interleukin-8 and Thrombosis

The hypercoagulable state associated with malignancy is well described. However, the mechanisms by which tumors cause this hypercoagulable state are yet to be fully understood. This review summarizes the available literature of human and animal studies examining NETs and cancer-associated thrombosis. The methods for detecting and quantifying NET formation are growing but are not yet standardized in practice. Furthermore, it is important to distinguish between measuring neutrophil activation and NET formation, as the former can be present without the latter. Citrullination of histones by peptidylarginine deiminase 4 (PAD4) is considered one of the key pathways leading to NET formation. Cancer cells can prime neutrophils toward NET formation through the release of soluble mediators, such as interleukin-8, and activation of platelets, and may cause excess NET formation. Dismantling NETs through exogenous deoxyribonuclease has been shown to degrade NETs and reduce thrombus formation in vitro but may simultaneously release prothrombotic NET components, such as DNA and histones. Inhibiting PAD4 is far from clinical trials, but animal models show promising results with a potentially favorable safety profile. Interestingly, results from animal studies suggest that several therapies approved for other indications, such as interleukin-1 receptor blockade and JAK inhibition, may mitigate excessive NET formation or the prothrombotic effects of NETs in cancer. It is yet to be determined if inhibition of NET formation reduces cancer-associated thrombosis also in the clinical setting.

Topics: Animals; Deoxyribonucleases; DNA; Extracellular Traps; Histones; Humans; Interleukin-8; Neoplasms; Neutrophils; Protein-Arginine Deiminases; Receptors, Interleukin-1; Thrombophilia; Thrombosis

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

This study was to investigate the efficacy of low molecular weight heparin (LMWH) therapy in patients with spinal trauma after part concentrated screw (PCS) pedicle screw surgery (PSS) and its influence on blood parameters and the incidence of deep venous thrombosis. Prospectively, 36 patients with spinal trauma who underwent PSS were randomly divided into an experimental group (n = 18) and a control group (n = 18). The experimental group was treated with LMWH after the operation. Changes in the vascular endothelial function, inflammatory factors and other blood indexes, and the incidence of deep venous thrombosis in lower extremities were compared between the two groups before and after the surgery. Compared to pre-surgery, the levels of endothelin (ET) and tissue plasminogen activator (tPA) in the experimental group decreased significantly after surgery (all P < 0.001), while the levels of ET increased and tPA decreased significantly in the control group (all P < 0.001). In addition, compared with pre-surgical levels, interleukin-8 (IL-8), IL-6 and procalcitonin (PCT) decreased significantly in the experimental group after surgery while there was a significant increase in these cytokines in the control group (all P < 0.001), with a significant difference in the cytokine levels between the two groups post-surgery (P < 0.01). After the surgery, plasma viscosity, erythrocyte electrophoresis time and platelet aggregation rate in the control group were significantly increased from pre-surgery levels (all P < 0.001), and these levels were also significantly higher than in the experimental group (P < 0.01). The D-dimer (D-D) level in both groups also increased significantly after surgery (all P < 0.001), and the level post-surgery was significantly higher in the experimental group as compared to the control group (P < 0.01). Finally, the incidence of deep venous thrombosis in the experimental group was significantly lower than in the control group (P < 0.05). LMWH is beneficial in reducing the degree of hypercoagulability, hyperviscosity and inflammatory reaction in patients with spinal trauma who underwent PSS. It also effectively reduced the occurrence of deep vein thrombosis in lower limbs after surgery. Thus, it is a candidate for further clinical development.

Topics: Adult; Anticoagulants; Blood Coagulation; Bone Screws; Endothelins; Endothelium, Vascular; Erythrocytes; Female; Heparin, Low-Molecular-Weight; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Membrane Proteins; Pedicle Screws; Procalcitonin; Prospective Studies; Spinal Injuries; Thrombosis; Venous Thrombosis; Viscosity

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The cardiopulmonary bypass (CPB) circuit induces blood activation and a systemic inflammatory response in cardiac surgical patients. The CPB circuit treated with surface-modifying additive (SMA) has been found to reduce blood activation by in vitro and ex vivo experiments. This study evaluates the surface thrombogenicity and complement activation of SMA circuits during clinical CPB.. Twenty patients undergoing coronary artery bypass grafting were randomly divided into two groups. In the SMA group (n = 10), all blood-contacting surfaces in the CPB circuit were treated or coated with SMA, whereas in the control group (n = 10) patients were perfused with an identical circuit without treatment.. During CPB, platelet count and beta-thromboglobulin were found similar in both the SMA and the control groups. Prothrombin activation indicated by fragment F1 + 2 was found less in the SMA group (p < 0.05). After CPB, platelet deposition on the CPB circuit was significantly less (p < 0.05) in the SMA group than in the control group as assessed by the labeled monoclonal antibody against platelet glycoprotein IIIa. Complement activation identified by C3a and terminal complex C5b-9 did not differ between the two groups, but C4a generation was less in the SMA group (p < 0.05). Leukocyte activation identified by elastase and cytokine release indicated by interleukin-8 were found uniformly in both groups. Postoperatively, chest tube drainage, blood transfusion, duration of ventilatory support, as well as the intensive care unit and hospital stay were not significantly different between the two groups.. These preliminary clinical results suggest that SMA inhibits platelet interaction with the biomaterial surface of the CPB circuit. Complement activation assessed by the terminal complement complex is not influenced by SMA. The clinical benefit of this surface-modifying technique has yet to be assessed in a larger population of patients undergoing cardiac operations.

