Upregulation of Nrf-2 attenuates oxidative stress-induced complement activation-associated endothelial injury and apoptosis in transplant-associated thrombotic microangiopathy.

Key Points dsDNA production peaks 14 days after HSCT, likely a result of IL-8–driven neutrophil recovery. dsDNA production may serve as a mechanistic link between endothelial injury, TA-TMA, and GVHD.

Download Full-text

Endothelial Injury, Neutrophil Extracellular Traps, and Complement Activation in Thrombotic Microangiopathy and GVHD

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2016.12.458 ◽

2017 ◽

Vol 23 (3) ◽

pp. S232-S233

Author(s):

Nicholas J. Gloude ◽

Sonata Jodele ◽

Nathan Luebbering ◽

Kelly E. Lake ◽

Adam Lane ◽

...

Keyword(s):

Complement Activation ◽

Thrombotic Microangiopathy ◽

Neutrophil Extracellular Traps ◽

Endothelial Injury ◽

Extracellular Traps

Download Full-text

Interferon-complement loop in transplant-associated thrombotic microangiopathy

Blood Advances ◽

10.1182/bloodadvances.2020001515 ◽

2020 ◽

Vol 4 (6) ◽

pp. 1166-1177 ◽

Cited By ~ 9

Author(s):

Sonata Jodele ◽

Mario Medvedovic ◽

Nathan Luebbering ◽

Jenny Chen ◽

Christopher E. Dandoy ◽

...

Keyword(s):

Complement Activation ◽

Thrombotic Microangiopathy ◽

Mononuclear Cells ◽

Transcriptional Regulatory Network ◽

Tissue Injury ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Endothelial Injury ◽

Hematopoietic Stem ◽

Complement Pathways

Abstract Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

Download Full-text

Faculty Opinions recommendation of Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727807448.793540016 ◽

2017 ◽

Author(s):

Cheng-Hock Toh

Keyword(s):

Complement Activation ◽

Thrombotic Microangiopathy ◽

Endothelial Injury

Download Full-text

Complement activation in thrombotic microangiopathy

Hämostaseologie ◽

10.5482/hamo-12-12-0025 ◽

2013 ◽

Vol 33 (02) ◽

pp. 96-104 ◽

Cited By ~ 15

Author(s):

R. Tati ◽

D. Karpman

Keyword(s):

Complement Activation ◽

Thrombotic Microangiopathy ◽

Vascular Wall ◽

Endothelial Injury ◽

Host Cells ◽

Wall Thickening ◽

Vascular Lumen ◽

Vessel Lumen ◽

Complement Dysregulation ◽

Subendothelial Matrix

SummaryThe endothelium lining the vascular lumen is continuously exposed to complement from the circulation. When erroneously activated on host cells, complement may generate a deleterious effect on the vascular wall leading to endothelial injury, exposure of the subendothelial matrix and platelet activation.In this review the contribution of complement activation to formation and maintenance of the pathological lesion termed thrombotic microangiopathy (TMA) is discussed. TMA is defined by vessel wall thickening affecting mainly arterioles and capillaries, detachment of the endothelial cell from the basement membrane and intraluminal thrombosis resulting in occlusion of the vessel lumen. The TMA lesion occurs in haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS is further sub-classified as associated with Shiga toxin-producing Escherichia coli (STEC-HUS) or with complement dysregulation (atypical HUS) as well as other less common forms. The contribution of dysregulated complement activation to endothelial injury and platelet aggregation is reviewed as well as specific complement involvement in the development of HUS and TTP.

Download Full-text

HUS and the case for complement

Blood ◽

10.1182/blood-2015-03-569277 ◽

2015 ◽

Vol 126 (18) ◽

pp. 2085-2090 ◽

Cited By ~ 17

Author(s):

Edward M. Conway

Keyword(s):

Escherichia Coli ◽

Renal Failure ◽

Shiga Toxin ◽

Complement Activation ◽

Thrombotic Microangiopathy ◽

Response To Treatment ◽

Microangiopathic Hemolytic Anemia ◽

New Knowledge ◽

Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

Download Full-text

Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2021.115412 ◽

2021 ◽

Vol 414 ◽

pp. 115412 ◽

Cited By ~ 1

Author(s):

PauloC. Gregório ◽

Regiane S. da Cunha ◽

Gilson Biagini ◽

Bruna Bosquetti ◽

Júlia Budag ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Injury ◽

Lysosomal Dysfunction ◽

And Oxidative Stress

Download Full-text

CTRP3 protects against uric acid-induced endothelial injury by inhibiting inflammation and oxidase stress in rats

