Higher Myeloperoxidase Levels Research Articles

High levels of soluble P-selectin, neutrophil extracellular traps, and myeloperoxidase as risk factor of deep vein thrombosis in malignancy patients receiving platinum-based chemotherapy

Backgrounds Venous Thromboembolism (VTE) is a disease entity comprising Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). VTE events increase the mortality rate of patients with cancer receiving platinum-based chemotherapy. Soluble P-Selectin, Neutrophil Extracellular Traps (NET), and myeloperoxidase (MPO) are risk factors associated with DVT in malignancy patients receiving platinum-based chemotherapy. The purpose of this study was to determine the role of soluble P-selectin, NET, and MPO as risk factors for DVT in patients with malignancy receiving platinum-based chemotherapy. Patients and Methods This study used a case-control design (matched pair case-control study) based on age and gender. The case group consisted of subjects with DVT, whereas the control group consisted of subjects without DVT. The subjects were 31 in each case and control groups. Soluble P-selectin, NET, and MPO levels were measured in each group. Results The mean age of case group was 50.26±12.15 years meanwhile in control group was 52.81±11.64 years. In the case group, 71% of the subjects were female, whereas 51.6% of the control group were male. Most subjects, either in the case group (71%) or the control group (71%), used carboplatin. In the case group, cervix malignancy was the most common malignancy (32.3%), whereas in the control group, it was nasopharyngeal malignancy (25.8%). High soluble P-selectin level was a risk factor for DVT (OR 3.38, CI 1.180 – 9.780, p=0.02). A high NET level was also a risk factor for DVT (OR 2.88, CI 1.026-8.074, p=0.04). The high MPO levels in this study could not be proven as a risk factor. Conclusions Soluble P-selectin and NET are risk factors that play a role in the pathophysiology of DVT through the pathomechanism of immunothrombosis induced by endothelial injury and activation of monocytes and neutrophils due to the use of platinum-based chemotherapy.

A reactive monocyte subset characterized by low expression of CD91 is expanded during sterile and septic inflammation.

This study was undertaken to assess CD91 expression on monocytes and changes in monocyte subset distribution during acute tissue damage and bloodstream infection (BSI). We investigated blood specimens from healthy individuals, trauma and cardiac surgery patients as a model of tissue damage, and patients with BSI, by flow cytometry using a panel of antibodies comprising CD45, HLA-DR, CD14, CD16 and CD91 for the identification of monocyte subsets. While infrequent in healthy subjects, CD91low/neg monocyte levels were markedly high in BSI, trauma and after cardiac surgery. This monocyte subset expanded up to15-fold in both patient cohorts, whereas CD14+CD16+ inflammatory monocytes were multiplied by a factor of 5 only. CD14+CD91low monocytes displayed a significantly lower density of HLA-DR and markedly reduced expression of CD300e, compared to the other subsets. They also expressed high levels of myeloperoxidase and showed robust phagocytic and oxidative burst activity. Expansion of CD91low monocytes is a sensitive marker of acute inflammatory states of infectious and non-infectious etiology.

Causal relationship between levels of myeloperoxidase and obstructive sleep apnea: a bidirectional two-sample Mendelian randomization study.

Several observational studies have investigated the association between myeloperoxidase (MPO) and obstructive sleep apnea (OSA). However, the nature of this relationship remains uncertain due to potential selection and confounding biases. To resolve this, we conducted a bidirectional two-sample Mendelian randomization (MR) study to scrutinize the causal relationship between MPO and OSA. Instrumental variables (IVs) for OSA were sourced from the publicly available FinnGen dataset, encompassing 38,998 OSA cases and 336,659 controls. Data on MPO were sourced from a study of 21,758 individuals conducted by the European Bioinformatics Institute (EBI). The primary MR analysis utilized the inverse-variance weighted (IVW) method, with MR-Egger intercept and leave-one-out methods assessing pleiotropy and Cochran's Q test determining heterogeneity. The IVW analysis indicated a causal relationship between heightened MPO levels and an increased incidence of OSA. Individuals with elevated MPO levels manifested a higher propensity to develop OSA, exhibiting an odds ratio (OR) of 1.075 and a 95% confidence interval (CI) of 1.011-1.143 (p = 0.021). Conversely, the reciprocal analysis unveiled no significant association between OSA and heightened MPO levels (p = 0.643). No directional pleiotropy was identified through the MR-Egger intercept test (p > 0.05). Our study provides evidence of an association between elevated MPO levels and an increased incidence of OSA. However, OSA does not necessarily lead to elevated MPO levels. When patients present with high MPO levels, screening for OSA may be advisable, considering their clinical characteristics.