Topics: beta-Thromboglobulin; Blood Platelets; Cardiopulmonary Bypass; Complement Activation; Complement C3a; Complement C4a; Complement Membrane Attack Complex; Coronary Artery Bypass; Evaluation Studies as Topic; Female; Humans; Interleukin-8; Leukocyte Elastase; Leukocytes; Male; Middle Aged; Peptide Fragments; Platelet Adhesiveness; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Prothrombin; Surface-Active Agents; Systemic Inflammatory Response Syndrome; Thrombosis

Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation. Forty-five landrace pigs, average 17 kg (range 8.5-30), underwent intravenous air infusion for 300 or 360 minutes (n=29) or served as sham (n=14). Fourteen pigs were excluded due to e.g. infections or persistent foramen ovale. Blood was analyzed for white blood cells (WBC), complement activation (C3a and terminal C5b-9 complement complex [TCC]), cytokines, and hemostatic parameters including thrombin-antithrombin (TAT) using immunoassays and rotational thromboelastometry (ROTEM). Lung tissue was analyzed for complement and cytokines using qPCR and immunoassays. Results are presented as medians with interquartile range.. Venous air embolism in pigs activated C3 without a corresponding C5 activation and triggered thromboinflammation, consistent with a C3-dependent mechanism. C3-inhibition might represent a therapeutic approach to attenuate this response.

Topics: Animals; Complement C3; Complement Membrane Attack Complex; Cytokines; Embolism, Air; Inflammation; Interleukin-6; Interleukin-8; Swine; Thromboinflammation; Thrombosis

Prevalence of acute ische-mic stroke (AIS) is increased in patients with coronavirus disease 2019 (COVID-19). A proposed hypothesis is increased virus-induced propensity to hypercoagulation resulting in arterial thrombosis. Our aim was to provide evidence regarding the involvement of neutrophil extracellular trap (NET) formation (NETosis) in COVID-19 related AIS.. Twenty-six consecutively enrolled COVID-19+ pneumonia patients with AIS, 32 COVID-19+ pneumonia patients without AIS and 24 AIS patients without COVID-19 infection were included to the study. Clinical characteristics of recruited patients were collected. Serum levels of citrullinated histone H3 (H3Cit; a factor of NETosis), IL-8 and C5a (mediators associated with NETosis) were measured by ELISA (enzyme-linked immunosorbent assay).. H3Cit levels were significantly higher in COVID-19+ AIS patients, whereas all study groups showed comparable IL-8 and C5a levels. There were no significant differences among etiological subgroups of AIS patients with or without COVID-19. AIS patients with COVID-19 showed relatively increased white blood cell, lymphocyte, neutrophil, D-dimer, C-reactive protein and procalcitonin levels than control groups. H3Cit levels did not correlate with clinical/prognostic features and inflammation parameters. H3Cit and IL-8 levels were correlated in COVID-19 patients without stroke but not in COVID-19 positive or negative AIS patients.. Increased levels of inflammation parameters and H3Cit in COVID-19 related AIS suggest that NETosis may cause susceptibility to arterial thrombosis. However, H3Cit levels do not correlate with clinical severity measures and inflammation parameters diminishing the prognostic biomarker value of NETosis factors. Moreover, the link between IL-8 and NETosis appears to be abolished in AIS.. A Covid-19-betegek körében megnő az akut ischaemiás stroke (AIS) prevalenciája. Egy hipotetikus mechanizmus szerint a vírus megnöveli a hiperkoagulációs hajlamot, ami arteriális thrombosist eredményez. Vizsgálatunk célja az volt, hogy bizonyítsuk: a neutrophil extracelluláris csapdaképződés (NETosis) közreműködik a Covid-19-cel összefüggő AIS kialakulásában.. A vizsgálatba n = 26, AIS-ban szenvedő Covid-19-pneumoniás beteget, n = 32 AIS nélküli Covid-19-pneumoniás beteget és n = 24 AIS-ban igen, de Covid-19-ben nem szenvedő beteget vontunk be. Összegyűjtöttük a betegek klinikai adatait. ELISA-val mértük a citrullinált hiszton H3 (H3Cit; a NETosis egy faktora), az IL-8 és a C5a (NETosis-asszociált faktorok) szérumszintjét.. A Covid-19 + AIS betegekben szignifi­kánsan magasabb volt a H3Cit-szint, míg az IL-8- és C5a-szintek hasonlóak voltak valamennyi csoportban. A covidos és nem covidos AIS-betegek etiológiaalapú alcsoportjaiban nem találtunk szignifikáns különbségeket. A kont­rollcsoportokkal összehasonlítva, a Covid-19 + AIS betegekben megemelkedett a fehérvérsejt-, a lymphocyta-, és a neutrophilszám, továbbá megnőttek a D-dimer-, C-reaktív protein- és prokalcitoninszintek. A H3Cit-szintek nem függtek össze sem a klinikai/prognosztikus jellem­zőkkel, sem a gyulladásos paraméterekkel. A H3Cit- és az IL-8-szintek összefüggésben álltak egymással az AIS nélküli Covid-19-betegek esetében, azonban nem korreláltak a Covid-pozitív vagy -negatív AIS-betegek esetén.. A Covid-19-cel szövődött AIS esetében a gyulladásos paraméterek és a H3Cit megnövekedett szintje azt sugallja, hogy a NETosis arteriális thrombosis iránti fogékonyságot eredményezhet. Mindazonáltal az az eredmény, miszerint a H3Cit-szintek nem korrelálnak a klinikai súlyossággal és a gyulladásos paraméterekkel, lehetetlenné teszi a NETosis-faktorok prognosztikus biomarkerként való használatát. Ráadásul úgy tűnik, hogy az IL-8 és a NETosis közötti kapcsolat megszűnik AIS esetén.

