risk allele and early-onset PE development (OR 2.2, p = 0.03). Among the EOPE group, 5 % [OR(95 %CI) 0.94 (0.29–3.12)] of the study population carried two risk alleles, 49 % [OR(95 %CI) 1.34 (0.77–2.3)] carried at least one risk allele, while 46 % of the participants did not carry either risk allele, compared to the normotensive pregnant group, where 52 % carried no risk allele, 42 % had at least one risk allele and 6 % of the women had both risk alleles. ConclusionOur results suggest that maternal APOL1 G1 risk allele may contribute to the development of early-onset PE in South African pregnant women of African ancestry either directly or by transmission of a APOL1 risk allele to the foetus.

A Systematic Review of Vascular Structure and Function in Pre-eclampsia: Non-invasive Assessment and Mechanistic Links.

Hypertensive disorders of pregnancy, such as pre-eclampsia, are known to be independently associated with the development of premature cardiovascular disease (CVD) in women. In pre-eclampsia, the placenta secretes excess anti-angiogenic factors into the maternal circulation, leading to widespread endothelial damage, and inflammation. This endothelial damage is evidenced to persist beyond the acute illness. However, whether it is permanent and responsible for the elevated rates of premature CVD seen in this at-risk group remains unclear. A systematic review of the available literature with respect to vascular structure and function prior to, during and after a pregnancy complicated by pre-eclampsia was performed. Studies non-invasively assessing vascular structure using carotid intima-media thickness (CIMT), retinal microvasculature caliber, CT coronary angiogram, or coronary calcium scores were included. Vascular function was assessed using brachial flow-mediated dilation (FMD), pulse wave analysis (PWA), and peripheral arterial tonometry (PAT). In total 59 articles were included (13 CIMT, 5 CTCA/Ca score, five retinal microvasculature, 27 FMD, 7 PAT, and 14 PWV/PWA), consisting of prospective and retrospective cohort, and case-control studies. Change in vascular structure was evidenced with significant increases in CIMT by 73–180 μm greater than that of non-affected women. This is tempered by other studies reporting resolution of structural changes postpartum, highlighting the need for further research. Accelerated coronary calcification and plaque deposition was identified, with greater rates of increased calcium scores and subclinical coronary artery disease shown by CTCA in women with a history of pre-eclampsia at 30 years postpartum. Impaired endothelial function was consistently reported prior to, during and immediately after pregnancy as evidenced by differences in FMD of 1.7–12.2% less than non-affected women, an increase in PWV by 13.2–26%, and reduced retinal microvascular caliber and arterial elasticity indices. The evidence was less conclusive for the persistence of long-term endothelial dysfunction. Understanding the underlying mechanistic links between pre-eclampsia and CVD is a key step to identifying targeted therapies aimed at “repairing the endothelium” and attenuating risk. This review has highlighted the need for a greater understanding of vascular structure and function following pre-eclampsia through high quality studies with large sample sizes, particularly in the longer postpartum period when clinical CVD disease starts to manifest.

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines.

Preeclampsia is becoming an increasingly common diagnosis in the developed world and remains a high cause of maternal and fetal morbidity and mortality in the developing world. Delay in childbearing in the developed world feeds into the risk factors associated with preeclampsia, which include older maternal age, obesity, and/or vascular diseases. Inadequate prenatal care partially explains the persistent high prevalence in the developing world. In this review, we begin by presenting the most recent concepts in the pathogenesis of preeclampsia. Upstream triggers of the well described angiogenic pathways, such as the heme oxygenase and hydrogen sulfide pathways, as well as the roles of autoantibodies, misfolded proteins, nitric oxide, and oxidative stress will be described. We also detail updated definitions, classification schema, and treatment targets of hypertensive disorders of pregnancy put forth by obstetric and hypertensive societies throughout the world. The shift has been made to view preeclampsia as a systemic disease with widespread endothelial damage and the potential to affect future cardiovascular diseases rather than a self-limited occurrence. At the very least, we now know that preeclampsia does not end with delivery of the placenta. We conclude by summarizing the latest strategies for prevention and treatment of preeclampsia. A better understanding of this entity will help in the care of at-risk women before delivery and for decades after.

Identification of cell-binding adhesins of Leptospira interrogans.

