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28 December 2021: Review Articles

A Review of the Impact of Neutrophils and Neutrophil Extracellular Traps (NETs) on the Development of Aortic Aneurysms in Animal and Human Studies

Milena Michalska ABCDEFG* , Tadeusz Grochowiecki AEFG , Tomasz Jakimowicz DEF , Sławomir Nazarewski D

DOI: 10.12659/MSM.935134

Med Sci Monit 2021; 27:e935134

Table 2 Summary of published studies that include influence on neutrophil extracellular traps in aortic aneurysm.

NoAuthorYearModelPopulationControl group
1.Sandrine Delbosc et al []64 2011
2.Humin Yan et al []67 2016
3.Akshaya K. Meher et al []47 2018
4.Michael Spinosa et al []62 2018
5.Silvia D. Visonà et al []72 2018
6.Patrick Haider et al []73 2020
7.Wolf Eilenberg et al []74 2021
8.Ming Wei et al []75 2021
9.Akrivi Chrysantho-poulou et al []77 2021
1.Cancer, infection, and any immune-mediated diseaseH1, Cit-H4, elastaseImmunofluorescenceNETs are abundant in AAA ILTsThe enlarged concentration of cf-DNA in plasma and conditioned medium between AAA patients and healthy volunteersIncreased circulating MPO-DNA complexes in AAAChronic -bacteremia prompt neutrophil recruitment in experimental AAA
Cit-H4Western blot
cf-DNAQuant- it Picogreen, dsDNA Reagent, Invitrogen
MPO, MPO-DNA complexes, Anti-P.gingivalis IgELISA
MMP-9Gelatin zymography
Bacterial endotoxin released by ILTLimulus Amebocyte Lysate (LAL) chromogenic endpoint assay)
DNA extraction and bacterial DNA amplificationQIamp DNA Blood Midi Kit (Qiagen) PCR
Neutrophil isolationImmunofluorescence
2.DNA-CRAMP complexesGeneration of DNA-CRAMP complexesIn elastase-induced murine aortic tissues NETs are observed, mainly in the adventitiaNeutrophil proteases and NETs play an important role in the development of AAA
Elastin degradation,macrophage, CD3+ T cells, DCsImmunohistochemistryAAA is triggered by the DNA-CRAMP complexINF I and DCs promote the inflammatory responses of AAA
IFN I, Histone H2B, MPO, CRAMPImmunofluorescence
DCsFlow cytometric analysis
GelatinaseZymography
NET stimulation (by LPS or C5a)Fluorescence microscope
Cytokine analysisCytometric bead arrays
3.NEImmunofluorescenceNETosis is reduced by blocking IL-1β, in human AAA NETs coexist with IL-1β
Cit-H3Western blot
Ly-6B.2 (neutrophil indicator) Alfa-smooth muscle alkaline phosphataseImmunohistochemistryHuman neutrophils can produce ceramide by IL-1β stimulation, decreased ceramide synthesis attenuates NETosisThe initial phase of murine experimental AAA includes development of NETsFor AAA mice development, IL-1β expression in neutrophils is necessary
cf-DNAQuant-iT PicoGreen dsDNA Reagent ThermoFisher, Scientific
Neutrophil culture and NETs induce, CerS6Flow cytometry
Ceramide isolationLiquid chromatography-mass spectrometry
4.RvD1IL-1betaRvD1 ELISAIn the Ang II mouse model, RvD1 reduced AAAs and decreased Cit-H3
CitH3Western blotTreatment RvD1 displays lower stain for markers of NETosis
NEImmunohistochemistry
MMP-2MMP-9Gelatin zymographyIn the treatment group RvD1, IL-1β is decreased, whereas IL-10 is increased
5.Chronic aortitis and periaortitis, purely traumatic dissections, incomplete samplingα-smooth muscle alpha-actin (SMA) MPOCit-H3α-CD3, α-CD68 (macrophages identificator)CD31 and CD34 (EC identificator)ImmunohistochemistryThe presence of NEU and NETs were increased significantly in subacute infiltering dissections but decreased in early organized and late scarring groupsThere were high numbers of MPO neutrophils in acute dissection but the Cit-H3 NETS levels were relatively little
Dissection age (4 phases)Histological
6.Cit-H4MPOCD68Ly6GPolarization of macrophagesImmunofluorescenceNETs develop voluntarily in human blood clotDifferently polarized macrophages can degrade NETs by DNA uptake by individuals’ mechanismsNETs were found in all vessels aortic wall; most NET were found in the abluminal section and then in the luminal part
DNA uptake from blood clots by macrophagesFlow cytometry
Degradation of NETs in vitroFluorescenceDNase1L3 can be produced by generated macrophages
Protein quantification (DNase)ELISA and flow cytometryBlockage of macropinocytosis cause enlarge NET burden and decreased thrombus degradation
DNase 1L1ImmunofluorescenceReginal concertation of macrophages is inversely connected with NETs in human AAA
Apoptosis assessmentFlow cytometry
DNA extractionPCR and electrophoresis
7.Recent tumors (Cit-H3MPOcf-DNA-histone complexesIL-1betaELISAThe level of Cit-H3 in plasma can be a biomarker of AAA enlargementAfter repairing AAA level of Cit-H3 is decreased
Ly6GCit-H4ImmunofluorescenceBlocking the citrullination in histone can prevent the development of AAA in an Ang II-induced model
NGALelastaseMass spectrometers (Luminex MagPix)
8.MPOImmunohistochemistryIn vitro and in vivo NET formation is enhanced by Ang IIIn vitro PAD4 inhibition (by YW3-56) reduced Ang II-induced NET formationPAD4 inhibition prevent AAA rapture and decline VSMC apoptosisBy p38/JNK pathway NET enhance VSMC apoptosis
Cit-H3Ly6GNEImmunofluorescence
dsDNAPAD4Quant-iT PicoGreen dsDNA Assay Kit Thermo Fisher, Scientific
Depletion of VSMCAnnexin V/PI apoptosis detection kit (556547, BD biosciencesFlow cytometry
Neutrophil isolationImmunofluorescence
p38p-JNKWestern blot
9.AgeMPONECit-H4ImmunofluorescenceThe development of NETs is induced by Ang II in a ROS/autophagy-dependent mechanismIn fibrotic renal and aneurysmal aortic tissue are noticeable NETs from NEU with tissue factor expression
Cit-H3ELISA
TFTF activity assay
MPO/DNA complexesELISA
RNA isolationPCR
Neutrophil isolation and viabilityFlow cytometry

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750