Topics: COVID-19; Histones; Humans; Inflammation; Interleukin-8; Ischemic Stroke; Pneumonia; Stroke; Thrombosis

Venous thrombosis (VT) is one of the most frequent cardiovascular diseases, which seriously endangers people's health. Recently, the protective role of epigallocatechin-3-gallate (EGCG) against multiple cardiovascular diseases has been well studied. Nevertheless, whether EGCG is implicated in the progression of VT is still unclear.. Rat models of VT were established by inferior vena cava (IVC) ligation. Histological characterization of the IVC tissues was examined by hematoxylin-eosin (H&E) staining. TUNEL assay was utilized to detect cell apoptosis in IVC tissues. The concentrations of the oxidative stress biomarkers, malondialdehyde (MDA) and superoxide dismutase (SOD), were estimated by corresponding kits. In addition, the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 in rat plasma were estimated by ELISA. Further, the expression levels of apoptosis markers (Bax, Bcl-2, and Cleaved-caspase 3) as well as key molecules p-PI3K and p-AKT in phosphoinositide 3-kinase (PI3K)/AKT signaling pathway were assessed by western blot.. Compared to the sham group, the model group showed obvious thrombus formation in IVC tissues, while the EGCG treatment significantly repressed thrombosis. EGCG inhibited cell apoptosis in IVC tissues of VT rat models. The decreased SOD concentration and increased MDA concentration in the plasma of VT rats were reversed by EGCG treatment. Additionally, the elevated levels of TNF-α, IL-6 and IL-8 in the plasma of VT rats can be partially reduced by the treatment of EGCG. Finally, we also found that EGCG reduced the levels of phosphorylated (p)-PI3K and p-AKT in IVC tissues of VT rat models, indicating that the hyperactivation of the PI3K/AKT signaling pathway was inhibited by EGCG.. This study proves that EGCG alleviates thrombosis, cell apoptosis, inflammatory response, and oxidative stress injury in VT by inactivating PI3K/AKT signaling pathway.

Topics: Animals; Apoptosis; Catechin; Interleukin-6; Interleukin-8; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Superoxide Dismutase; Thrombosis; Tumor Necrosis Factor-alpha

Patients with malignancy have higher risk of developing venous thromboembolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. The study was approved by the local ethics committee on human research, and written informed consent was obtained from all the study participants. After written informed consent was obtained, a precise medical history was taken, with particular attention to questions about the presence of thrombotic risk factors at the onset of VTE. We retrospectively enrolled 50 patients with Venous Thromboembolism (DVT and PTE) having malignancy and 50 healthy controls from January 2020 to December 2020. DVT were diagnosed using peripheral vascular duplex ultrasonography while PTE was confirmed in all cases by computed tomography. Patients having treatment with anticoagulant therapy, recent surgery less than 8 days previously, refusal or inability to give informed consent, and inability for ascending contrast venography or inadequate results of the venographic examination were excluded from the study. Biomarkers have been specifically investigated for their capacity of predicting venous thromboembolism (VTE) during the course of disease. The relationships between inflammation markers e.g., IL-6, IL-8 and CRP as indicators of the inflammatory process and clinical venous thromboembolism need to be investigated. We investigated IL-6, IL-8 and CRP in 50 patients with venous thromboembolism having malignancy and reported that patients having venous thromboembolism have increased levels of IL-6, IL-8 and CRP (p value < 0.05). Our study concluded that in cancer patients, inflammatory biomarkers play significant role in developing venous thromboembolism. This supports the hypothesis that, markers of systemic inflammatory response are involved in development of thromboembolism in patients with malignancy.

Topics: Biomarkers; Humans; Incidence; Interleukin-6; Interleukin-8; Neoplasms; Pulmonary Embolism; Retrospective Studies; Risk Factors; Systemic Inflammatory Response Syndrome; Thrombosis; Venous Thromboembolism

Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.. We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics.. We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.. The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10. LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

Topics: Adult; Aged; B7-H1 Antigen; Bronchoalveolar Lavage Fluid; COVID-19; Critical Illness; Female; Humans; Interleukin-3 Receptor alpha Subunit; Interleukin-8; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome; SARS-CoV-2; Scavenger Receptors, Class E; Thrombosis

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.

