Faculty Opinions recommendation of Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.

Background Tourniquets are often used as part of orthopedic surgery but may cause local and remote organ injury. The authors hypothesized that the procedures used to induce ischemia (circulatory occlusion or exsanguination) may have differential effects on the metabolic state of the muscle that should be reflected in the interstitial levels of metabolites. Methods Microdialysis probes were implanted in both quadriceps femoris muscles of 18 patients. Interstitial fluid was obtained during tourniquet-induced ischemia and reperfusion and was analyzed for glucose, lactate, choline, and purines by high-performance liquid chromatography. Results At a flow rate of 2 microl/min, the average baseline concentrations in the dialysate were 2.5 mM for glucose, 1.7 mM for lactate, 5.2 microM for choline, and 14.3 microM for hypoxanthine. Circulatory occlusion by tourniquet caused a 40% decrease of the extracellular glucose concentration within 30 min. Concomitantly, the interstitial levels of lactate and hypoxanthine increased in a linear fashion to 206% (lactate) and 241% (hypoxanthine) of basal values. The extracellular concentration of choline was also significantly elevated. After exsanguination, the glucose levels were significantly more reduced (by 65%), and the levels of lactate (to 268%) and hypoxanthine (to 286%) were more increased than after circulatory occlusion alone. Conclusion Our microdialysis results demonstrate that the interstitial concentrations of glucose, lactate, and hypoxanthine, which are indicators of tissue ischemia, change more prominently after exsanguination than after circulatory occlusion alone.

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Deficiency of AMPKα1 Exacerbates Intestinal Injury and Remote Acute Lung Injury in Mesenteric Ischemia and Reperfusion in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22189911 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9911

Author(s):

Hannah V. Hayes ◽

Vivian Wolfe ◽

Michael O’Connor ◽

Nick C. Levinsky ◽

Giovanna Piraino ◽

...

Keyword(s):

Lung Injury ◽

Mesenteric Ischemia ◽

Vascular System ◽

Adenosine Monophosphate ◽

Organ Injury ◽

Ischemia And Reperfusion ◽

Loss Of Function ◽

Neutrophil Sequestration ◽

Remote Organ ◽

Remote Organ Injury

Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.

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The screening of albumin as a key serum component to prevent neutrophil extracellular traps release by selectively inhibiting mitochondrial ROS generation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0670 ◽

2020 ◽

Author(s):

Yue Zheng ◽

Yuanfeng Zhu ◽

Xin Liu ◽

Hang Zheng ◽

Yongjun Yang ◽

...

Keyword(s):

Neutrophil Extracellular Traps ◽

Extracellular Dna ◽

Organ Injury ◽

Ros Generation ◽

Ros Production ◽

Serum Free ◽

Extracellular Traps ◽

Mitochondrial Ros ◽

Serum Component ◽

Microbial Defense

Neutrophil extracellular traps (NETs) are extracellular DNA webs released from neutrophils to mediate host anti-microbial defense. As NETs could also induce thrombosis and cause organ injury, their release should be strictly controlled. However, it is not well understood about the intrinsic mechanisms that prevent unfavorable NETs. Herein, an accidental finding of NETs release from human peripheral neutrophils was firstly described in serum free culture, and it was also determined as a conserved effect for serum to prevent NETs. In contrast to canonical NETs induced by phorbol-12-myristate-13-acetate (PMA), NETs formation by serum free culture was rapid and without prevalent NETosis. Next, albumin was screened out as a key serum component that mediated the suppression of NETs. Moreover, NETs induced upon serum or albumin deficiency were independent of the canonical pathway that involves NOX2 activation and cytosol ROS production. Instead, the generation of mitochondrial ROS (mtROS) was upregulated to promote NETs release. Albumin exhibited mtROS scavenging activity and thus inhibited NETs. Serum free culture also induces the release of NET-bound oxidized mtDNA which stimulated IFN-β production. Overall, our research provides new evidences that characterize the NETs production in serum free culture and determine the mechanisms of serum albumin to inhibit NETs.

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Targeting neutrophil extracellular traps in severe acute pancreatitis treatment

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820974913 ◽

2020 ◽

Vol 13 ◽

pp. 175628482097491

Author(s):

Jing Hu ◽

Hongxin Kang ◽

Huan Chen ◽

Jiaqi Yao ◽

Xiaolin Yi ◽

...

Keyword(s):

Acute Pancreatitis ◽

Severe Acute Pancreatitis ◽

Inflammatory Cells ◽

Neutrophil Extracellular Traps ◽

Multiple Organ ◽

Organ Injury ◽

Normal Tissues ◽

Pathogen Invasion ◽

Extracellular Traps ◽

Abdominal Disease

Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.

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