Correlation between SARS-CoV-2 infection and autoimmune rheumatic diseases: a comprehensive analysis of blood biomarkers in COVID-19 patients.

This study aimed to better understand the link between SARS-CoV-2 infection and autoimmune rheumatic diseases (ARDs) development by analyzing blood samples from 200 registered participants, and measuring biomarkers, such as cell-free DNA, MPO (myeloperoxidase), cathepsin S, and complement type 2 receptor. Blood samples were collected from 200 participants (100 females and 100 males; age range: 17-55 years). Participants were divided into five groups based on their COVID-19, SARS-CoV-2 nucleocapsid-specific IgG, and COVID-19 vaccination status. The Enzyme-Linked Immunosorbent Assay (ELISA) was used to identify the biomarkers. ANOVA and t-tests revealed that the group of COVID-19 positive, SARS-CoV-2 nucleocapsid-specific IgG negative, and non-vaccinated individuals had the greatest average value for cathepsin S (p = 0.03). This suggests a correlation between the presence of COVID-19 and autoimmune disorders. The group with the greatest average value of cell-free DNA was the COVID-19-negative, SARS-CoV-2 nucleocapsid-specific IgG-negative, vaccinated group (p = 0.03). This may suggest that even though they had not contracted the disease, they may have had a stronger immune response to the virus since vaccines can stimulate an immune response even in individuals who have not been infected by the virus. Furthermore, the SARS-Cov-2 nucleocapsid-specific IgG+ and COVID-19 positive groups had higher levels of myeloperoxidase, a neutrophil protein linked to inflammation and tissue damage, suggesting a higher risk of autoimmune rheumatologic illnesses (p = 0.02). The study suggests a correlation between COVID-19 status and the development of autoimmune disorders, as well as a potential link between a COVID-19 infection and a strong immune response. However, this study had limitations - the selection of participants and a small sample size, which offers potential for further research and examination.

Autologous MPO Knock-out Hematopoietic Stem and Progenitor Cells for Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive condition for which there is no cure. Even with substantial pharmacologic advances in the modern treatment era, existing treatments provide only symptomatic relief and survival remains unacceptably poor. Patients who fail to respond to medications usually have the worst prognosis and patients with persistently elevated pulmonary pressure and right heart failure usually die within 5 years. PAH is a severe complication of Systemic sclerosis (SSc) affecting approximately 8%-12% of patients. SSc affects 13.5-44.3 per 100,000 individuals and is complex and diverse, with limited treatment options. SSc-associated PAH is the second largest group of patients with PAH. Once diagnosed, it becomes the leading cause of mortality among this patient population, with a 50% mortality rate within 3 years of PAH diagnosis. Inflammation and endothelial injury being the main components of the syndrome, investigation regarding the underlying mechanisms of this immune response may lead to the development of a new efficient therapy. There is extensive evidence for a pathogenic role for neutrophil myeloperoxidase (MPO) in PAH disease. PAH patients with higher levels of MPO have a poorer outcome. Studies in murine models of PAH demonstrate significant disease amelioration by elimination of neutrophil MPO by hematopoietic stem cell (HSC) transplantation with HSC lacking MPO from germline MPO gene knock-out. We developed a gene therapy approach to PAH in which autologous HSCs will undergo gene editing using CRISPR/Cas9 to achieve bi-allelic disruption of the MPO gene. These MPO-knock-out HSCs will then be autologous transplanted. That autologous transplantation of HSPC in which the MPO gene is disrupted is expected to prevent progression of PAH due to the essential role of neutrophil MPO activity on disease development. We identified a sgRNA that leads to high frequency disruption of MPO in primary human CD34+ hematopoietic stem and progenitor cells (HSPC), leading to efficient elimination of MPO protein in the resultant neutrophils. That sequence was assessed for genome-wide off-target and showed no detectable locus, validating it as a lead candidate for safe gene editing strategy. We validated in an in vitro neutrophil differentiation model the functional efficiency of the knock-out. MPO KO differentiated cells exhibit reduced neutrophil extracellular traps formation (NETosis) and absence of MPO protein. An optimized gene editing protocol for HSC was optimized and showed consistent allelic disruption over 80%. The edited cells retain hematopoietic potential and showed no skewing in the generated lineages in an in vitro colony forming assay. We developed a surrogate gene editing protocol for murine cells and optimized electroporation to achieve high allelic disruption of the murine MPO gene in lineage negative murine hematopoietic cells. The protocol will be tested in a hypoxia-induced PAH murine model. The presented work can represent a major improvement for PAH patient. The limited therapeutic options and severity of the disease urges to develop new approaches. The gene therapy protocol developed showed promising result in vitro and rely on clinical evidences for the implication of MPO in the disease. Results will be tested in a pre-clinical murine model

