Lub luag haujlwm tshiab ntawm Neutrophils hauv Pathogenesis Ntawm Thrombosis hauv COVID-19
Mar 24, 2022
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
Valeria Iliadi, Ina Konstantinidou & et al.
1. Taw qhia
Tus kab mob tshiab coronavirus 2019 (COVID-19) tau tshaj tawm thawj zaug hauv Wuhan, Tuam Tshoj, thaum Lub Kaum Ob Hlis 2019[1]. Thaum Lub Peb Hlis 11, 2020, Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv (World Health Organization) tau qhia txog kev noj qab haus huv thoob ntiaj teb thaum muaj xwm txheej ceev ntawm COVID-19 yog tus kabmob kis thoob ntiaj teb. Raws li lub Peb Hlis 28, 2021, 126,359.540 tus neeg mob ntawm COVID-19 tau lees paub, thiab 2,769,473 tus neeg tuag tau tshaj tawm thoob ntiaj teb [2]. Lub etiology ntawm tus kab mob yog mob hnyav acute respiratory syndrome coronavirus 2 (SARS CoV-2), ib lub hnab ntawv, zoo-sensitive RNA belongs rau -coronaviruses [3].
Yav dhau los tau tshaj tawm tias cov ntshav nce siabneutrophilsyog qhov taw qhia ntxov ntawm SARS-CoV-2 tus kab mob hnyav [4]. Ntxiv mus, qhov nce ntawm qhov sib txawv coagulation tsis, xws li D-dimers, prothrombin lub sij hawm (PT), fibrinogen, thiab fibrinogen degradation khoom (FDPs), tau pom nyob rau hauv cov neeg mob nrog COVID-19[5-10] . Lub coagulation mechanism muaj xws li cov proteins tshwj xeeb uas ua raws li ntuj anticoagulants, yog li tsis txhob tsim cov ntshav txhaws. Cov proteins no yog antithrombin (AT), protein C (PC), thiab protein S (PS). Cov txiaj ntsig ntawm kev tshawb fawb yav dhau los, txawm li cas los xij, zoo li muaj teeb meem. Zhang et al. tau tshaj tawm tias cov dej num ntawm cov protein C, protein S, thiab antithrombin tau qis dua qhov qub [11]. Ntxiv mus, Gazzaruso et al. tau tshaj tawm tias cov neeg mob COVID-19 muaj qib AT qis. Cov kws sau ntawv tau hais ntxiv tias AT muaj feem cuam tshuam nrog kev tuag hauv COVID-19 [12]. Antithrombin (AT) ua lub luag haujlwm tseem ceeb hauv COVID-19-induced coagulopathy, qhov twg cov qib AT qis tuaj yeem piav qhia qhov ua tsis tau zoo ntawm cov tshuaj tiv thaiv coagulants hauv cov neeg mob nrog COVID-19 [13]. Cov kev tshawb fawb saum toj no qhia txog lub luag haujlwm sib koom ua ke ntawm lub cev tiv thaiv kab mob thiab coagulation hauv kev txhim kho thrombotic tshwm sim hauv COVID-19.
Cov txheej txheem ntawm NETosis, nws lub luag haujlwm hauv kev ua haujlwm ntawm kev tiv thaiv kab mob thrombosis thiab COVID-19- cuam tshuam txog coagulopathy, thiab cov kev pabcuam kho mob tsomneutrophilstau tham hauv qhov kev tshuaj xyuas no.
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2. Neutrophils
Neutrophilsyog "Cinderella" ntawm lub cev tiv thaiv kab mob - tshwj tsis yog lawv lub luag haujlwm tseem ceeb hauv tus tswv tsev tiv thaiv kab mob - thiab ua lub luag haujlwm tseem ceeb hauv thrombosis.Neutrophilsyog tsim nyob rau hauv cov pob txha pob txha thiab circulate nyob rau hauv cov ntshav raws li dominant cov qe ntshav dawb. Kev tsiv teb tsaws Neutrophil yog qhov tseem ceeb rau kev tiv thaiv tus tswv thiab kev tshem tawm cov kab mob thaum kis kab mob [14]. Kev sib cuam tshuam ntawm neutrophil adhesion receptors thiab adhesion molecules ntawm beta2 integrin tsev neeg (CD11 / CD18) ntawm endothelial hlwb yog tsim nyog rau neutrophil activation thiab tsiv teb tsaws mus rau qhov chaw ntawm tus kab mob [15].
