Increased Inflammatory Properties of Neutrophils in Patients with Venous Thromboembolism and the Effect of Simvastatin on Abrogating Inflamed Neutrophils Adhesiveness

Abstract Neutrophils have a complex migrating process out of the vascular lumen, that consists of chemoattraction and rolling, followed by firm attachment and migration to extravascular tissues. In these sites, neutrophils are capable of promoting phagocytosis, secreting proteases, generating reactive oxygen species (ROS), and probably releasing neutrophil extracellular traps (NETs). Furthermore, neutrophil activation also induces major tissue injury associated with acute and chronic inflammatory disorders, such as the venous thromboembolism (VTE). Recently, animal models and clinical studies in acute VTE have explored the participation of neutrophils in the pathophysiology of VTE. However, VTE has been associated with a chronic inflammatory condition, and it remains unclear whether the activation of neutrophils is persistent after the acute phase of the disease. Furthermore, there are clinical evidences supporting that simvastatin may prevent VTE, since the drug has pleiotropic anti-inflammatory effects. The aim of this study is to evaluate the occurrence of neutrophil activation in patients with VTE compared to health controls and determines the effect of simvastatin in these adhesive properties of the neutrophils. Neutrophils were separated from blood collected over Ficoll-Paque densities. Neutrophils activation was determined by the expression of activated adhesive molecules (LFA-1/CD11a and MAC-1/CD11b) and ROS generation, detected by flow cytometry. Chemotaxis assays (chemoTx, Neuro Probe, Inc) and serum nucleosome, a marker of NETs, were quantified by optical density (OD) (Cell Death Detection ELISAPLUS Kit, Roche). Serum high sensitive CRP (hs-CRP) levels were measured in BN ProSpec System (Siemens) by nephelometry. For CD11a and CD11b integrins expression, cells were evaluated under basal conditions and after TNFα inflammatory stimulus, pretreated, or not, with simvastatin. For the migration assays, neutrophils were treated, or not, with IL-8, a neutrophil chemotactic factor. The results were displayed as mean and standard deviation (±SD). The study group consisted of thirty-seven patients with personal history of VTE, the median time since VTE occurred was 25 months (range 13 - 42 months), the event was spontaneous in 51.35% of the cases and 23 patients presented proximal VTE. Thirty-seven controls, matched with patients according to age, gender and ethnicity, were also included. The mean fluorescence intensity (MFI) of CD11a was higher in VTE patient neutrophils, both in basal conditions (30.84 ± 6.82 vs. 38.72 ± 22.75, P= 0.04) and after TNFα stimulus (34.09 ± 9.64 vs. 45.65 ± 33.06, P= 0.01). Higher MFI of CD11b was observed in patient neutrophils, compared with controls, only after TNFα stimulus (149.10 ± 52.74 vs. 200.0 ± 100.5, P= 0.02), and the stimulus was reverted by pre-treatment with simvastatin (200.8 ± 100.50 vs. 174.60 ± 80.63, P= 0.001). The amount of ROS (MFI) was similar in patients and controls (908.30 ± 423.7 vs. 844.0 ± 312.0, P= 0.83). Neutrophils from VTE patients also presented increased basal chemotaxis (17.55% ± 9.79 vs. 12.64% ± 4.78, P=0.02) and IL-8-stimulated chemotaxis (63.48% ± 29.73 vs. 49.88% ± 19.48%, P=0.06). Serum levels of nucleosomes were similar in patients and controls (1.05 ± 0.81 vs. 0.88 ± 0.62, P= 0.64), however higher levels of circulating nucleosomes were observed in patients with severe post-thrombotic syndrome (PTS), compared to patients with non-severe PTS, without PTS and controls (1.49 ± 0.81 vs. 1.06 ± 0.64 vs. 0.64 ± 0.60 vs. 0.88 ± 0.62, P=0.04). Furthermore, serum levels of hs-CRP were significantly higher in VTE patients when compared with controls (0.59 mg/dl ± 0.58 vs. 0.17 mg/dl ± 0.12, P=0.00). We demonstrated that patients with VTE presented patterns of neutrophil activation long time after the acute thrombotic episode. In particular, the stimuli for neutrophil adhesion and chemotaxis were higher in patients, as detected by the increased activation of adhesive molecules and cell migration. Furthermore, we observed that simvastatin may abrogate the expression of CD11b in inflamed neutrophils. Neutrophil activities associated with ROS generation and the releases of nucleosomes were not increased in these patients. The results may support the hypothesis that increased neutrophils activation is part of the chronic inflammatory condition associated with VTE and may be downregulated by the effects of simvastatin. Disclosures No relevant conflicts of interest to declare.