Reactive oxygen species downregulate dystroglycans in the megakaryocytes of rats with arterial hypertension

Hypertension is a multifactorial disease characterized by vascular and renal dysfunction, cardiovascular remodeling, inflammation, and fibrosis, all of which are associated with oxidative stress. We previously demonstrated cellular reactive oxygen species (ROS) imbalances may impact the structural and biochemical functions of blood cells and reported downregulation of β-dystroglycan (β-Dg) and overexpression of the epithelial sodium channel (ENaC) contribute to the pathophysiology of hypertension. In this study, we aimed to determine the expression of dystroglycans (Dg) and ENaC in platelet progenitors (megakaryocytes) and their surrounding niches. Thin sections of bone marrow from 5- and 28-week-old spontaneous hypertensive rats (SHR) were compared to age-matched normotensive rats (WKY). Cytometry and immunohistochemical assays demonstrated an oxidative environment in SHR bone marrow, characterized by high levels of myeloperoxidase and 3-nitrotyrosine and downregulation of peroxiredoxin II. In addition, transmission electron micrography and confocal microscopy revealed morphological changes in platelets and Mgks from SHR rats, including swollen mitochondria. Quantitative qRT-PCR assays confirmed downregulation of Dg mRNA and immunohistochemistry and western-blotting validated low expression of β-Dg, mainly in the phosphorylated form, in Mgks from 28-week-old SHR rats. Moreover, we observed a progressive increase in β-1 integrin expression in Mgks and extracellular matrix proteins in Mgk niches in SHR rats compared to WKY controls. These results indicate accumulation of ROS promotes oxidative stress within the bone marrow environment and detrimentally affects cellular homeostasis in hypertensive individuals.

Increased Myeloperoxidase Concentrations in Saliva could Reflect Increased Body Mass and Oral Microinflammation.

Increased myeloperoxidase (MPO) levels in saliva are thought to reflect ongoing periodontal inflammation. Less clear is whether and to what extent salivary MPO is increased as a result of systemic inflammation. In the present study, we aimed to determine which demographic, anthropometric, biochemical, and dental parameters affect the level of MPO in whole mixed saliva in healthy adults with no apparent inflammatory lesions in the oral cavity. Thus, 113 individuals, aged 20-61 years (including 30.1% men and 23.9% smokers), were examined. In the univariate analysis, higher levels of MPO in saliva were found to be associated with age, an increased body mass index (BMI), higher levels of cytokines tumour necrosis factor-α and interleukin-6, as well as poorer oral hygiene, gingival status, and lower saliva flow. Multivariate logistic regression analysis determined that the main predictors of MPO concentration in saliva were BMI and stimulated saliva flow rate. Overall, an increase in MPO in saliva could be related to an increase in BMI, possibly as a result of subclinical chronic microinflammation, which also involves the gingiva.

Current Smoking Determines the Levels of Circulating MPO and MMP-9 in Adults with Coronary Artery Disease and Obstructive Sleep Apnea.