Neutrophils 'Antimicrobial arsenal yog qhov zoo siab thiab suav nrog cov txheej txheem sib txawv xws li phagocytosis thiab degranulation. Xyoo 2004, Brinkmann et al. tau piav qhia txog qhov tshiab ntxiv tshuaj tiv thaiv kab mob ntawm cov tshuaj neutrophil hu ua neutrophil extracellular traps (NETs) [16]. NETs yog tsim los ntawm chromatin thiab dai kom zoo nkauj nrog ntau cov proteins uas muaj cov tshuaj tiv thaiv kab mob, xws li histones, elastase, thiab myeloperoxidase [17]. Tam sim no, nws tau lees paub tias muaj peb yam tshuaj tua kab mob ntawm cov tshuaj neutrophil: phagocytosis, degranulation, thiab NET tsim. NETs siv lawv cov tshuaj tua kab mob los ntawm cov kab mob immobilization ntawm kev nkag mus. Ntxiv mus, NETs cov khoom ntawm cov tshuaj tua kab mob peptides, histones, thiab DNA tsim cov tshuaj tiv thaiv kab mob ncaj qha [18-20]. Ntau xyoo dhau los, cov kws tshawb fawb tau nthuav tawm lub luag haujlwm tseem ceeb ntawmneutrophilsthiab neutrophil extracellular ntxiab (NETs) nyob rau hauv thrombo-o [21-24].
3. Induction thiab Molecular Mechanisms ntawm NET Tsim
Txog niaj hnub no, qhov dav spectrum ntawm stimuli tau lees paub tias yog inducers ntawm NET tsim (Table 1). Kev kis ncaj qha rau cov kab mob microbial, ob qho kab mob Gram-positive (Staphylococcus aureus, Staphylococcus suis, Streptococcus pyogenes, Streptococcus pneumonia) [8-10] thiab kab mob Gram-negative (Escherichia coli, Salmonella enterica, Shigella flexinosa), raug hyphae los yog poov xab (Candida albicans), thiab raug protozoan parasites (Leishmania amazonensis los yog Trypanosoma cruzi) muaj peev xwm induce NET tiam [25-27]. Tsis tas li ntawd, cov tshuaj xws li statins thiab tshuaj tua kab mob tuaj yeem qhib tauneutrophilslos tsim NETs [19,28]. Jhunjhunwala S et al. qhia ntxiv tias cov khoom siv cog tsis muaj menyuam tuaj yeem ua rau NET tsim [29].
Raws li thawj zaug pom los ntawm Zychlinsky li al., NET tsim nyob ntawm cov reactive oxygen hom (ROS) uas ua los ntawm NADPH oxidase [17]. Cov txheej txheem no tau lees paub hauv kev tshawb fawb ntawm cov neeg mob uas muaj kab mob granulomatous (CGD) [30]. Fuchs et al. txiav txim siab tias kev hloov pauv hauv nicotinamide adenine dinucleotide phosphate (NADPH) oxidase ncua NET tiam. Qhov zoo siab, cov txiaj ntsig hauv txoj kev tshawb no pom tau tias qhov sib ntxiv ntawm exogenous ROS rau CGDneutrophilstxhawb NET tsim [30]. Ib yam li ntawd, Bianchi et al. pom tias kev kho noob hauv tus neeg mob nrog CGD rov qab tsim NET los ntawmneutrophils, hais txog lub luag haujlwm ntawm kev ua haujlwm NADPH oxidase hauv NET tsim [31].
Papayannopoulos et al. Ntxiv rau kev ua haujlwm tshiab ntawm granular proteins xws li Neutrophil Elastase (NE) hauv kev tswj hwm ntawm chromatin ntom [32] Cov kws sau ntawv tau pom tias ua kom NE khiav tawm ntawm azurophilic granules thiab translocates mus rau lub nucleus qhov twg nws txhawb chromatin decondensation los ntawm nws qhov tshwj xeeb degradation. . Yog li ntawd, myeloperoxidase synergizes nrog NE los tsav chromatin decondensation, uas ua rau NET tsim. Lub decondensation ntawm chromatin, ib kauj ruam tseem ceeb ntawm NET tsim, yog txuam nrog hyper-citrullination ntawm Histone H3 los ntawm kev hloov ntawm histone arginine rau citrulline los ntawm peptidyl arginine deiminase 4 (PAD4), ib qho enzyme uas tshwj xeeb tshaj yog nplua nuj nyob rau hauv mature.neutrophils[33]. Hyperctrullination zoo li ua lub luag haujlwm tseem ceeb hauv NET tsim. Ib txoj kev tshawb fawb pom tau tias cov nas tsis muaj peev xwm hauv PAD 4 tsis tuaj yeem tsim NETs thiab nthuav tawm txo qis NET-dependent kab mob thiab tua [34].
