TO008INTRAVASCULAR NEUTROPHIL EXTRACELLULAR TRAP (NET) RELEASE PROMOTES VASCULAR INJURY AND TUBULAR NECROSIS UPON RENAL ISCHEMIA REPERFUSION

Ischemia reperfusion (IR) can lead to acute kidney injury and can be complicated by acute lung injury, which is one of the leading causes of acute kidney injury-related death. Peptidyl arginine deiminase-4 (PAD4) is a member of the PAD enzyme family and plays a critical role in inflammatory reactions and neutrophil extracellular trap formation in a variety of pathological conditions. It has been reported that PAD4 inhibition can protect certain organs from ischemic injury. In this study, we aimed to understand the mode of action of PAD4 in renal ischemia-reperfusion-mediated acute lung injury. Bilateral renal pedicle occlusion was induced for 30 min followed by reperfusion for 24 h. A specific inhibitor of PAD4, GSK484, was delivered via intraperitoneal injection to alter the PAD4 activity. The pulmonary PAD4 expression, pulmonary impairment, neutrophil infiltration, Cit-H3 expression, neutrophil extracellular trap formation, inflammatory cytokine secretion, and pulmonary apoptosis were analyzed. We found that renal ischemia reperfusion was associated with pulmonary pathological changes and increases in neutrophil infiltration, neutrophil extracellular trap formation, and inflammatory cytokine secretion in the lungs of the recipient animals. Suppression of PAD4 by GSK484 reduced remote lung injury by mitigating neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory factor secretion. Our findings demonstrate that specific PAD4 inhibition by GSK484 may be an effective strategy to attenuate distant lung injury complicating renal ischemia-reperfusion injury.

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The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury

AJP Renal Physiology ◽

10.1152/ajprenal.90576.2008 ◽

2009 ◽

Vol 297 (2) ◽

pp. F451-F460 ◽

Cited By ~ 23

Author(s):

Julia M. Huber ◽

Andrea Tagwerker ◽

Dorothea Heininger ◽

Gert Mayer ◽

Alexander R. Rosenkranz ◽

...

Keyword(s):

T Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Reversible Inhibitor ◽

Tubular Necrosis ◽

Proinflammatory Mediators ◽

Renal Ischemia Reperfusion Injury ◽

A Cell

Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of Bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt Bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in Bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in Bortezomib-treated mice as reflected by a decreased infiltration of CD4+ T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of Bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm2 and increased mRNA expression of proapoptotic factors were detected in kidneys of Bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of Bortezomib-treated mice. In summary, we provide evidence that Bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.

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Abstract 251: The Role of Adenosine Derived From Mesenchymal Stromal Cell on Neutrophil Extracellular Trap Formation in Myocardial Ischemia Reperfusion

Circulation Research ◽

10.1161/res.123.suppl_1.251 ◽

2018 ◽

Vol 123 (Suppl_1) ◽

Author(s):

Kai Xu ◽

Eric Shin ◽

Lanfang Wang ◽

Juline Deppen ◽

Rebecca Levit

Keyword(s):

Myocardial Ischemia ◽

Mesenchymal Stromal Cell ◽

Stromal Cell ◽

Ischemia Reperfusion ◽

Neutrophil Extracellular Trap ◽

Trap Formation ◽

Extracellular Trap ◽

Myocardial Ischemia Reperfusion

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Calcitriol and Erythropoietin Protect Against Cardiac Injury Induced by Renal Ischemia-Reperfusion

Biointerface Research in Applied Chemistry ◽

10.33263/briac106.67186727 ◽

2020 ◽

Vol 10 (6) ◽

pp. 6718-6727 ◽

Cited By ~ 1

Keyword(s):

Morphological Changes ◽

Ischemia Reperfusion ◽

Cardiac Injury ◽

Renal Ischemia ◽

Albino Rats ◽

Cardiac Damage ◽

Beneficial Effects ◽

Tubular Necrosis ◽

Wistar Albino Rats

Cardiac abnormalities and dysfunction are the most important complications after renal ischemia-reperfusion (IR). Thus, investigation and development of effective treatment to decrease cardiac damage induced by renal ischemia are necessary. This study examined the effects of treatment with calcitriol and erythropoietin (EPO) on cardiac injury induced by renal ischemia. Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion, followed by 24 h reperfusion. Calcitriol and EPO were administered before ischemia. After 24 h reperfusion, blood samples were collected for the determination of biochemical parameters, and kidney and cardiac samples were taken for histological studies. Renal IR increased BUN-Cr levels, lipid profiles, and myocardial injury markers (CK-MB and LDH). Histopathological findings of the IR group confirmed that there were glomerular atrophy and acute tubular necrosis in the renal tissues and lymphocyte infiltration and intercellular edema in the cardiac samples. Treatment with calcitriol and EPO boosted cardiac and renal functions and improved the morphological changes. It seems that calcitriol or EPO administration could protect against the kidney and cardiac damage induced by IR. Also, the combination of calcitriol and EPO may exert more beneficial effects than either agent used alone.

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Neutrophil extracellular trap formation and nuclease activity in septic patients

10.21203/rs.2.12307/v1 ◽

2019 ◽

Author(s):

Linda Cox ◽

Kai Walstein ◽

Lena Völlger ◽

Friederike Reuner ◽

Alexandra Bick ◽

...