(1) Background: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), in which a rupture of atherosclerotic plaques and oxidative stress play a role in the initiation and progression of the disorder. Circulating levels of myeloperoxidase (MPO), as an oxidative stress marker, as well as matrix metalloproteinase-9 (MMP-9), as a destabilizer of plaques, are known to be elevated in patients with CAD and are associated with worse prognosis. Some studies have suggested that OSA is associated with MPO and MMP-9, but the effect of OSA on these biomarkers in cardiac cohorts is unknown. (2) Aims: We addressed the determinants of high MPO and MMP-9 in a CAD cohort with concomitant OSA. (3) Materials and Methods: The current study was a secondary analysis of the RICCADSA trial that was conducted in Sweden between 2005 and 2013. A total of 502 revascularized CAD patients with OSA (apnea-hypopnea index [AHI] ≥ 15 events/h; n = 391) or no-OSA (AHI < 5 events/h; n = 101), based on a home sleep apnea test, and who had blood samples at baseline were included in the analysis. The patients were dichotomized into a high or low MPO and MMP-9 groups, based on the median cut-off values. (4) Results: The mean age of the participants was 63.9 (±8.6), and 84% of the study cohort were men. Median values of MPO and MMP-9 levels were 116 ng/mL and 269 ng/mL, respectively. In different multivariate linear and logistic regression models, neither OSA nor OSA severity in terms of AHI and oxygenation indices were associated with the high MPO and MMP-9 levels. Current smoking was significantly associated with both high MPO (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06-2.84; p = 0.030) and high MMP-9 levels (OR 2.41, 95% CI 1.44-4.03; p < 0.001), respectively. Other significant determinants were revealed as beta blocker use (OR 1.81, 95% CI 1.04-3.16; p = 0.036) for high MPO as well as male sex (OR 2.07, 95% CI 1.23-3.50; p = 0.006) and calcium antagonist use (OR 1.91, 95% CI 1.18-3.09; p = 0.008) for high MMP-9 levels. (5) Conclusions: Current smoking, but not OSA, was significantly associated with high MPO and MMP-9 levels in this revascularized CAD cohort. Smoking status should be seriously taken into consideration while evaluating the effects of OSA and its treatment on long-term adverse cardiovascular outcomes in adults with CAD.

Association of Plasma Myeloperoxidase with Inflammation and Diabetic status in HFpEF.

Inflammation and oxidative stress are thought to play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) through the development of endothelial dysfunction. Myeloperoxidase (MPO) functions as a link between oxidative stress and inflammation and is an interesting therapeutic target. The objective of this observational cohort study was to compare MPO levels between HFpEF and old controls, to define clinical characteristics associated with high levels of MPO and to assess the relation between MPO levels and vascular function. Patients with HFpEF (N = 55) and controls 60 years (N = 18) were prospectively included. All subjects underwent complete echocardiography and blood sampling. MPO levels were dosed by ELISA assay. Effective arterial elastance (Ea) and peripheral arterial tonometry (EndoPAT reactive hyperemia index RHI and augmentation index AIx) were used to assess vascular function. Characteristics between groups defined by the median of MPO were compared using independent samples t-test or chi square test. Patients with HFpEF (80 8.7 years, 65% female) had higher levels of MPO compared to controls (75 5.0 years, 72% female) (34.7 ng/mL [22.7; 44.0] vs 22.6 [18.2; 32.0], p = 0.026). MPO levels were correlated with markers of inflammation; C-reactive protein (Pearson's R = 0.46, p = 0.001) and neutrophile to lymphocyte ratio (R = 0.36, p = 0.031) and with signs of left ventricular (LV) remodelling and elevated filling pressures, namely NT-proBNP levels (R = 0.32, p = 0.019), decreased LV ejection fraction (LVEF, R = -0.36, p = 0.008) and E/e' ratio (R = 0.35, p = 0.011). HFpEF patients with levels of MPO above the median were more often men (48% vs 21%, p = 0.037) and suffered more often from diabetes (48% vs 18%, p = 0.017). Intriguingly, they had lower indices of vascular stiffness (augmentation index 11.1 [0.1; 30.7] vs 19.9 [10.5; 33.4], p = 0.018 and arterial elastance Ea 2.06 0.676 vs 2.43 0.721, p = 0.065) and there was no difference in endothelial function (1.82 [1.34; 2.30] vs 1.66 [1.32; 1.95], p = 0.55). HFpEF patients have higher levels of MPO than controls, reflecting leukocyte activation and oxidative stress. Among patients, high levels of MPO are associated with male sex, diabetic status, subtle left ventricular dysfunction and pronounced diastolic dysfunction. The association between oxidative stress and vascular stiffness, on the other hand could not be demonstrated. Clinical trial NCT03197350.