Table 1. NET inducers.tnterleukin8 (IL-8), qog necrosis factor- (TNFx), interferon- (IFN- y), interferon- (IFN-), granulocyte-macrophage colony-stimulating factor (GM-CSF ), lipopolysaccharides (LPS), thiab ntxiv tivthaiv 5a (C5a).
Lwm qhov kev koom tes hauv NET tso tawm yog autophagy. Ntau qhov kev tshawb fawb tau pom tias autophagy hloov pauv cov haujlwm neutrophil [3536]. Autophagy yog ib qho homeostatic mechanism koom nrog hauv programmed cell tuag. Autophagic machinery yog induced los ntawm PI3K hVPS34. Nws tau pom tias inhibition ntawm PI3K nrog 3-methyladenine (3-MA), wortmannin, thiab LY294002 inhibits autophagy. Ntxiv mus, autophagy yog tswj tsis zoo los ntawm cov protein kinase mammalian lub hom phiaj ntawm rapamycin (mTOR) [37].
Tsis ntev los no, Mazzoleni et al. qhia tias Panton-Valentine leukocidin (PVL) ua rau lwm txoj kev NETosis [38]. Txoj kev tshawb no tau pom tias PVL-induced NETs txawv ntawm NADPH oxidase-dependent NETosis thiab tsom rau mitochondria.
echinacoside cov tshuajhauvcistancherautiv thaiv kab mob
4. Neutrophils, NETs, thiab Endothelial puas
Cov kab mob endothelial (ECs) yog cov pob zeb tseem ceeb hauv kev saib xyuas cov hemostasis ib txwm. Kev ncaj ncees ntawm phab ntsa hlab ntsha, nyob rau hauv tandem nrog kev qhia ntawm ntau yam inhibitors xws li cov ntaub so ntswg pathway inhibitor (TFPI), thrombomodulin, protein C receptor, thiab heparin-zoo li proteoglycans, manifests anticoagulative kev txiav txim [39]. Endothelial cell puas kuj tau kuaj pom nyob rau hauv COVID-19 cov neeg mob raws li ib tug tshwm sim ntawm tus kab mob [40]. Cov ntawv tshaj tawm tsis ntev los no qhia tias COVID-19 cuam tshuam rau lwm yam kabmob hauv lub ntsws, xws li lub plawv thiab lub raum. Lindner et al. pom SARS-CoV-2 muaj nyob rau hauv cov ntaub so ntswg myocardial thaum lub sij hawm autopsy[41]. Ib qho ntawm cov txheej txheem ua tau ntawm ntau lub cev puas tsuaj tau txiav txim siab yog endothelium. COVID-19- cuam tshuam txog endothelium induces systemic vascular endothelial dysfunction, uas tau pom nyob rau hauv tus kab mob muaj teeb meem [42]. Sh et al. hypothesized tias endothelial hlwb tuaj yeem qhib los ntawm cov tshuaj tiv thaiv kab mob, NETs, thiab cov protein sib txawv, tshwj tsis yog hauv cov kab mob kis ncaj qha 43]. Ackermann thiab al. tau ua autopsies rau xya tus neeg mob uas tuag los ntawm COVID{11}} cuam tshuam los yog mob khaub thuas-kev ua pa tsis ua haujlwm. Daim ntawv tshaj tawm qhia tau hais tias qhov tshwm sim ntawm thrombus tsim nyob rau hauv pulmonary microvasculature yog kwv yees li cuaj npaug siab dua qhov cuam tshuam rau tus mob khaub thuas (p<0.001)[44]. in="" the="" same="" study,="" histological="" analysis="" of="" the="" lungs="" from="" patients="" who="" suffered="" influenza-associated="" respiratory="" failure="" showed="" diffuse="" alveolar="" damage="" with="" perivascular="" t-cell="" infiltration.="" conversely,="" histological="" analysis="" of="" the="" pulmonary="" vessels="" in="" patients="" with="" covid-19="" revealed="" widespread="" thrombosis="" with="" microangiopathy="" [44].="" at="" the="" beginning="" of="" 2021,="" evert="" et="" al.="" reported="" the="" same="" results="" in="" their="" own="" autopsy="" findings.="" the="" autopsy="" revealed="" that="" patients="" with="" severe="" diffuse="" alveolar="" damage="" had="" developed="" endothelium="" and="" capillaritis="" [45].="" to="" correlate="" endothelial="" dysfunction="" with="" in-hospital="" mortality,="" philippe="" et="" al.="" measured="" a="" panel="" of="" endothelial="" biomarkers="" and="" the="" von="" willebrand="" factor="" (vwf)="" in="" 208="" covid-19patients.="" according="" to="" the="" authors'="" data,="" the="" best="" predictor="" for="" in-hospital="" mortality="" was="" vwf="">
Skendros et al.investigated lub luag hauj lwm ntawm NET/platelet/thrombin axis nyob rau hauv ECs thiab qhia tau hais tias ntxiv inhibition muaj ib tug kho nyhuv nyob rau hauv SARS-CoV-2 kab mob, uas yog reflected los ntawm ib tug poob ntawm C-reactive protein thiab IL. -6 theem, cim kev txhim kho hauv lub ntsws ua haujlwm, thiab kev daws teeb meem ntawm SARS-CoV-2-sociated acute respiratory distress syndrome (ARDS) [47].