Topics: Animals; COVID-19; Humans; Interleukin-8; Lung; Mice; Neutrophil Activation; Neutrophils; Phenotype; SARS-CoV-2; Thrombosis

The role of inflammation in thrombotic complications of primary antiphospholipid syndrome (PAPS) is controversial. The aim of this study was to evaluate levels of inflammation and coagulation markers in patients with thrombotic PAPS (t-PAPS). Patients with t-PAPS and individuals with no history of thrombosis were enrolled. The association of t-PAPS with levels of tumor necrosis factor (TNF)-α, C-reactive protein (hs-CRP), interferon (IFN)-α, interleukins (IL)-6, -8, factor VIII (FVIII), von Willebrand factor (VWF) and tissue factor (TF) was evaluated by regression models. The levels of these markers were also compared between controls and subgroups of t-PAPS patients with triple positivity, recently diagnosed thrombosis, recurrent thrombosis and venous thrombosis. Patients with t-PAPS (n = 101) had a 8.6-fold increased levels of TNF-α, 90% increased levels of hs-CRP, 80% increased levels of IL-6, 30% increased levels of FVIIIAg, 50% increased levels of VWF and 66% increased levels of TF as compared to controls (n = 131), and the differences did not change after adjustments for sex, age and cardiovascular risk factors. Inflammatory markers were elevated in t-PAPS regardless of the aPL profile, number of previous thrombosis or time elapsed since diagnosis. TNF-α and IL-8 levels were higher in t-PAPS patients with venous thrombosis, in comparison with those with arterial thrombosis and controls. Patients with t-PAPS presented with increased levels of inflammatory and coagulation markers, which suggests that t-PAPS is associated not only with hypercoagulability but also with a persistent inflammatory state.

Topics: Adult; Antiphospholipid Syndrome; Biomarkers; Blood Coagulation; C-Reactive Protein; Case-Control Studies; Factor VIII; Female; Humans; Inflammation; Interferon-alpha; Interleukin-6; Interleukin-8; Male; Middle Aged; Thrombosis; von Willebrand Factor

To overcome the harmful side effects, low tolerance, and undesirable outcomes of the anticancer drugs, we used ethane-1,2-diamine to bridge antitumoral (

Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Glucuronic Acid; Indoles; Interleukin-8; Macrophages; Male; Mice; Mice, Inbred ICR; Microscopy, Atomic Force; Nanoparticles; Neoplasms, Experimental; P-Selectin; Phagocytosis; Quinolizines; Rats, Sprague-Dawley; Rats, Wistar; Thrombosis; Tissue Distribution; Tumor Necrosis Factor-alpha

The pathomechanisms of morbidity due to blood transfusions are not yet entirely understood. Elevated levels of red blood cell-derived microparticles (RMPs) are found in coagulation-related pathologies and also in stored blood. Previous research has shown that RMPs mediate transfusion-related complications by the intrinsic pathway. We hypothesized that RMPs might play a role in post-transfusion thrombotic complications by enhancing procoagulant activity also through the extrinsic pathway of coagulation.. In this laboratory study, blood from 18 healthy volunteers was stimulated with microparticles from expired stored red blood cells. Various clotting parameters were recorded. Flow cytometry, enzyme-linked immunosorbent assays, and real-time polymerase chain reaction were used to investigate possible mediating mechanisms.. The addition of RMPs shortened the clotting time from 194 to 161 seconds (p < 0.001). After incubation with RMPs, there was increased expression of tissue factor (TF) on monocytes and in plasma. TF messenger RNA expression increased in a time-dependent and concentration-dependent manner. There was a significant induction of interleukin-1β and interleukin-6. After stimulation with RMPs, there was a significant increase in the number of activated platelets, an increased percentage of PAC-1/CD62P (procaspase activating compound-1/platelet surface P-selectin) double-positive platelets, and an increased number of platelet-neutrophil duplets and platelet-monocyte duplets, indicating enhanced interaction of platelets with neutrophils and monocytes. Levels of CXCL-8 (C-X-C motif chemokine ligand 1) and interleukin-6 were significantly higher after treatment with RMPs.. Our results suggest that RMPs trigger coagulation through TF signaling, induce the secretion of proinflammatory cytokines, and induce cell-cell interaction between platelets and neutrophils. Thus, under certain conditions, RMPs could play a role in post-transfusion complications through these mechanisms.