Myeloperoxidase: A Circulating Marker of Inflammation and Tooth Infection

BackgroundAtherosclerotic cardiovascular disease and tooth infection are common in primary care, and both significantly reduce quality of life. Our study aimed to examine signs of vascular inflammation associated with loss of tooth vitality before and after a single tooth extraction. MethodsAn observational cohort study was performed with adults who had a nonvital tooth and an indicated desire for tooth extraction. Concentrations of total cholesterol, high-density lipoprotein-cholesterol, high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), and troponin T were measured in venous blood serum or plasma at baseline and 6-weeks after tooth extraction. ResultsCirculating hs-CRP levels were > 3 mg/dL in 15 participants (68.2%) and MPO levels were > 350 pmol/L in 9 (40.9%) of 22 participants at baseline. After tooth extraction (n = 18), MPO levels decreased significantly compared with baseline (P < .00006) and hs-CRP levels moved directionally downward. The response rate for MPO was 88.9% (confidence interval: 65.1%-98.6%) from visit 1 to visit 2. Those with high MPO levels at baseline demonstrated larger reductions in MPO levels by visit 2 than those with lower baseline MPO levels (r = .81; P < .0001). A total of 13 individuals (72.2%) achieved MPO levels < 350 pmol/L and 11 (61.1%) achieved hs-CRP levels < 3 mg/dL at visit 2. Total cholesterol, high-density lipoprotein-cholesterol, and troponin T levels did not significantly change from visit 1 to visit 2. ConclusionA link between dental infection and circulating levels of inflammation was observed, suggesting that oral infection could be a risk factor for atherosclerotic cardiovascular disease.

Chronic Methylmercury Intoxication Induces Systemic Inflammation, Behavioral, and Hippocampal Amino Acid Changes in C57BL6J Adult Mice.

Methylmercury (MeHg) is highly toxic to the human brain. Although much is known about MeHg neurotoxic effects, less is known about how chronic MeHg affects hippocampal amino acids and other neurochemical markers in adult mice. In this study, we evaluated the MeHg effects on systemic lipids and inflammation, hippocampal oxidative stress, amino acid levels, neuroinflammation, and behavior in adult male mice. Challenged mice received MeHg in drinking water (2 mg/L) for 30 days. We assessed weight gain, total plasma cholesterol (TC), triglycerides (TG), endotoxin, and TNF levels. Hippocampal myeloperoxidase (MPO), malondialdehyde (MDA), acetylcholinesterase (AChE), amino acid levels, and cytokine transcripts were evaluated. Mice underwent open field, object recognition, Y, and Barnes maze tests. MeHg-intoxicated mice had higher weight gain and increased the TG and TC plasma levels. Elevated circulating TNF and LPS confirmed systemic inflammation. Higher levels of MPO and MDA and a reduction in IL-4 transcripts were found in the hippocampus. MeHg-intoxication led to increased GABA and glycine, reduced hippocampal taurine levels, delayed acquisition in the Barnes maze, and poor locomotor activity. No significant changes were found in AChE activity and object recognition. Altogether, our findings highlight chronic MeHg-induced effects that may have long-term mental health consequences in prolonged exposed human populations.

Myeloperoxidase as therapeutic target in HFpEF

Abstract Background Inflammation and oxidative stress are thought to play an important role in the pathophysiology of HFpEF through the development of endothelial dysfunction. Myeloperoxidase (MPO), a leukocyte-derived enzyme, functions as a link between oxidative stress and inflammation and is an interesting therapeutic target. Purpose To compare MPO levels between HFpEF and old controls and to define clinical characteristics associated with high levels of MPO. Methods Patients with HFpEF (N=55) and controls &amp;gt;60 years (N=18) were prospectively included. All subjects underwent complete echocardiography and standard biology. MPO levels were dosed by ELISA assay. Endothelial function was assessed by peripheral arterial tonometry through the reactive hyperemia index (RHI). Characteristics were compared using independent samples t-test or chi square test. Results Patients with HFpEF (80±8.5 years, 65% female) had higher levels of myeloperoxidase compared to controls (74±6.2 years, 72% female) (34.7 ng/mL [22.7; 43.9] versus 22.5 [18.1; 31.9], p=0.026) (Figure 1). HFpEF patients with levels of MPO above the median were more often men and diabetic and had higher levels of NTproBNP and CRP. However, MPO levels were not associated with endothelial function measured by RHI (Table 1). Conclusion(s) HFpEF patients have higher levels of myeloperoxidase than control subjects, reflecting leukocyte activation and oxidative stress. Myeloperoxidase levels are associated with inflammation and disease severity. Myeloperoxidase inhibitors could be useful for the treatment of HFpEF patients, especially in the subgroup of patients with diabetes. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Fondation Damman