Keyword(s):

Healthy Volunteers ◽

Nuclease Activity ◽

Positive Control ◽

Neutrophil Extracellular Trap ◽

Average Percentage ◽

Molecular Pattern ◽

Extracellular Trap ◽

Net Release

Abstract Background: There is little knowledge, whether in patients with sepsis neutrophil extracellular trap (NET) formation and NET degrading nuclease activity are altered. Thus, we tested the hypotheses that 1) NET formation from neutrophils of septic patients is increased compared to healthy volunteers, both without stimulation and following incubation with mitochondrial DNA (mtDNA), a damage-associated molecular pattern, or phorbol 12-myristate 13-acetate (PMA; positive control); and 2) serum nuclease activities are increased as well. Methods: We included 18 septic patients and 27 volunteers in this prospective observational trial while study was registered retrospectively. Blood was withdrawn and NET formation from neutrophils in vitro was quantified (average percentage of neutrophils showing NET formation on an image) without stimulation and following incubation with mtDNA (10µg/well) or PMA (25nmol). Serum nuclease activity was assessed using gel electrophoresis. Results: In contrast to our hypothesis, compared to healthy volunteers unstimulated NET release from neutrophils in septic patients was decreased by 46.3% (4.3%±1.8 SD vs. 8.2%±2.9, p≤0.0001) and 48.1% (4.9%±2.5 vs. 9.4%±5.2, p=0.002) after 2 and 4 hours of incubation. mtDNA further decreased NET formation in neutrophils from septic patients (4.7%±1.2 to 2.8%±0,8; p=0.03) but did not alter NET formation in neutrophils from volun-teers. As expected, PMA, as positive control, increased NET formation to 73.2% (±29.6) in septic patients and to 91.7% (±7.1) in volunteers after 4 hours of incubation (p=0.22). Serum nuclease activity (range: 0-6) was decreased in septic patients by 39.6% (3±2 vs 5±0; median and ICR, p=0.0001) compared to volunteers. Conclusions: Unstimulated NET formation and nuclease activity are decreased in septic patients and mtDNA can further reduce NET formation. Thus, neutrophils from septic patients show decreased NET formation in vitro despite diminished nuclease activity in vivo. Trail registration DRKS00007694, German Clinical Trials database (DRKS). Registered retrospectively 06.02.2015.

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Neutrophil extracellular traps and thrombosis in COVID-19

10.1101/2020.04.30.20086736 ◽

2020 ◽

Cited By ~ 23

Author(s):

Yu Zuo ◽

Melanie Zuo ◽

Srilakshmi Yalavarthi ◽

Kelsey Gockman ◽

Jacqueline A. Madison ◽

...

Keyword(s):

Inflammatory Diseases ◽

Histone H3 ◽

Neutrophil Extracellular Traps ◽

Neutrophil Extracellular Trap ◽

Dna Complexes ◽

Extracellular Traps ◽

Free Dna ◽

Extracellular Trap ◽

Net Release ◽

D Dimer

ABSTRACTHere, we report on four patients whose hospitalizations for COVID-19 were complicated by venous thromboembolism (VTE). All demonstrated high levels of D-dimer as well as high neutrophil-to-lymphocyte ratios. For three patients, we were able to test sera for neutrophil extracellular trap (NET) remnants and found significantly elevated levels of cell-free DNA, myeloperoxidase-DNA complexes, and citrullinated histone H3. Neutrophil-derived S100A8/A9 (calprotectin) was also elevated. Given strong links between hyperactive neutrophils, NET release, and thrombosis in many inflammatory diseases, the potential relationship between NETs and VTE should be further investigated in COVID-19.

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Protective Effect of CXCR3+CD4+CD25+Foxp3+Regulatory T Cells in Renal Ischemia-Reperfusion Injury

Mediators of Inflammation ◽

10.1155/2015/360973 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Cao Jun ◽

Li Qingshu ◽

Wei Ke ◽

Li Ping ◽

Dong Jun ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Tubular Necrosis ◽

Renal Ischemia Reperfusion Injury ◽

Histology Score

Regulatory T cells (Tregs) suppress excessive immune responses and are potential therapeutic targets in autoimmune disease and organ transplantation rejection. However, their role in renal ischemia-reperfusion injury (IRI) is unclear. Levels of Tregs and expression of CXCR3 in Tregs were analyzed to investigate their function in the early phase of renal IRI. Mice were randomly divided into Sham, IRI, and anti-CD25 (PC61) + IRI groups. The PC61 + IRI group was established by i.p. injection of PC61 monoclonal antibody (mAb) to deplete Tregs before renal ischemia. CD4+CD25+Foxp3+Tregs and CXCR3 on Tregs were analyzed by flow cytometry. Blood urea nitrogen (BUN), serum creatinine (Scr) levels, and tubular necrosis scores, all measures of kidney injury, were greater in the IRI group than in the Sham group. Numbers of Tregs were increased at 72 h after reperfusion in kidney. PC61 mAb preconditioning decreased the numbers of Tregs and aggravated kidney injury. There was no expression of CXCR3 on Tregs in normal kidney, while it expanded at 72 h after reperfusion and inversely correlated with BUN, Scr, and kidney histology score. This indicated that recruitment of Tregs into the kidney was related to the recovery of renal function after IRI and CXCR3 might be involved in the migration of Tregs.

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