Leptospirosis is a globally distributed bacterial infectious disease caused by pathogenic members of the genus Leptospira. Infection can lead to illness ranging from mild and non-specific to severe, with jaundice, kidney and liver dysfunction, and widespread endothelial damage. The adhesion of pathogenic Leptospira species (spp.), the causative agent of leptospirosis, to host tissue components is necessary for infection and pathogenesis. While it is well-established that extracellular matrix (ECM) components play a role in the interaction of the pathogen with host molecules, we have shown that pathogenic Leptospira interrogans binds to host cells more efficiently than to ECM components. Using in vitro phage display to select for phage clones that bind to EA.hy926 endothelial cells, we identified the putative lipoproteins LIC10508 and LIC13411, and the conserved hypothetical proteins LIC12341 and LIC11574, as candidate L. interrogans sv. Copenhageni st. Fiocruz L1–130 adhesins. Recombinant LIC11574, but not its L. biflexa homologue LBF1629, exhibited dose-dependent binding to both endothelial and epithelial cells. In addition, LIC11574 and LIC13411 bind to VE-cadherin, an endothelial cell receptor for L. interrogans. Extraction of bacteria with the non-ionic detergent Triton X-114 resulted in partitioning of the candidate adhesins to the detergent fraction, a likely indication that these proteins are outer membrane localized. All candidate adhesins were recognized by sera obtained from leptospirosis patients but not by sera from healthy individuals as assessed by western blot. This work has identified bacterial adhesins that are potentially involved in L. interrogans infection of the mammalian host, and through cadherin binding, may contribute to dissemination and vascular damage. Our findings may be of value in leptospirosis control and prevention, with the bacterial adhesins potentially serving as targets for development of diagnostics, therapeutics, and vaccines.

Neutrophil-derived microparticles induce myeloperoxidase-mediated damage of vascular endothelial cells.

BackgroundUpon activation neutrophil releases microparticles - small plasma membrane vesicles that contain cell surface proteins and cytoplasmic matter, with biological activities. In this study we investigated the potential role of myeloperoxidase in the endothelial cell injury caused by neutrophil-derived microparticles.ResultsMicroparticles were produced by activating human neutrophils with a calcium ionophore and characterized by flow cytometry and transmission and scanning electron microscopy. Myeloperoxidase activity was measured by luminol-dependent chemiluminescence. Neutrophil microparticles-induced injuries and morphological alterations in human umbilical vein endothelial cells (HUVECs) were evaluated by microscopy and flow cytometry. Neutrophil microparticles were characterized as structures bounded by lipid bilayers and were less than 1 μm in diameter. The microparticles also expressed CD66b, CD62L and myeloperoxidase, which are all commonly expressed on the surface of neutrophils, as well as exposition of phosphatidylserine. The activity of the myeloperoxidase present on the microparticles was confirmed by hypochlorous acid detection. This compound is only catalyzed by myeloperoxidase in the presence of hydrogen peroxide and chloride ion. The addition of sodium azide or taurine inhibited and reduced enzymatic activity, respectively. Exposure of HUVEC to neutrophil microparticles induced a loss of cell membrane integrity and morphological changes. The addition of sodium azide or myeloperoxidase-specific inhibitor-I consistently reduced the injury to the endothelial cells. Taurine addition reduced HUVEC morphological changes.ConclusionsWe have demonstrated the presence of active myeloperoxidase in neutrophil microparticles and that the microparticle-associated myeloperoxidase cause injury to endothelial cells. Hence, the microparticle-associated myeloperoxidase-hydrogen peroxide-chloride system may contribute to widespread endothelial cell damage in conditions of neutrophil activation as observed in vasculitis and sepsis.

FRI0498 A Quantitative Videocapillaroscopic Study about the Relationship of Avascular Areas with the Clinical Characteristics and Disease Severity in Patients with Systemic Sclerosis

BackgroundSeveral studies have been carried out in systemic sclerosis (SSc) in order to correlate the microvascular damage with the clinical features and/or organ involvement, most of them by using the...

A Case of Immune Thrombocytopenic Purpura Associated with Scrub Typhus

Thrombocytopenia is a common manifestation of rickettsial disease. However, the pathogenesis of thrombocytopenia in many rickettsial diseases is poorly understood. Thrombocytopenia may be associated with consumption due to widespread endothelial damage or disseminated intravascular coagulation, hypersplenism, decreased marrow production, and immune-mediated platelet destruction. Some reports have found anti-platelet antibodies detected in thrombocytopenic patients with rickettsial disease. In addition to thrombocytopenia, facial palsy and Guillain-Barre syndrome were also reported as immune-mediated phenomena in scrub typhus. Here we report a case diagnosed as immune-mediated thrombocytopenia associated with scrub typhus. This is the first report of immune thrombocytopenic purpura (ITP) associated with scrub typhus in Korea. The patient exhibited eschar with a high titer of anti-tsutsugamushi antibody, thrombocytopenia, severe gastrointestinal hemorrhage, and purpura on the lower region of both legs. After steroid treatment, the sustained thrombocytopenia recovered. (Korean J Med 2014;86:362-366)

Ischaemia Modified Albumin- An Indicator of Widespread Endothelial Damage in Diabetes Mellitus

Ischaemia Modified Albumin- An Indicator of Widespread Endothelial Damage in Diabetes Mellitus Hyperglycaemia in Type 2 Diabetes mellitus has been implicated in the pathogenesis and progression of the disease process with micro vascular complications as per various researches. Generation of free radicals with oxidative stress and associated ischemia leading to endothelial damage and subsequent inflammation, results in long term complications like retinopathy, neuropathy and nephropathy in type 2 Diabetes mellitus. A positive association of increased level of oxidative stress markers like Malondialdehyde (MDA) has been detected in Diabetes associated with complications.