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5. Neutrophils, NETs, thiab Thromboinflammation
Sib nrug los ntawm cov khoom muaj zog tiv thaiv kab mob, los ntawm NETs,neutrophilskuj induce ib tug vigorous procoagulant teb. Kev ua kom lub cev coagulation yog ib qho tseem ceeb ntawm kev tiv thaiv tus tswv tsev uas tiv thaiv kev sib kis ntawm cov kab mob ntawm fibrin deposition thiab thrombus tsim. Txawm hais tias cov kev tshawb fawb yav dhau los tau qhia tiasneutrophilstau tab sis tsis tsim TF, uas yuav txo qhov tseem ceeb ntawmneutrophilsNyob rau hauv thrombosis, nws yog feem ntau lees txais niaj hnub no tias neutrophil-derived TF muaj feem xyuam rau thrombosis [48]. Tsis tas li ntawd, NET tso tawm tau tshwm sim los ua ib qho tseem ceeb rau kev ua haujlwm ntawm neutrophil-txog thrombo o, muab lub scaffold rau platelet entrapment thiab ua kom tom qab. Lub luag haujlwm tseem ceeb ntawm NETs hauv neutrophil-txog thromboinflammation tau raug pov thawj siv ob qho tib si hauv vitro thiab ex vivo qauv, suav nrog hauv sepsis, tob venous thrombosis (DVT), thiab malignancies (Table 2) [49,50]. Lub xub ntiag ntawm NETs tsis ntev los no tau pom nyob rau hauv thrombi nyob rau hauv ib tug murine qauv ntawm tob vein thrombosis [49]. Brill et al.reported tias NETs 'excellular chromatin, uas tej zaum yuav los ntawmneutrophils, yog ib feem ntawm lub venous thrombus thiab hais tias ob qho tib si DNA scaffold thiab histones tshwm sim los pab rau lub pathogenesis ntawm DVT nyob rau hauv nas. NETs tuaj yeem muab lub hom phiaj tshiab rau DVT kev txhim kho tshuaj. Ntxiv mus, Kambas et al. pom tau hais tias qhov kev qhia ntawm bioactive TF hauv NETs tuaj yeem ua rau muaj kev coagulation cascade [51]. Cov kws sau ntawv no tau tso lub teeb pom kev ntawm kev koom tes ntawm autophagic machinery hauv kev qhia ntawm TF hauv NETs thiab tom qab ua kom cov thrombi tsim.
Tshwj xeeb, hauv SARS Cov-2 cov neeg mob, Leppkes et al. qhia tau hais tias tus kab mob hnyav ua rau NET tsim nyob rau hauv lub microvessels. Lub intravascular tsim ntawm NETs nrog platelet aggregation ua rau lub cev puas tsuaj vim lub nkoj ceev ceev occlusion [52]. Ntxiv mus, Nicolai et al. tau sau tseg tias inflammatory microvascular thrombi uas muaj NETs thiab platelets tuaj yeem pom nyob rau hauv lub raum, ntsws, thiab lub plawv.COVID-19cov neeg mob [53].
Platelet-neutrophil kev koom tes yog ib qho tseem ceeb ntawm kev tiv thaiv kab mob hauv lub cev uas ua rau cov kab mob thrombosis. Tom qab von Willebrand factor-dependent priming, platelets tuaj yeem cuam tshuamneutrophilsob qho tib si los ntawm kev sib cuam tshuam ncaj qha thiab dhau los ntawm kev tso tawm cov neeg sib khom lus soluble [54-56. Platelets secrete ntau yam sib txawv molecules. Inorganic polyphosphate (PolyP) yog ib qho tseem ceeb ntawm platelet-dense granules uas koom nrog coagulation thiab o. Lub luag haujlwm tseem ceeb ntawm platelet-tso PolyP tau pom hauv kev ua haujlwm ntawm Morrissey li al. [57].