The Relationship between Selected Inflammation and Oxidative Stress Biomarkers and Carotid Intima-Media Thickness (IMT) Value in Youth with Type 1 Diabetes Co-Existing with Early Microvascular Complications.

Recent years have confirmed the importance of oxidative stress and biomarkers of inflammation in estimating the risk of cardiovascular disease (CVD) and explaining not fully understood pathogenesis of diabetic macroangiopathy. We aimed to analyze the relation between the intima-media thickness (IMT) of common carotid arteries and the occurrence of classical cardiovascular risk factors, together with the newly proposed biomarkers of CVD risk (high-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), adiponectin, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and vitamin D) in youth with type 1 diabetes (T1D) recognized in screening tests to present early stages of microvascular complications (VC). The study group consisted of 50 adolescents and young adults with T1D, mean age 17.1 years (10–26 age range), including 20 patients with VC (+) and 30 VC (−). The control group (Control) consisted of 22 healthy volunteers, mean age 16.5 years (11–26 age range). In the VC (+) patients, we found a significantly higher concentration of HbA1c, lipid levels, hsCRP and NT-proBNP. BMI and blood pressure values were highest in the VC (+) group. Higher levels of MPO and lower levels of vitamin D were found in both diabetic groups vs. Control. IMT in VC (+) patients was significantly higher and correlated positively with HbA1c, hsCRP, NT-pro-BNP and negatively with vitamin D levels. In conclusion, youth with T1D and VC (+) present many abnormalities in the classical and new CVD biomarkers. hsCRP and MPO seem to be the most important markers for estimating the risk of macroangiopathy. NT-proBNP may present a possible marker of early myocardial injury in this population.

RGD-Labeled Hemocytes With High Migration Activity Display a Potential Immunomodulatory Role in the Pacific Oyster Crassostrea gigas.

Immunocyte migration to infection sites is important for host cellular defense, but the main types of migrating hemocytes and their mechanisms against pathogen invasions are unclear in invertebrates. In the present study, a population of hemocytes in the Pacific oyster Crassostrea gigas labeled with a fluorescein isothiocyanate (FITC)-conjugated Arg-Gly-Asp (RGD)-containing peptide was sorted. RGD+ hemocytes were characterized by a smaller cell size and cytoplasmic-nucleo ratio, fewer cytoplasmic granules, and higher levels of myeloperoxidase, reactive oxygen species, and intracellular free calcium concentration. RGD+ hemocytes exhibited a high level of migration activity, which was further induced after V. splendidus infection. Transcriptome analysis revealed that RGD+ hemocytes highly expressed a series of migration-related genes, which together with migration-promoting genes were significantly upregulated after V. splendidus infection. The neuroendocrine system was also proven to regulate the migration activity of RGD+ hemocytes, especially with the excitatory neuroendocrine factor dopamine, which promoted migration activity as confirmed by receptor blocking assays. Meanwhile, RGD+ hemocytes could highly express immunomodulatory factor interleukin (IL)-17s and their receptor genes, which was positively related to the production of antimicrobial peptides in whole hemocytes after V. splendidus infection. Collectively, this study identified a specific hemocyte population, i.e., RGD+ hemocytes, that shows high migration activity in response to pathogen infection and exerts a potential immunomodulatory role by highly expressing IL-17s that might enhance the hemocytes’ antimicrobial peptide production in oysters.

Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes.

Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.