Experimental Biology and Medicine ◽

10.1177/15353702211047183 ◽

2021 ◽

pp. 153537022110471

Author(s):

Junxia Zhang ◽

Xue Lin ◽

Jinxiu Xu ◽

Feng Tang ◽

Lupin Tan

Keyword(s):

Oxidative Stress ◽

Uric Acid ◽

Inflammatory Responses ◽

Umbilical Vein ◽

Specific Inhibitor ◽

Endothelial Damage ◽

Endothelial Injury ◽

Sprague Dawley ◽

Protein Levels ◽

And Oxidative Stress

Hyperuricemia, which contributes to vascular endothelial damage, plays a key role in multiple cardiovascular diseases. This study was designed to investigate whether C1q/tumor necrosis factor (TNF)-related protein 3 (CTRP3) has a protective effect on endothelial damage induced by uric acid and its underlying mechanisms. Animal models of hyperuricemia were established in Sprague-Dawley (SD) rats through the consumption of 10% fructose water for 12 weeks. Then, the rats were given a single injection of Ad-CTRP3 or Ad-GFP. The animal experiments were ended two weeks later. In vitro, human umbilical vein endothelial cells (HUVECs) were first infected with Ad-CTRP3 or Ad-GFP. Then, the cells were stimulated with 10 mg/dL uric acid for 48 h after pretreatment with or without a Toll-like receptor 4 (TLR4)-specific inhibitor. Hyperuricemic rats showed disorganized intimal structures, increased endothelial apoptosis rates, increased inflammatory responses and oxidative stress, which were accompanied by reduced CTRP3 and elevated TLR4 protein levels in the thoracic aorta. In contrast, CTRP3 overexpression decreased TLR4 protein levels and ameliorated inflammatory responses and oxidative stress, thereby improving the morphology and apoptosis of the aortic endothelium in rats with hyperuricemia. Similarly, CTRP3 overexpression decreased TLR4-mediated inflammation, reduced oxidative stress, and rescued endothelial damage induced by uric acid in HUVECs. In conclusion, CTRP3 ameliorates uric acid-induced inflammation and oxidative stress, which in turn protects against endothelial injury, possibly by inhibiting TLR4-mediated inflammation and downregulating oxidative stress.

Download Full-text

Abstract 893: Contrast Medium-Induced Renal Damage is Tightly Associated with Endothelial Injury in Patients

Circulation ◽

10.1161/circ.118.suppl_18.s_626-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kazuko Tajiri ◽

Hidekazu Maruyama ◽

Satoshi Sakai ◽

Noritake Shimojo ◽

Hideaki Aihara ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Function ◽

Contrast Medium ◽

Renal Damage ◽

Cell Activation ◽

Endothelial Damage ◽

Endothelial Injury ◽

Specific Marker ◽

Before And After ◽

Renal Tubular

Background: Contrast-induced nephropathy (CIN) remains a common complication of radiographic procedures. We hypothesized that endothelial dysfunction is the main cause of CIN. To clarify whether contrast medium-induced renal damage is associated with endothelial injury, we measured microparticles derived from endothelial cells as markers of endothelial injury. Circulating microparticles are shed from cell surface respond to cell activation and apoptotic stimuli, reflecting the condition of damaged cells. Methods: Renal function of 35 adult patients was analyzed before and after the use of contrast medium for coronary angiography. Parameters for renal function and urinary 15-isoprostane F2t, a specific marker of oxidative stress were measured before and after radiocontrast administration. Flow cytometry was used to count circulating CD34 + microparticles, which is regarded as one of markers for endothelial damage. Results: The decrease of estimated glomerular filtration rate positively correlated with the amount of contrast medium (r=0.427; P=0.013). Urinary N-acetyl-beta-D-glucosaminidase, a marker of renal tubular injury, was increased after angiography (from 7.6+/− 6.8 to 9.1 +/− 6.0 U/g-CRE, P=0.011). Furthermore, urinary 15-isoprostane F2t positively correlated with the volume of contrast medium (r=0.421; P=0.012). CD34+ microparticle was significantly increased after angiography (1.3-fold increased from basal level, P=0.0017). The increase of CD34+ microparticle was associated with the insult of contrast medium, but not of the amount. Conclusion: Radiocontrast impaired renal function in accordant with the increase of oxidative stress. The release of CD34+ microparticle was also increased by use of radiocontrast. These data suggest that CIN is tightly associated with endothelial injury mediated by radiocontrast-induced oxidative stress.

Download Full-text