Topics: Blood Coagulation; Blood Preservation; Cell Communication; Cell-Derived Microparticles; Erythrocytes; Humans; Inflammation; Interleukin-6; Interleukin-8; Monocytes; Platelet Activation; RNA, Messenger; Thromboplastin; Thrombosis; Transfusion Reaction

Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases.. We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1.. These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Topics: Blood Coagulation; Chemokine CCL2; Gene Expression; Humans; Interleukin-8; Monocytes; Stroke; Thrombolytic Therapy; Thrombosis; Transcription, Genetic

Cerebral ischemic-reperfusion injury as an inflammatory and microcirculation dysfunction pathological condition negatively affects the clinical outcome of stroke patients. The novel inflammatory procoagulant protein fgl2 has been reported to play a role in some inflammatory and coagulation dysregulation diseases. This study aimed to examine the relationship between fgl2 expression and infarct size in an acute cerebral ischemic-reperfusion rat model. We studied fgl2 mRNA and protein expressions in cerebral tissue and peripheral macrophages, and the expressions of several inflammatory factors (TNF-α, IL-1β, MCP-1, and IL-8) in serum samples from rats with acute cerebral ischemic-reperfusion injury. Fiber microthrombosis in situ contributed to the microvascular thrombosis in acute cerebral ischemic-reperfusion injury, and fgl2 expression tended to strongly correlate with cerebral infarct size. The expression levels of the other inflammatory factors significantly increased but weakly correlated with cerebral infarct size. These findings support the potential of fgl2 level as a novel biomarker of acute cerebral ischemic-reperfusion injury.

Topics: Animals; Biomarkers; Chemokine CCL2; Cytokines; Fibrinogen; Gene Expression Regulation; Inflammation; Interleukin-1beta; Interleukin-8; Macrophages; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 3; Reperfusion Injury; RNA, Messenger; Thrombosis; Tumor Necrosis Factor-alpha

Statins are widely used for primary and secondary prevention of coronary atherosclerosis. Simvastatin, besides its lipid lowering properties, has various anti-inflammatory effects. The aim of this study was to assess whether simvastatin modulates the vascular effects of interleukin (IL)-17, an emerging actor in atherosclerosis.. The effect of simvastatin was assessed in human umbilical vein endothelial cells treated by IL-17 alone or combined with tumour necrosis factor (TNF)-α, with or without mevalonate, an inhibitor of simvastatin. Its effects on IL-17-induced cytokine or chemokine expression were assessed at the mRNA level using qRT-PCR or protein level by ELISA. Its effect on the IL-17-induced pro-thrombotic state and cell invasion was assessed using a lumi-aggregometer and a Matrigel assay, respectively.. Simvastatin decreased IL-17-induced IL-6, IL-8, CX3CL-1, RANTES mRNA and CX3CL-1 and CCL20 production. Simvastatin restored the level of IL-33 mRNA which was decreased by IL-17. It reduced the expression of IL-17-induced pro-thrombotic genes such as tissue factor. Simvastatin restored the level of platelet aggregation to normal levels. Simvastatin enhanced the expression of CD39 and thrombomodulin mRNA initially reduced by IL-17 and TNF-α combination. Simvastatin suppressed IL-17-induced endothelial cells invasion. All these effects were reversed by the addition of mevalonate. Finally, simvastatin had an additive effect with infliximab to decrease the effect of the combination of IL-17 and TNF-α on IL-6 mRNA expression. Similar conclusion was obtained with rosuvastatin.. Statins inhibit the pro-inflammatory, thrombotic and pro-aggregation effects of IL-17 on vessels. This provides a new understanding of the beneficial effects of statins in blood vessel inflammation.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Anticholesteremic Agents; Antirheumatic Agents; Atherosclerosis; Drug Interactions; Endothelial Cells; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Infliximab; Interleukin-17; Interleukin-6; Interleukin-8; Platelet Aggregation; Simvastatin; Thrombosis; Tumor Necrosis Factor-alpha

In this study, the role of Chlamydia pneumoniae in triggering platelets to induce the inflammatory potential chemokines CCL3, CCL5, CCL7 and CXCL8 in atherosclerotic patients was investigated.. Venous blood from control subjects (n = 35) and atherosclerotic patients (n = 35) was collected in tubes with and without EDTA. Platelets from controls and patients were separated from whole blood and then stimulated with lipopolysaccharide (LPS), live C. pneumoniae and heat-treated C. pneumoniae. The ability of C. pneumoniae and its LPS to stimulate platelets and expression of CCL3, CCL5, CCL7 and CXCL8 was assessed with immunofluorescence. Immunosorbent assays were used to detect anti-C. pneumoniae antibodies in sera from patients and healthy subjects.. Nonstimulated platelets from patients showed significant expression of CCL3, CCL5, CCL7 and CXCL8 compared to controls (p < 0.0001). Stimulation of platelets from patients with live and heat-treated C. pneumoniae and its LPS demonstrated significant induction of chemokines compared to similarly stimulated platelets from controls (p < 0.01). After stimulation with heat-treated C. pneumoniae chemokine expression in platelets from controls was significantly lower than after stimulation with live C. pneumoniae (p < 0.01), which was not the case when platelets from patients were stimulated. Increased levels of anti-C. pneumoniae antibodies were detected in sera from patients compared to healthy subjects, suggesting prior C. pneumoniae exposure.. Our data demonstrated an interactive link between C. pneumoniae and platelets in atherosclerotic patients, leading to induction of potential chemokines and possibly disease development.