Mycoplasma suis infection results endothelial cell damage and activation: new insight into the cell tropism and pathogenicity of hemotrophic mycoplasma

Hemotrophic mycoplasmas (HM) are highly specialized red blood cell parasites that cause infectious anemia in a variety of mammals, including humans. To date, no in vitro cultivation systems for HM have been available, resulting in relatively little information about the pathogenesis of HM infection. In pigs, Mycoplasma suis-induced infectious anemia is associated with hemorrhagic diathesis, and coagulation dysfunction. However, intravasal coagulation and subsequent consumption coagulopathy can only partly explain the sequence of events leading to hemorrhagic diathesis manifesting as cyanosis, petechial bleeding, and ecchymosis, and to disseminated coagulation. The involvement of endothelial activation and damage in M. suis-associated pathogenesis was investigated using light and electron microscopy, immunohistochemistry, and cell sorting. M. suis interacted directly with endothelial cells in vitro and in vivo. Endothelial activation, widespread endothelial damage, and adherence of red blood cells to the endothelium were evident in M. suis-infected pigs. These alterations of the endothelium were accompanied by hemorrhage, intravascular coagulation, vascular occlusion, and massive morphological changes within the parenchyma. M. suis biofilm-like microcolonies formed on the surface of endothelial cells, and may represent a putative persistence mechanism of M. suis. In vitro analysis demonstrated that M. suis interacted with the endothelial cytoskeletal protein actin, and induced actin condensation and activation of endothelial cells, as determined by the up-regulation of ICAM, PECAM, E-selectin, and P-selectin. These findings demonstrate an additional cell tropism of HM for endothelial cells and suggest that M. suis interferes with the protective function of the endothelium, resulting in hemorrhagic diathesis.

Responses of Human Endothelial Cells to Pathogenic and Non-Pathogenic Leptospira Species

Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but causes infections in animals and humans in temperate regions as well. The agents of leptospirosis comprise several members of the genus Leptospira, which also includes non-pathogenic, saprophytic species. Leptospirosis can vary in severity from a mild, non-specific illness to severe disease that includes multi-organ failure and widespread endothelial damage and hemorrhage. To begin to investigate how pathogenic leptospires affect endothelial cells, we compared the responses of two endothelial cell lines to infection by pathogenic versus non-pathogenic leptospires. Microarray analyses suggested that pathogenic L. interrogans and non-pathogenic L. biflexa triggered changes in expression of genes whose products are involved in cellular architecture and interactions with the matrix, but that the changes were in opposite directions, with infection by L. biflexa primarily predicted to increase or maintain cell layer integrity, while L. interrogans lead primarily to changes predicted to disrupt cell layer integrity. Neither bacterial strain caused necrosis or apoptosis of the cells even after prolonged incubation. The pathogenic L. interrogans, however, did result in significant disruption of endothelial cell layers as assessed by microscopy and the ability of the bacteria to cross the cell layers. This disruption of endothelial layer integrity was abrogated by addition of the endothelial protective drug lisinopril at physiologically relevant concentrations. These results suggest that, through adhesion of L. interrogans to endothelial cells, the bacteria may disrupt endothelial barrier function, promoting dissemination of the bacteria and contributing to severe disease manifestations. In addition, supplementing antibiotic therapy with lisinopril or derivatives with endothelial protective activities may decrease the severity of leptospirosis.

Levels of circulating endothelial cells in normotensive and severe preeclamptic pregnancies

Preeclampsia is a disease hypothesized to originate from widespread endothelial dysfunction or damage. This study investigated whether circulating endothelial cells (CEC) can serve as a surrogate marker for disease severity in patients with preeclampsia, and if their number correlates to serum endothelial biomarkers for activation, dysfunction, or damage of those cells. Blood was drawn consecutively from 30 patients admitted with a diagnosis of severe preeclampsia. Thirty healthy, normotensive, patients matched for age, body mass index, and gestational age served as a control group. We determined the number of CEC and serum concentrations of biomarkers indicative of endothelial damage (thrombomodulin) and activation (E-selectin), and the antiangiogenic protein (endoglin), which reflects endothelial dysfunction. Median CEC counts did not differ significantly between preeclamptic patients and the control group (median 5.3 vs. 3.5 CEC/mL, respectively) and were mostly within the normal range (i.e., <20 CEC/mL). However, serum concentrations of thrombomodulin (median 3.6 vs. 5.2 ng/mL; P = 0.006), E-selectin (median 32.0 vs. 42.9 ng/mL; P = 0.02), and especially endoglin (median 5.0 vs. 76.2 ng/mL; P < 0.0001) were significantly increased in severe preeclamptic patients. CEC counts did not correlate with any of the clinical parameters or routinely determined laboratory indices. Preeclampsia is characterized by endothelial dysfunction and activation rather than actual endothelial damage as characterized by increased CEC counts.