Tsis tas li ntawd, NET tsim kuj tuaj yeem raug ntxias los ntawm kev siv tshuaj kho mob. Extracorporeal membrane oxygenation (ECMO) kho tau siv los txhim kho cov pa oxygenation ntawm cov neeg mob uas raug kev txom nyem los ntawmCOVID-19. Thaum kawg, cov neeg tuag tau poob qis ntawm cov neeg mob uas tau txais ECMO. Txawm li cas los xij, cov teeb meem thrombotic tseem nquag. Raws li cov chaw txawv teb chaws, cov khoom siv biomaterials ntawm ECMOsystems tuaj yeem ua rau NET tsim nyob rau hauv ib qho platelet ywj siab [58]. Txhawm rau ntsuas qhov tshwm sim no, Winnersbach li al. tau kawm txog cov nyhuv ntawm ECMO ntawm platelet functions thiab thrombotic teeb meem. Hauv txoj kev tshawb no, platelet-poor (PLT-) thiab naive (PLT ntxiv) heparinized tib neeg cov ntshav tau ncig rau 6h hauv ob qhov sib npaug hauv vitro test circuits siv rau ECMO li. Cov kws sau ntawv tau tshaj tawm tias qhov depletion ntawm PLTs nyob rau hauv ECMO system yog txuam nrog kev txwv PLT activation tab sis tsis txaus los tiv thaiv cov hlab ntsha [59].
Table 2. Kev tshawb fawb ntawm NETs nyob rau hauv thrombo-o.Myeloperoxidase, MPO; Neutrophil Elastase, NE; High Mobility Group Box1, HMGB-1; Deoxyribonucleic acid, DNA; ST-segment nce myocardial infarction, STEM; Interleukin-1b, IL-1b; Interleukin-17, IL-17; Western blot, WB; Immunohistochemistry staining, IHC; systemic lupus erythematosus, SLE; Kev tswj hwm hauv kev txhim kho thiab DNA kev puas tsuaj cov lus teb 1, REDD-1; thiab Deep Vein Thrombosis, DVT.
6. Neutrophils, NETs, thiab mob ntsws puas hauv COVID-19
Lub ntsws yog thawj lub cev uas SARS-CoV-2 tawm tsam. Tom qab tuaj txog ntawm alveoli, SARS-CoV-2 ua rau lub cev tiv thaiv kab mob los ntawm kev ua kom cov alveolar macrophages. Tom qab ntawd, cov kab mob kis tau ua kom muaj kev sib txuas ua ke ntawm txoj kev lectin. Lub complementary peptides C3a thiab C5a, tsim los ua ib feem ntawm kev ua kom lub zog ntxiv, txhawb kev tsiv teb tsaws chaw.neutrophilsmus rau qhov chaw kis kab mob. Lub complement membrane nres complex (MAC) ces exerts cell puas, yog li tsim kev puas tsuaj-associated molecular qauv (DAMPs). Tsis tas li ntawd, SARS-CoV-2 S protein txhawb lub ntsws epithelial hlwb kom tso cov proteins tshwj xeeb xws li epithelial membrane protein 2(Emp2). Lub Emp2 ntawm alveolar epithelial hom 1 hlwb upregulates neutrophil migration. Raws li ib feem ntawm thawj kab ntawm innate tiv thaiv kab mob, lub tshuab txaisneutrophilsua lub luag haujlwm tiv thaiv hauv ntau yam kab mob los ntawm phagocytosis, degranulation, thiab NET tsim. Tsis tas li ntawd, activatedneutrophils, ua ke nrog macrophages, yog lub luag haujlwm rau kev zais cov cytokines xws li IL-1b, IL-2R, IL-6, IL-8, TNF- , thiab lwm yam [{ {5}}]. Kev tshawb fawb txog ntsws histopathology hauv COVID-19 kev kis tus kab mob thiab ua pa tsis ua pa hnyav tau pom tias muaj qhov sib txawv ntawm cov alveolar puas thiab tsim cov thrombi hauv cov hlab ntsha peripheral pulmonary. Interestingly, visualization ntawm neutrophil-nplua nuj o thiab neutrophil extracellular ntxiab ntawm qhov chaw ntawm tus kab mob tau lees paub lub luag hauj lwm ntawmneutrophilshauv COVID-19- hais txog kev tiv thaiv kab mob [67,68]. Veras et al.ascertained that SARS-CoV-2 can induce NET formation through healthyneutrophils, uas nyob ntawm angiotensin-hloov enzyme 2 lossis hyper citrullination [69]. Zuo et al.confirmed qhov tshwm sim nyob rau hauv ib qho kev kawm ex vivo. Hauv kev kawm sera los ntawm COVID-19 cov neeg mob, cov kws sau ntawv tau kuaj pom ntau dua NET cov cim (cell-dawb DNA, myeloperoxidase (MPO)DNA