Inflammation-dependent oxidative stress metabolites as a hallmark of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with poor prognosis and no cure. Substantial evidence implicates inflammation and associated oxidative stress as a potential mechanism for ALS, especially in patients carrying the SOD1 mutation and, therefore, lacking anti-oxidant defense. The brain is particularly vulnerable to oxidation due to the abundance of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), which can give rise to several oxidized metabolites. Accumulation of a DHA peroxidation product, CarboxyEthylPyrrole (CEP) is dependent on activated inflammatory cells and myeloperoxidase (MPO), and thus marks areas of inflammation-associated oxidative stress. At the same time, generation of an alternative inactive DHA peroxidation product, ethylpyrrole, does not require cell activation and MPO activity. While absent in normal brain tissues, CEP is accumulated in the central nervous system (CNS) of ALS patients, reaching particularly high levels in individuals carrying a SOD1 mutation. ALS brains are characterized by high levels of MPO and lowered anti-oxidant activity (due to the SOD1 mutation), thereby aiding CEP generation and accumulation. Due to DHA oxidation within the membranes, CEP marks cells with the highest oxidative damage. In all ALS cases CEP is present in nearly all astrocytes and microglia, however, only in individuals carrying a SOD1 mutation CEP marks >90% of neurons, thereby emphasizing an importance of CEP accumulation as a potential hallmark of oxidative damage in neurodegenerative diseases.

Abstract 9610: High Levels of Myeloperoxidase Are Similar Across ASCVD Risk Groups and Are Associated with Markers of Liver Fibrosis and Kidney Function in a Workforce Population

Background: High blood levels of free myeloperoxidase (MPO) identify patients at risk for cardiovascular disease. We investigated levels of MPO according to 10-year ASCVD risk and the association between high MPO and markers of liver fibrosis and kidney disease. Methods: The study included participants in employer-sponsored annual health assessment (August 2020 to March 2021, n=33,984, 63% women, median age 47, IQR 36 to 56). Age and sex adjusted logistic models assessed the association between high MPO and non-alcoholic fatty liver disease (NAFLD) fibrosis score, liver Fibrosis-4 (FIB4) score, and estimated glomerular filtration rate (eGFR), stratified by 10-year ASCVD risk groups. Results: High MPO (&gt;540 pmol/L) was found in 3% (n =925), 4% (n=184), and 5% (n =63) of the low (&lt;7.5%), intermediate (7.5% to 20%), and high (&gt;20% or prevalent disease) ASCVD risk groups, respectively. High MPO (&gt;540 vs. ≤540 pmol/L) was associated with high NAFLD fibrosis score (&gt;0.676 vs. &lt;-1.455): OR = 4.7, 95%CI 3.5 to 6.2, high FIB4 score (&gt;3.25 vs. ≤3.25): OR =3.4, 95%CI 1.8 to 6.4 and low eGFR (&lt;60 vs. ≥60 mL/min/1.73m 2 ): OR =1.8, 95%CI 1.4 to 2.4. The associations varied according to ASCVD risk (Figure). In the high ASCVD risk group, MPO was not associated with either NAFLD fibrosis score, FIB4 score, or eGFR (P ≥0.2 for all) and the risk differed according to ASCVD risk group (&gt;20% vs. ≤20%) for NAFLD fibrosis score (P int =0.03) and eGFR (P int =0.01). Conclusion: The fraction of those with high MPO did not appreciably differ across ASCVD risk groups and most participants with high MPO levels in this workforce population were in the low ASCVD risk group. This observation is consistent with the hypothesis that subjects in the high ASCVD risk group are more likely to be receiving preventive therapies, whereas guidelines dictate that those in moderate and low risk groups may not. Investigating the association of MPO levels in ASCVD risk groups according to preventive therapy intensity is warranted.

Homocitrullination of lysine residues mediated by myeloid-derived suppressor cells in the tumor environment is a target for cancer immunotherapy

BackgroundHomocitrullination is the post-translational modification of lysine that is recognized by T cells.MethodsThis study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and binding immunoglobulin protein and used human leukocyte antigen...