Topics: Adult; Arteriosclerosis; Blood Platelets; Case-Control Studies; Chemokine CCL3; Chemokine CCL5; Chemokine CCL7; Chemokines; Chlamydia Infections; Chlamydophila pneumoniae; Female; Humans; Immunoenzyme Techniques; Interleukin-8; Male; Middle Aged; Thrombosis

Shear stress has an established effect on mature endothelial cells, but less is known about how shear stress regulates endothelial progenitor cells (EPCs). In vitro expanded EPCs isolated from adult human blood represent a novel tool in regenerative vessel therapy. However, in vitro culturing may generate cells with unfavourable properties. The aim of the present study was therefore to assess whether shear stress may influence the inflammatory and thrombotic phenotype of in vitro expanded EPCs. In late outgrowth EPCs, 6 hours of shear stress (6.0 dynes/cm2) significantly reduced the mRNA levels of IL-8, COX2, and tissue factor (TF) compared to static controls. This was associated with a reduced TF activity. In contrast, mRNA expression of NOS3 was significantly increased following 6 and 24 hours of shear stress. In accordance with this, NOS3 protein expression was increased following 24 hours of shear stress. Overall stimulation with the proinflammatory mediator, TNFalpha, for the final 2 hours increased the mRNA expression of IL-6, IL-8, MCP-1, ICAM1, and TF. However exposure to 6 hours of shear stress significantly suppressed the inductory potential of TNFalpha to increase the mRNA levels of IL-6, IL-8, COX2, and TF. Additionally, TNFalpha increased TF activity approximately 10 times, an effect that was also significantly reduced by exposure to 6 and 24 hours of shear stress. The effect of shear on the gene levels of TF and NOS3 were not blocked by the NOS inhibitor L-NAME. These observations suggest that EPCs are capable of functionally responding to shear stress.

Topics: Cells, Cultured; Chemokine CCL2; Cyclooxygenase 2; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Mechanotransduction, Cellular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; RNA, Messenger; Stem Cells; Stress, Mechanical; Thromboplastin; Thrombosis; Time Factors; Tumor Necrosis Factor-alpha

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor-alpha superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor kappaB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor kappaB activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin.

Topics: Blood Coagulation; Cell-Derived Microparticles; Cells, Cultured; Culture Media, Conditioned; Endothelial Cells; Gene Expression Profiling; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA Interference; RNA, Small Interfering; Signal Transduction; Thrombin; Thrombosis; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor RelA; Transfection; Up-Regulation

Chlamydophila abortus is a Gram-negative obligate intracellular bacterium that causes infectious abortion in sheep (ovine enzootic abortion, OEA) and humans. Infected placentas recovered from sheep that experience OEA have thickened membranes, contain dense inflammatory cellular infiltrates and show evidence of intravascular thrombosis. Despite widespread inflammation, chlamydial multiplication is restricted to the chorionic trophoblast cells. To investigate the potential role of trophoblast in the initiation and propagation of placental inflammation during OEA, the AH-1 ovine trophoblast cell line was experimentally infected with C. abortus and analysed for the release of pro-inflammatory mediators. C. abortus was found to induce the release of both tumour necrosis factor-alpha (TNFalpha) and CXCL8 (interleukin-8) from AH-1 cells in a dose- and time-dependent manner. Ultra-violet (UV)-killed organisms did not elicit this profile, indicating that intracellular multiplication of C. abortus was required for release of these pro-inflammatory mediators. Exposure of AH-1 cells to recombinant ovine TNFalpha alone resulted in the release of CXCL8, suggestive of a self-propagating inflammatory cytokine and chemokine cascade. These data indicate a primary role for trophoblast in the initiation and propagation of placental inflammation during chlamydial abortion.

Topics: Abortion, Veterinary; Animals; Cell Line; Cell Proliferation; Chlamydophila; Chlamydophila Infections; Dose-Response Relationship, Immunologic; Female; Homeostasis; Inflammation; Interleukin-8; Pregnancy; Pregnancy Complications, Infectious; Sheep; Thrombosis; Trophoblasts; Tumor Necrosis Factor-alpha

Topics: Blood Coagulation; Cell-Derived Microparticles; Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Thrombin; Thrombosis; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor RelA; Up-Regulation

The molecular regulation for the transition from stable to vulnerable plaque remains to be elucidated. Heme oxygenase 1 (HO-1) and its metabolites have been implicated in the cytoprotective defense against oxidative injury in atherogenesis. In this study, we sought to assess the role of HO-1 in the progression toward plaque instability in carotid artery disease in patients and in a murine model of vulnerable plaque development.. Atherectomy biopsy from 112 patients with clinical carotid artery disease was collected and stratified according to characteristics of plaque vulnerability. HO-1 expression correlated closely with features of vulnerable human atheromatous plaque (P<0.005), including macrophage and lipid accumulation, and was inversely correlated with intraplaque vascular smooth muscle cells and collagen deposition. HO-1 expression levels correlated with the plaque destabilizing factors matrix metalloproteinase-9, interleukin-8, and interleukin-6. Likewise, in a vulnerable plaque model using apolipoprotein E(-/-) mice, HO-1 expression was upregulated in vulnerable versus stable lesions. HO-1 induction by cobalt protoporphyrin impeded lesion progression into vulnerable plaques, indicated by a reduction in necrotic core size and intraplaque lipid accumulation, whereas cap thickness and vascular smooth muscle cells were increased. In contrast, inhibition of HO-1 by zinc protoporphyrin augmented plaque vulnerability. Plaque stabilizing was prominent after adenoviral transduction of HO-1 compared with sham virus-treated animals, providing proof that the observed effects on plaque vulnerability were HO-1 specific.. Here we demonstrate in a well-defined patient group and a murine vulnerable plaque model that HO-1 induction reverses plaque progression from a vulnerable plaque to a more stable phenotype as part of a compensatory atheroprotective response.