complexes, thiab/los yog citrullinated histone H3)[4]. Ib yam li ntawd, Ng et al. tshawb xyuas NET cov cim hauv COVID-19 cov neeg mob piv rau cov tib neeg noj qab haus huv, thiab tag nrho cov cim tau pom tias tau nce siab. Cov kws sau ntawv xaus lus tias NETs ua lub luag haujlwm tseem ceeb hauv kev kis kab mob thiab cov teeb meem thrombotic [70]. Cov txiaj ntsig no kuj tsis ntev los no tau pom los ntawm Wang et al. Nyob rau hauv tag nrho cov ntaub so ntswg transcriptomic tsom xam ntawm lub ntsws cov ntaub so ntswg thiab bronchoalveolar lavage kua (BALF). Nyob rau hauv txoj kev tshawb no, qhov tseem ceeb tshaj plaws-tswj cov cim cim, ob qho tib si hauv lub ntsws cov ntaub so ntswg thiab hauv BALF, tau pom nyob rau hauvneutrophils(84 noob). Ntawm 84 cov noob no, 16 noob yog NET-koom nrog cov noob. Ntawm cov NE1-cov noob caj noob ces, cov noob txhawb nqa ntawm cov protein arginine deiminase hom 4 (PAD4) ua kom thiab ROS cov noob muaj feem cuam tshuam [71].
Kev tshawb pom kab mob los ntawm kev kuaj mob ntawm cov neeg mob COVID-19 tau qhia txog lub luag haujlwm tseem ceeb ntawmneutrophilshauv hyperinflammatory [72-74]. Zuag qhia tag nrho, neutrophil infiltration los ntawm Neutrophil plugs tau kuaj pom hauv COVID-19 cov neeg mob ntawm Neutrophil Elastase (NE), Myeloperoxidase (MPO), thiab Citrullinated Histone H3 (citH3) staining. Qhov tseem ceeb, cov kev tshawb pom no tau nthuav tawm NETs thiab platelets [74]. Ntawm qhov tod tes, Sinha et al. txheeb xyuas 39 tus neeg mob uas raug mob los ntawm ARDS vim yog COVID-19 thiab tshaj tawm tias ARDS tsis cuam tshuam nrog kev mob siab dua |75]. Ntxiv mus, ARDS hauv pawg neeg no tau cuam tshuam nrog qhov qis dua ntawm hyperinflammatory phenotype hauv kev sib piv rau cov neeg mob sib tw tau txais los ntawm HARP-2 kev tshawb fawb (UK multicenter, randomized tswj simvastatin) [75].
Qhov tseem ceeb, Calfee et al. qhia tias kev raug mob ntawm lub ntsws ncaj qha cuam tshuam nrog kev mob ntsws loj heev ntawm lub ntsws epithelial, qhov sib txawv ntawm kev raug mob endothelial feem ntau tau pom nyob rau hauv kev raug mob ntsws tsis ncaj [76]. Raws li qhov kev tshawb pom no, cov kws sau ntawv tau qhia ntau hom subtypes ntawm ARDS vim yog COVID-19.
7. Neutrophils, NETs, thiab raum puas hauv COVID-19 Thromboinflammation
Txawm hais tias lub tshuab ua pa yog thawj lub hom phiaj ntawm SARS-CoV-2, mob raum raug mob (AKI) kuj tau piav qhia hauv cov neeg mob uas raug mob los ntawm COVID-19 [77]. Lub raum zoo li yog lub cev loj thib ob uas cuam tshuam nrog COVID-19- cuam tshuam txog thrombo o. Cytokine cua daj cua dub, raug mob endothelial, thiab neutrophil extracellular ntxiab tso tawm yog qee yam ntawm cov txheej txheem pathophysiological uas ua rau lub raum capillary thrombosis thaum lub sij hawm COVID-19 kab mob [78]. Cov tsos mob ntawm lub raum kev koom tes muaj xws li cov ntshav creatinine ntxiv nrog lossis tsis muaj proteinuria tshiab. Cheng et al. tshaj tawm tias kab mob raum muaj feem cuam tshuam nrog qhov ntsuas kev tuag siab hauv cov neeg mob nrog COVID-19[79]. Kev tshuaj xyuas lub raum histopathological ntawm cov neeg mob nrog COVID{11}} tau lees paub tias muaj cov kab mob cuam tshuam nrog cov kab mob xws li vasculitis, o, thiab platelets nrog erythrocyte aggregates cuam tshuam lub lumen ntawm cov hlab ntsha. Tsis tas li ntawd, ib qho kev ntsuam xyuas hluav taws xob microscopic pom cov kab mob coronavirus zoo li hauv tubular epithelium thiab podocytes. Immunostaining tsom xam tau qhia tias ACE2 receptors tau kho dua tshiab hauv cov neeg mob COVID{15}} thiab colocalized nrog SARS-CoV-2 