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NADPH Oxidase 2 Is Critical for Heterotypic Neutrophil-Platelet Interactions during Vascular Inflammation

Blood ◽

10.1182/blood.v124.21.459.459 ◽

2014 ◽

Vol 124 (21) ◽

pp. 459-459

Author(s):

Jing Li ◽

Kyungho Kim ◽

Robert K. Andrews ◽

Jaehyung Cho

Keyword(s):

Nadph Oxidase ◽

Ligand Binding ◽

Calcium Signaling ◽

Calcium Release ◽

Conflicts Of Interest ◽

Vascular Inflammation ◽

Neutrophil Activation ◽

Ros Generation ◽

Nadph Oxidase 2

Abstract Intravital microscopic studies have shown that neutrophil-platelet interactions on activated endothelial cells are the major determinant of vascular occlusion under thromboinflammatory conditions. Heterotypic neutrophil-platelet interactions are mainly mediated by two crucial receptors and counter receptors, P-selectin-P-selectin glycoprotein ligand-1 and glycoprotein Ibalpha-alphaMbeta2 integrin. Although the major receptors and counter receptors are well identified, it remains unclear how heterotypic cell-cell interactions are regulated during vascular disease. Recently, we demonstrated that neutrophil AKT2 is a key regulator for neutrophil-platelet interactions during vascular inflammation. Since it is known that AKT2 is important for NADPH oxidase 2 (NOX2) activity and reactive oxygen species (ROS) generation during neutrophil activation, we investigated whether NOX2 regulates the heterotypic neutrophil-platelet interaction during vascular inflammation. Using real-time fluorescence intravital microscopy, we found that platelet-neutrophil interactions are nearly completely inhibited during TNF-alpha-induced cremaster venular inflammation in NOX2 KO mice, compared with WT mice. Studies with bone marrow chimera further demonstrated that both hematopoietic and endothelial cell NOX2 are crucial for neutrophil-platelet interactions on the inflamed venules. In vitro studies with neutrophils and platelets isolated from WT and NOX2-deficient mice indicated that both neutrophil and platelet NOX2 are required for neutrophil-platelet aggregation under shear conditions. Using ROS scavengers and NOX2 KO cells, we observed that neutrophil NOX2-generated ROS regulate the activation and ligand-binding activity of alphaMbeta2 integrin during neutrophil activation and that platelet NOX2-produced ROS are important for P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Ibalpha. Interestingly, neutrophil NOX2 was crucial for store-operated calcium entry (SOCE), but not calcium release from the endoplasmic reticulum, whereas platelet NOX2 modulated intracellular calcium release, but not SOCE. We further demonstrated that the differential regulation of platelet and neutrophil NOX2 in calcium signaling correlates with the differences in the phosphorylation of AKT, ERK, and p38MAPK, suggesting the importance of AKT and its downstream molecules for NOX2-mediated calcium signaling. Our results indicate that neutrophil and platelet NOX2-produced ROS play critical roles in regulating the function of surface receptors required for heterotypic neutrophil-platelet interactions during vascular inflammation. Disclosures No relevant conflicts of interest to declare.