Topics: Aged; Animals; Apolipoproteins E; Carotid Artery Diseases; Collagen; Disease Models, Animal; Disease Progression; Female; Heme Oxygenase-1; Humans; Hyperlipidemias; Interleukin-6; Interleukin-8; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Mutant Strains; Middle Aged; Muscle, Smooth, Vascular; Thrombosis; Transfection

The outcome of liver transplantation is steadily improving. Still there is need for earlier detection of complications like hepatic artery thrombosis and rejection. The aim of this study was to explore whether microdialysis with a 100-kDa cutoff filter could be used to monitor local inflammation after liver transplantation.. Twenty patients undergoing liver transplantations were observed for 1 week posttransplant. Microdialysis catheters were introduced in each liver lobe subcutaneously and metabolic parameters (glucose, pyruvate, glycerol, and lactate), cytokines (interleukin [IL]-6, IL-8, monocyte chemottractic protein-1, and inducible protein [IP]-10), and complement activation (C5a) were measured.. Fourteen patients experienced an uneventful course, judged clinically by ultrasound Doppler and by metabolic markers including lactate and the ischemia indicator lactate-to-pyruvate ratio. All patients with uneventful course had a consistent rise in IP-10 from 200 to 3000 pg/mL after transplantation, whereas the other cytokines stayed low. Two patients with rejection showed a selective increase in IL-8 and C5a, starting 2 to 4 days before alanine transferase increased, reaching 10- to 50-fold increase compared with baseline levels, and decreased rapidly after start of antirejection therapy. C5a concentration was substantially increased in these two patients at the time of transplantation. A third patient developed a hepatic artery thrombosis and rejection and showed a rapid rise in intrahepatic lactate and a complex inflammatory pattern.. Microdialysis using a 100-kDa filter is a promising way of monitoring the inflammatory reaction after liver transplantation. Increase in IP-10 reflects a normal pathophysiologic response posttransplant, whereas IL-8 and C5a were increased only in patients with rejection.

Topics: Adolescent; Adult; Aged; Biomarkers; Child; Child, Preschool; Complement Activation; Complement C5a; Cytokines; Female; Graft Rejection; Hepatitis; Humans; Infant; Interleukin-8; Liver; Liver Transplantation; Male; Membranes, Artificial; Microdialysis; Middle Aged; Molecular Weight; Monitoring, Physiologic; Thrombosis; Time Factors; Treatment Outcome

Myeloid-related protein 8 (MRP8) and MRP14, S100 proteins secreted by activated phagocytes, bind specifically to endothelial cells. The endothelial response to MRP8/MRP14, however, is unknown. Using oligonucleotide microarray analysis, we show for the first time that MRP8/MRP14 induce a thrombogenic, inflammatory response in human microvascular endothelial cells by increasing the transcription of proinflammatory chemokines and adhesion molecules and by decreasing the expression of cell junction proteins and molecules involved in monolayer integrity. All changes on the gene expression level could be confirmed using biochemical and functional assays. We demonstrated that the expression of MRP8/MRP14 closely correlated with the inflammatory activity in systemic vasculitis, confirming the important role of these proteins for distinct inflammatory reactions in endothelia. MRP8/MRP14 may represent novel targets for anti-inflammatory strategies.

Topics: Calgranulin A; Calgranulin B; Capillaries; Capillary Permeability; Cells, Cultured; Endothelial Cells; Gene Expression; Humans; Intercellular Adhesion Molecule-1; Intercellular Junctions; Interleukin-8; Oligonucleotide Array Sequence Analysis; Thrombosis; Vasculitis

Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis, fibrosis and vascular occlusion after radiation therapy. Statins have been reported to improve endothelial function; however, this beneficial effect on endothelial cells has never been investigated after irradiation. Therefore, using human microvascular endothelial cells from lung that had been irradiated with 5 or 10 Gy, we assessed the effect of pravastatin on endothelial activation by ELISA, cell-ELISA and electrophoretic mobility shift assay and increased blood-endothelial cell interactions by a flow adhesion assay. Pravastatin inhibited the overproduction of monocyte chemoattractant protein 1, IL6 and IL8 and the enhanced expression of intercellular adhesion molecule 1 but had no effect on platelet-endothelial cell adhesion molecule 1 expression. Moreover, pravastatin down-regulated the radiation-induced activation of the transcription factor activator protein 1 but not of nuclear factor-kappaB. Finally, an inhibition by pravastatin of increased adhesion of leukocytes and platelets to irradiated endothelial cells was observed. The effect of pravastatin was maintained up to 14 days after irradiation and was reversed by mevalonate. Pravastatin exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells. Statins may be considered in therapeutic strategies for the management of patients treated with radiation therapy.