nucleoprotein. Cov yam ntxwv xws li cov kab mob hypoxia, txawv txav coagulation, thiab cov tshuaj tau los yog hyperventilation-relevant rhabdomyolysis ua rau mob raum raug mob [80]. Tsis tas li ntawd, kev ua kom lub zog ntxiv tuaj yeem cuam tshuam rau lub raum raug mob hauv COVID-19. Siv immunohistochemistry rau cov ntsiab lus ntxiv Clq, MASP-2, C3b, C3d, C4d, thiab C5b-9, Pfister et al.investigated qhov kev koom tes ntawm lub complement system nyob rau hauv lub raum raug mob nyob rau hauv rau lub raum biopsies los ntawm autopsy cov ntaub ntawv ntawm cov neeg mob nrog COVID-19 [81]. Ob qho khoom siv C3 cleavage (C3b thiab C3d) tau kuaj pom hauv lub raum cov hlab ntsha thiab glomerular capillaries ntawm COVID-19 biopsies. Lub membrane nres complex C5b-9(MAC) feem ntau tso rau hauv peritubular capillaries, lub raum arterioles, thiab tubular hauv qab daim nyias nyias.
8. Neutrophils, NETs, thiab Kawasaki Kab Mob
Kab mob Kawasaki (KD) yog ib qho mob febrile systemic vasculitis hauv cov hlab ntsha me thiab nruab nrab uas ua rau cov hlab ntsha tawg (CALs) hauv cov menyuam yaus, tshwj xeeb hauv Nyiv [82,83]. Txij li tus kab mob Kawasaki nthuav tawm cov qauv raws caij nyoog thiab hauv cheeb tsam, nws tau pom tias lwm yam kab mob tuaj yeem ua rau KD. Tseeb tiag, tus mob coronavirus HCoV-229E raug txheeb xyuas tias yog qhov tseem ceeb hauv kev tsim kho KD[84]. Txij li KD kev kuaj mob tsuas yog ua raws li cov txheej txheem kho mob, feem ntau siv cov cim biochemical xws li CRP tsis tuaj yeem paub qhov txawv ntawm KD los ntawm cov kab mob sib kis. Hauv cov ntsiab lus no, kev nkag siab zoo dua ntawm cov txheej txheem pathophysiological ntawm KD tuaj yeem pab nrhiav pom cov biomarkers tshiab rau kev tshawb pom ntxov ntawm KD.
Kev tshawb fawb histopathologic ntawm KD vasculitis lesions tau pom tias cov hlwb tseem ceeb yog CD163 monocytes / macrophages thiab CD3 T hlwb [85]. Lwm cov kab mob inflammatory, xws lineutrophils, thiab neutrophil-tsav proinflammatory cytokine ntau lawm kuj ua rau EC puas. Armaroli thiab al. qhia tias kev puas tsuaj EC nrog nce qib S100A12 hauv cov neeg mob KD tau nruj me ntsis raws li interleukin -1 (IL-1 ) signaling (p<0.001)[86]. although="" it="" was="" previously="" shown="" that="" sars-cov-2="" infection="" is="" a="" type="" of="" net="" opathy,="" yamashita="" et="" al.reported="" for="" the="" first="" time="" that="" serum="" from="" kd="" patients="" can="" stimulate="" net="" formation="" in="" human="">neutrophilsnyob rau hauv vitro [87] Txoj kev tshawb no pom tau tias kev tsim NET yog lub hauv paus tseem ceeb ntawm cov kab mob pathophysiological hauv SARS-CoV-2 kab mob thiab Kawasaki-zoo li syndrome 87]. Qhov txiaj ntsig no pom zoo nrog kev tshawb fawb los ntawm Pouletty li al. uas qhia tau hais tias Kawasaki-zoo li tus mob no cuam tshuam nrog SARS-CoV-2 kab mob hauv menyuam yaus [88]. Tsis tas li ntawd, Jing et al. txheeb xyuas lub luag haujlwm ntawm neutrophil extracellular ntxiab (NETs) hauv pathogenesis ntawm KD [89]. Cov kws sau ntawv pom tias covneutrophilsntawm KD cov neeg mob induced NET tsim thiab hais tias cov NETs ho nce pro-inflammatory cytokine ntau lawm thiab NF-kB activation nyob rau hauv peripheral ntshav mononuclear hlwb (PBMCs). Tsis tas li ntawd, cov qauv hauv vitro hauv kab lis kev cai endothelial cell tau pom tias muaj kev nthuav qhia ntau ntxiv ntawm vascular endothelial kev loj hlob yam A(VEGF-A) thiab hypoxia-inducible factor-1a (HIF-1x). Cov txiaj ntsig no qhia tau hais tias NETs yog cov tseem ceeb hauv cov kab mob ntawm KD thiab Kawasaki-zoo li tus mob.