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Role of Inflammatory Markers in Elderly Type 2 Diabetic Patients with Mild Cognitive Impairment

Current Diabetes Reviews ◽

10.2174/1573399814666180423113341 ◽

2019 ◽

Vol 15 (3) ◽

pp. 247-253 ◽

Cited By ~ 2

Author(s):

Salwa S. Hosny ◽

Ahmed M. Bahaaeldin ◽

Mohamed S. Khater ◽

Meram M. Bekhet ◽

Hayam A. Hebah ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Elderly Patients ◽

Vascular Disease ◽

Plasma Glucose ◽

Serum Levels ◽

Diabetic Patients ◽

Hs Crp ◽

And Control

<P>Background: Type 2 diabetes (T2DM) is a risk factor for Alzheimer’s disease and mild cognitive impairment. The etiology of cognitive impairment in people with T2DM is uncertain but, chronic hyperglycemia, cerebral micro vascular disease, severe hypoglycemia, and increased prevalence of macro vascular disease are implicated. </P><P> Objectives: To determine the serum levels of soluble vascular adhesion molecule (sVCAM-1) and highly sensitive C-reactive protein (hs-CRP) in elderly type 2 diabetics with mild cognitive impairment (MCI). Methods: Our study was conducted on 90 elderly subjects (aged 60 years old or more). They were divided into Group І, 30 patients with T2DM and mild cognitive impairment, group ІІ, 30 patients with T2DM without cognitive impairment and group III, 30 healthy subjects as a control group. They were subjected to history taking, full clinical examination, anthropometric measurement, the Addenbrooke’s Cognitive Examination III (ACE---III 2012), Fasting plasma glucose, 2 hours plasma glucose, HbA1c, lipid profile, protein/creatinine ratio, serum sVCAM-1 and hs-CRP. Results: Serum levels of sVCAM-1 in diabetic elderly patients with MCI were significantly higher (946.7 ± 162.01 ng/ml) than diabetic elderly patients without cognitive impairment (479.06 ± 65.27 ng/ml) and control (263.7 ± 72.05 ng/ml) with (P=0.002). Serum levels of Hs-CRP in diabetic elderly patients with MCI were significantly higher than as diabetic elderly patients without cognitive impairment and control with (P=0.005). Conclusion: Elderly diabetic patients with mild cognitive impairment have higher levels of soluble adhesion molecules and markers of low-grade systemic inflammation than other groups.</P>

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FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00542-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Dezhong Wang ◽

Yuan Yin ◽

Shuyi Wang ◽

Tianyang Zhao ◽

Fanghua Gong ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Metabolic Regulation ◽

Cardiac Injury ◽

Serum Levels ◽

Ros Generation ◽

Dependent Manner ◽

Cardiac Tissues ◽

Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

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S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00652-5 ◽

2021 ◽

Author(s):

Quang Luu Quoc ◽

Youngwoo Choi ◽

Tra Cao Thi Bich ◽

Eun-Mi Yang ◽

Yoo Seob Shin ◽

...

Keyword(s):