Topics: Arteriosclerosis; Cells, Cultured; Chemokine CCL2; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Mevalonic Acid; NF-kappa B; Pravastatin; Radiotherapy; Thrombosis

Nuclear factor kappa B (NF-kappa B) activation has been observed in human atherosclerotic plaques and is enhanced in unstable coronary plaques, but whether such activation has a protective or pathophysiological role remains to be determined. We addressed this question by developing a short-term culture system of cells isolated from human atherosclerotic tissue, allowing efficient gene transfer to directly investigate signaling pathways in human atherosclerosis. We found that NF-kappa B is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-kappa B activation can be blocked by overexpression of I kappa B alpha or dominant-negative I kappa B kinase (IKK)-2 but not dominant-negative IKK-1 or NF-kappa B-inducing kinase, resulting in selective inhibition of inflammatory cytokines (tumor necrosis factor alpha, IL-6, and IL-8), tissue factor, and matrix metalloproteinases without affecting the antiinflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-kappa B activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective up-regulation of major proinflammatory and prothrombotic mediators of the disease.

Topics: Actins; Adenoviridae; Arteriosclerosis; CD3 Complex; CD40 Ligand; Cells, Cultured; Gene Transfer, Horizontal; Humans; I-kappa B Kinase; Inflammation; Interleukin-6; Interleukin-8; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Myocytes, Smooth Muscle; NF-kappa B; NF-kappa B p50 Subunit; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases; Thromboplastin; Thrombosis; Tissue Inhibitor of Metalloproteinase-1; Transcription Factor RelA

Thrombosis is a life-threatening complication that occurs in a subset of patients with heparin-induced thrombocytopenia (HITT). The pathogenic mechanisms underlying the variable occurrence of thrombosis in HITT is poorly understood. It was hypothesized that monocyte activation leading to tissue factor expression may play a role in promoting a thrombogenic state in HITT. This study demonstrates that a human platelet factor 4 (PF4)/heparin-specific murine monoclonal antibody (KKO) binds to peripheral blood-derived human monocytes in a PF4-dependent manner. KKO and antibodies from patients with HITT induce monocytes to synthesize and secrete interleukin-8 and induce cell-surface procoagulant activity, which is abrogated following treatment with antihuman tissue factor antibody. The findings suggest a novel mechanism by which PF4/heparin antibodies may promote a hypercoagulable state in patients with HITT. (Blood. 2001;98:1252-1254)

Topics: Antibodies, Monoclonal; Autoantibodies; Coagulants; Heparin; Humans; Interleukin-8; Monocytes; Platelet Factor 4; Thrombocytopenia; Thrombophilia; Thromboplastin; Thrombosis

Antitissue factor antibody attenuated the coagulopathic and lethal responses to LD100 Escherichia coli, whereas active site inhibited factor Xa inhibited only the coagulopathic response. In this study, we wished to determine: (1) whether active site inhibited factor VIIa blocks the coagulopathic and/or attenuates the lethal effects of LD100 E coli and (2) whether these effects are accompanied by attenuation of the inflammatory cytokine response to LD100 E coli. Eight baboons infused for 2 hours with LD100 E coli also were given five bolus infusions of DEGR VIIa of 280 microg/kg at T = -10 minutes, +2, 4, 6, and 8 hours and observed for changes in vital signs, and the concentrations of hemostatic components (fibrinogen, platelets, fibrin degradation products) and inflammatory mediators (tumor necrosis factor [TNF], interleukin-6 [IL-6], IL-8) at T = 0, 1, 2, 4, 6, and 8 hours. Eight control baboons were also infused with LD100 E coli alone and followed as described above. Four of the eight baboons treated with DEGR VIIa were permanent 7-day survivors versus none in the control group. The mean survival times for the treated and control groups were 116 +/- 22 and 26 +/- 8 hours, respectively. These values differed significantly from each other, (P = .0008). The decrease in platelet and fibrinogen concentrations and the increase in fibrin degradation products observed in the control group were significantly attenuated in the treated group, as was thrombosis of renal glomerular capillaries. Treatment with DEGR VIIa showed no effect on the peak TNF response to LD100 E coli at T = 2 hours (170 +/- 32 v 120 +/- 35 ng/mL). DEGR VIIa, however, did attenuate the IL-6 and IL-8 responses at T = 8 hours (ie, the IL-6 concentrations were 81 +/- 10 for treated and 1,256 +/- 236 for the control groups and the IL-8 concentrations were 28 +/- 3.9 for the treated and 60 +/- 8.2 for the control group). These values for IL-6 and IL-8 differed significantly from each other between the treated and control groups (P = .0001 and .0074, respectively). It should be noted that the initial responses of IL-6 and IL-8 up to T = 4 hours were not attenuated. We concluded that DEGR VIIa treatment attenuates inflammatory, as well as hemostatic system responses to LD100 E coli. We hypothesize that this occurs through interference with the assembly and/or interactions of tissue factor/VIIa complexes.

Topics: Animals; Binding Sites; Blood Coagulation; Capillaries; Escherichia coli Infections; Factor VIIa; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Interleukin-6; Interleukin-8; Interleukins; Kidney Glomerulus; Kinetics; Papio; Platelet Count; Thrombosis; Tumor Necrosis Factor-alpha