Emodin improves alveolar hypercoagulation and inhibits pulmonary inflammation in LPS-provoked ARDS in mice via NF-κB inactivation

BackgroundAlveolar hypercoagulation and pulmonary inflammation are important characteristics and they regulate each other in acute respiratory distress syndrome (ARDS). NF-κB pathway has been confirmed to be involved in regulation of this crosstalk. Emodin, a traditional Chinese herb, shows potent inhibitory effect on NF-κB pathway, but whether it is effective in alveolar hypercoagulation and pulmonary inflammation in ARDS remains to be elucidated. PurposeThe aim of this experiment was to evaluate the efficacy of emodin on LPS-provoked alveolar hypercoagulation and excessive pulmonary inflammation in ARDS, and its potential mechanism. MethodsMice ARDS was set up through LPS (40 μl, 4 mg/ml) inhalation. Male mice were randomly received with BPS, LPS only, LPS+ emodin (5 mg/kg, 10 mg/kg, 20 mg/kg, respectively) and BAY65-1942, an inhibitor of IKKβ. After 48 h of LPS stimulation, pulmonary pathological injury, expressions of Tissue factor (TF), plasminogen activator inhibitor (PAI)-1, activated protein C (APC), collagen Ⅰ, collagen III, interleukin (IL) 8, IL-1β and tumor necrosis factor (TNF)-α in lung tissues, as well as concentrations of antithrombin III (AT III), procollagen peptide type III (PIIIP), soluble thrombomodulin (sTM), thrombin antithrombin complex (TAT), myeloperoxidase (MPO) and the percentage of inflammatory cells in bronchoalveolar lavage fluid (BALF) were all determined. NF-κB pathway activation as well as NF-κB DNA binding activity in pulmonary tissue were simultaneously checked. ResultsLPS stimulation resulted in obvious lung injury, excessive inflammatory cells infiltration, which all were dose-dependently ameliorated by emodin. Expressions of TF, PAI-1, collagen Ⅰ and collagen III as well as IL-8, IL-1β and TNF-α in pulmonary tissue were all elevated while APC decreased under LPS provocation, which were all reversed by emodin treatment in dose-dependent manner. LPS promoted the secretions of PIIIP, sTM, TAT and inhibited AT III production in BALF, and resulted in high levels of MPO and the percentage of inflammatory cells in BALF, all of which were significantly and dose-dependently attenuated while AT III production was increased by emodin. Meanwhile, emodin effectively inhibited NF-κB pathway activation and attenuated p65 DNA binding activity induced by LPS inhalation. Emodin and BAY-65-1942 had similar impacts in this experiment. ConclusionsEmodin improves alveolar hypercoagulation and fibrinolytic inhibition and depresses excessive pulmonary inflammation in ARDS mice in dose-dependent manner via NF-κB inactivation. Our data demonstrate that emodin is expected to be an effective drug in alveolar hypercoagulation and pulmonary inflammation in ARDS.

Prognostic value of myeloperoxidase in patients with peripheral artery disease.

The involvement of myeloperoxidase in the production of dysfunctional high-density lipoproteins and oxidised biomolecules leads to oxidative stress in the blood vessel endothelium. This prospective cohort study aimed to examine the prognostic value of myeloperoxidase in patients with peripheral artery disease in relation to major adverse cardiac events (MACEs), target lesion revascularisation, and major adverse limb events (MALEs) and its association with multi-bed vascular disease, which is defined as any combination of the following: peripheral artery disease and coronary artery disease. Myeloperoxidase levels were measured in patients with peripheral artery disease and coronary artery disease during angiography. A total of 94 patients were analysed and followed up regarding their MACEs, target lesion revascularisation, and MALEs from August 2016 until February 2019. Among patients with peripheral artery disease, the rates of MACE and mortality were higher in patients with high myeloperoxidase levels than in those with low myeloperoxidase levels; the myeloperoxidase levels were 3.68 times higher in these patients (p < 0.0001). Patients with peripheral artery disease and coronary artery disease (multi-bed vascular disease) had higher myeloperoxidase levels than those with only peripheral artery disease and only coronary artery disease (one-bed vascular disease). Peripheral artery disease patients with higher myeloperoxidase levels had significantly higher rates of limb ischaemia, requiring further revascularisation than those with low myeloperoxidase levels. High myeloperoxidase levels suggest poor outcomes and are associated with MACE and limb ischaemia. Our findings indicated that myeloperoxidase levels could become a prognostic marker and may be used in conjunction with other methods for risk stratification in patients with peripheral artery disease and multi-bed vascular disease.