Calcium Binding ◽

Macrophage Polarization ◽

Serum Levels ◽

Lavage Fluid ◽

Airway Epithelial Cells ◽

Neutrophil Activation ◽

Neutrophil Extracellular Trap ◽

Airway Epithelial ◽

Asthmatic Patients ◽

M1 Macrophage

AbstractThe biomarkers and therapeutic targets of neutrophilic asthma (NA) are poorly understood. Although S100 calcium-binding protein A9 (S100A9) has been shown to correlate with neutrophil activation, its role in asthma pathogenesis has not been clarified. This study investigated the mechanism by which S100A9 is involved in neutrophil activation, neutrophil extracellular trap (NET)-induced airway inflammation, and macrophage polarization in NA. The S100A9 levels (by ELISA) in sera/culture supernatant of peripheral blood neutrophils (PBNs) and M0 macrophages from asthmatic patients were measured and compared to those of healthy controls (HCs). The function of S100A9 was evaluated using airway epithelial cells (AECs) and PBNs/M0 macrophages from asthmatic patients, as well as a mouse asthma model. The serum levels of S100A9 were higher in NA patients than in non-NA patients, and there was a positive correlation between serum S100A9 levels and sputum neutrophil counts (r = 0.340, P = 0.005). Asthmatic patients with higher S100A9 levels had lower PC20 methacholine values and a higher prevalence of severe asthma (SA) (P < .050). PBNs/M0 macrophages from SA released more S100A9 than those from non-SA patients. PBNs from asthmatic patients induced S100A9 production by AECs, which further activated AECs via the extracellular signal-regulated kinase (ERK) pathway, stimulated NET formation, and induced M1 macrophage polarization. Higher S100A9 levels in sera, bronchoalveolar lavage fluid, and lung tissues were observed in the mouse model of NA but not in the other mouse models. These results suggest that S100A9 is a potential serum biomarker and therapeutic target for NA.

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Pilonidal Cyst of the Penis Mimicking Carcinoma

Case Reports in Urology ◽

10.1155/2013/984757 ◽

2013 ◽

Vol 2013 ◽

pp. 1-2

Author(s):

Luigi Cormio ◽

Francesca Sanguedolce ◽

Paolo Massenio ◽

Giuseppe Di Fino ◽

Giuseppe Carrieri

Keyword(s):

Differential Diagnosis ◽

Pilonidal Sinus ◽

Rare Case ◽

Subcutaneous Tissue ◽

Sinus Tract ◽

Penile Carcinoma ◽

Inflammatory Condition ◽

Pilonidal Cyst ◽

Chronic Inflammatory Condition

Pilonidal sinus is a long-standing chronic inflammatory condition consisting of a sinus tract from the skin-lined orifice extending into subcutaneous tissue, with hairs attached to the wall of the tract and projecting outside of the opening. Penile location is rare, and differential diagnosis with severe balanoposthitis, epidermal cysts, and neoplasms can be difficult. We report a rare case of pilonidal cyst located between coronal sulcus and prepuce which, due to its ulcerated aspect and absence of a tract with projecting hairs, simulated a penile carcinoma.

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TNF-Alpha Inhibitors and Ustekinumab for the Treatment of Psoriasis: Therapeutic Utility in the Era of IL-17 and IL-23 Inhibitors

Journal of Psoriasis and Psoriatic Arthritis ◽

10.1177/24755303211047479 ◽

2022 ◽

pp. 247553032110474

Author(s):

Julie J. Hong ◽

Edward K. Hadeler ◽

Megan L. Mosca ◽

Nicholas D. Brownstone ◽

Tina Bhutani ◽

...

Keyword(s):

Treatment Resistance ◽

Risk Patient ◽

Tnf Alpha ◽

Inflammatory Condition ◽

Biologic Therapies ◽

Malignancy Risk ◽

Patient Demographics ◽

The Past ◽

Chronic Inflammatory Condition ◽

Patient Subgroups

Psoriasis is a chronic inflammatory condition for which eleven FDA-approved biologic therapies are approved. Over the past decade, studies have documented the higher efficacy of IL-17 and IL-23 inhibitors for the treatment of psoriasis compared to the TNF-alpha inhibitors and ustekinumab, an IL-12/23 inhibitor. Despite this, there remains an important role for the use of TNF-alpha inhibitors and ustekinumab in the treatment of psoriasis. Here, we review how considerations of infection and malignancy risk, patient demographics, treatment resistance, and comorbidities may make certain TNF-alpha inhibitors or ustekinumab an excellent choice for therapy in particular patient subgroups.

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Basal high-sensitivity-C-reactive protein levels in patients with spontaneous venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th04-11-0745 ◽

2005 ◽

Vol 93 (03) ◽

pp. 488-493 ◽

Cited By ~ 23

Author(s):

Rainer Vormittag ◽

Thomas Vukovich ◽

Verena Schönauer ◽

Stephan Lehr ◽

Erich Minar ◽

...

Keyword(s):

Risk Factor ◽

Venous Thromboembolism ◽

Statistical Significance ◽

Factor V Leiden ◽

High Sensitivity ◽

Prothrombin G20210a ◽

Factor V ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp

SummaryThe role of C-reactive protein (CRP) in venous thromboembolism (VTE) is still under discussion because of controversial results in the literature. Conflicting data may have partly been due to bias by exogenous factors altering CRP levels. We investigated CRP concentrations in patients with spontaneous VTE applying a study design that allowed the measurement of basal high sensitivity (hs)-CRP levels. Patients with a history of deep vein thrombosis (DVT, n=117) and pulmonary embolism (PE, n=97) were compared to healthy individuals (n=104). Hs-CRP levels (mg/dl) were significantly higher in patients (n=214, median/interquartile range: 0.171/0.082–0.366) than in controls (0.099/0.053–0.245, p=0.001). The unadjusted odds ratio (OR) for VTE per 1 mg/dl increase of CRP was 2.8 [95% confidence interval (CI): 1.1–6.8, p=0.03]. This association remained significant after adjustment for factor V Leiden, prothrombin G20210A and factor VIII activity above 230% (OR = 2.9, 95% CI [1.1–7.5]), but became remarkably attenuated and lost its statistical significance after adjustment for BMI alone (OR = 1.7 [0.7–4.0]). CRP was also not independently associated with VTE in subgroups of patients (those with DVT without symptomatic PE, those with PE and patients without established risk factor) in multiple regression analysis. In summary, we observed significantly higher basal hs-CRP levels in patients with spontaneous VTE compared to healthy controls. This association was independent of hereditary and laboratory risk factors for VTE, but lost its significance after adjustment for BMI. Increased basal CRP levels do not appear to represent an independent risk factor for VTE.

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Serum levels of vitamin D are not associated with future risk of venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th12-10-0728 ◽

2013 ◽

Vol 109 (05) ◽

pp. 885-890 ◽

Cited By ~ 14

Author(s):

Gunhild Lerstad ◽

Guri Grimnes ◽

Sigrid K. Brækkan ◽

Anders Vik ◽

Jan Brox ◽

...

Keyword(s):

Vitamin D ◽

Venous Thromboembolism ◽

Statistical Power ◽

Cox Regression ◽

Multivariable Analysis ◽

Indirect Evidence ◽

Serum Levels ◽

Vitamin D Status ◽

Future Risk

SummaryPrevious studies have provided indirect evidence for a possible association between vitamin D status and risk of venous thromboembolism (VTE). However, no study has so far investigated the association between serum levels of 25-hydroxyvitamin D (25(OH)D), the biomarker of vitamin D status, and risk of VTE. The aim of our study was to investigate whether high levels of 25(OH)D were associated with decreased risk of VTE in a prospective population-based study. Serum levels of 25(OH)D were measured in 6,021 men and women, aged 25–84 years, who participated in the Tromsø Study in 1994–1995. Incident VTE-events were registered from date of inclusion through the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) for VTE. There were 201 incident VTE-events during a median of 10.7 years of follow-up. The risk of VTE did not decrease per one standard deviation (SD) (19.8 nmol/l) increase in serum 25(OH)D (multivariable HR 1.02; 95% CI 0.91–1.22). Moreover, subjects with serum 25(OH)D ≥ 70 nmol/l (upper quartile) did not have decreased risk of VTE compared to those ≤ 44 nmol/l (lower quartile) in age- and sex-adjusted analysis (HR 0.91, 95% CI: 0.60–1.37, p for trend across quartiles 0.9) or multivariable analysis adjusted for age, sex, body mass index, smoking, and physical activity (HR 0.76, 95% CI: 0.45–1.28, p for trend across quartiles 0.9). Subgroup analyses showed no associations between serum levels of 25(OH)D and unprovoked or provoked VTE. In conclusion, in our study, normal serum levels of 25(OH)D were not associated with future risk of VTE, suggesting that vitamin D status does not play an important role in the pathogenesis of VTE. However, our findings did not apply to subjects with vitamin D deficiency (< 30 nmol/l) due to lack of statistical power among these subjects.

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Serum levels of 25(OH)D are not associated with venous thromboembolism in the elderly population

Thrombosis and Haemostasis ◽

10.1160/th15-02-0148 ◽

2016 ◽

Vol 115 (01) ◽

pp. 169-175 ◽

Cited By ~ 1

Author(s):

Aurélien Delluc ◽

Marie-Pierre Moineau ◽

Cécile Tromeur ◽

Maelenn Gouillou ◽

Karine Lacut ◽

...

Keyword(s):

Vitamin D ◽

Venous Thromboembolism ◽

Seasonal Variations ◽

Elderly Population ◽

Serum Levels ◽

The Elderly ◽

Vitamin D Status ◽

Increased Risk ◽

Vitamin D Levels ◽

Walking Capacity

SummaryThe prevalence of both vitamin D deficiency and venous thromboembolism (VTE) is important in the elderly. Previous studies have provided evidence for a possible association between vitamin D status and the risk of VTE. Thus, we aimed to investigate the association between vitamin D levels and VTE in the population aged 75 and over included in the EDITH case-control study. The association between vitamin D status and VTE was analysed. We also analysed the monthly and seasonal variations of VTE and vitamin D. Between May 2000 and December 2009, 340 elderly patients (mean age 81.5 years, 32 % men) with unprovoked VTE and their controls were included. The univariate and multivariate analysis found no significant association between serum levels of vitamin D and the risk of unprovoked VTE. In the unadjusted analysis, a higher BMI was statistically associated with an increased risk of VTE (OR 1.09; 95 % CI 1.05–1.13) whereas a better walking capacity and living at home were associated with a decreased rate of VTE: OR 0.57; 95 % CI 0.36–0.90 and 0.40; 95 % CI 0.25–0.66, respectively. Although not significant, more VTE events occurred during winter (p=0.09). No seasonal variations of vitamin D levels were found (p=0.11). In conclusion, in contrast with previous reports our findings suggest that vitamin D is not associated with VTE in the elderly population.

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Cardiopulmonary Manifestations of Ankylosing Spondylitis

International Journal of Rheumatology ◽

10.1155/2011/728471 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 33

Author(s):

Mahnaz Momeni ◽

Nora Taylor ◽

Mahsa Tehrani

Keyword(s):

Ankylosing Spondylitis ◽

Cardiac Dysfunction ◽

Spontaneous Pneumothorax ◽

Pulmonary Complications ◽

Inflammatory Condition ◽

Stepwise Approach ◽

Conduction Disturbances ◽

Chronic Inflammatory Condition ◽

Pulmonary Manifestations ◽

Valve Diseases

Ankylosing spondylitis is a chronic inflammatory condition that usually affects young men. Cardiac dysfunction and pulmonary disease are well-known and commonly reported extra-articular manifestation, associated with ankylosing spondylitis (AS). AS has also been reported to be specifically associated with aortitis, aortic valve diseases, conduction disturbances, cardiomyopathy and ischemic heart disease. The pulmonary manifestations of the disease include fibrosis of the upper lobes, interstitial lung disease, ventilatory impairment due to chest wall restriction, sleep apnea, and spontaneous pneumothorax. They are many reports detailing pathophysiology, hypothesized mechanisms leading to these derangements, and estimated prevalence of such findings in the AS populations. At this time, there are no clear guidelines regarding a stepwise approach to screen these patients for cardiovascular and pulmonary complications.

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