9. Neutrophils, NETs, thiab Therapeutical Interventions in COVID-19
Nws yog cov ntaub ntawv zoo uasneutrophilsyog cov yam tseem ceeb hauv cytokine cua daj cua dub thiab cov teeb meem thrombotic tau ntsib los ntawmCOVID-19cov neeg mob thiab hais tias kho lub hom phiaj ntawmneutrophilsTej zaum yuav ua rau mob hyperinflammatory syndrome hauv COVID-19. Yog li, ntau qhov kev tshawb fawb tau hais tias NETs tuaj yeem yog lub hom phiaj kho mob hauvCOVID-19cov neeg mob (Table 3) [90-93].
Table 3. Kev kho lub hom phiaj ntawm Neutrophil Extracellular Traps. Peptidylarginine deiminases-4, PAD-4; Neutrophil Elastase, NE;High Mobility Group Box1,HMGB-1;Deoxyribonucleic Acid, DNA; Interleukin-1b, IL-1b, thiab Interleukin-17, IL{{8 }}.
9.1.Interleukin Targeting
Cov cytokines koom nrog hauv pathogenesis ntawm lub ntsws mob hauv COVID-19 suav nrog IL-1, IL-6, IL-8, thiab TNF- [94]. Thaum lub sijhawm pib ntawm tus kabmob kis thoob ntiaj teb, kev tswj hwm tawm ntawm daim ntawv pov thawj FDA pom zoo los tiv thaiv interleukin tshuaj tau tshaj tawm. Txawm li cas los xij, cov txiaj ntsig ntawm kev tshawb fawb muaj feem cuam tshuam.
Ntau qhov kev tshawb fawb ntawm COVID-19 cov neeg mob tau tshaj tawm cov txiaj ntsig zoo ntawm interleukin-1 antagonists [95,96]. Txawm li cas los xij, lub hom phiaj ntawm IL-1 receptors los ntawm anakinra (ib qho IL-1 receptor antagonist (Ra)) hauv COVID-19 tseem tsis paub meej. Txog niaj hnub no, muaj peb qhov FDA pom zoo los tiv thaiv IL-1 tus neeg sawv cev: Anakinra yog IL{10}} receptor inhibitor, thaum canakinumab thiab rilonacept yog IL{11}} inhibitors. Anakinra tau tshaj tawm hauv kev kho mob ntawm COVID-19. Kev tswj hwm ntawm anakinra rau COVID{13}} cov neeg mob tau pom tias muaj kev nyab xeeb thiab tej zaum yuav cuam tshuam nrog kev txo qis hauv kev tuag thiab kev xav tau ntawm cov tshuab ua pa [96]. Ntawm qhov tod tes, CORIMUNO-ANA-1 txoj kev tshawb fawb tau tshaj tawm tias Anakinra tsis tau txhim kho cov txiaj ntsig ntawm cov neeg mob uas mob me-rau-nruab nrab COVID{19}} mob ntsws [97]. Ib yam li ntawd, ib qho kev tshawb fawb txog kev sib piv ntawm ib lub hauv paus tau ua los ntawm de la Calle li al., uas tau tshaj tawm tias kev kho mob nrog anakinra tsis tuaj yeem txhim kho cov kev mob tshwm sim ntawm cov neeg mob tocilizumab-refractory hnyav COVID-19 [98].
Ntau qhov kev tshawb fawb soj ntsuam txuas ntxiv tau siv los tiv thaiv IL-6 hauv cov txheej txheem kho mob rau COVID-19. Guaraldi et al.ua txoj kev tshawb fawb ntawm cov neeg mob laus los soj ntsuam lub luag haujlwm ntawm kev tiv thaiv IL-6 hauv kev txo qis kev pheej hmoo ntawm kev tuag hauv cov neeg mob uas muaj tus kab mob COVID-19. Txoj kev tshawb fawb soj ntsuam no suav nrog 544 tus neeg mob COVID-19 hnyav; 365 ntawm cov neeg mob no tau txais cov qauv kev cai, thaum 179 tus neeg mob ntxiv tau kho nrog tocilizumab (ib monoclonal antibody uas khi rau IL-6 receptor). Cov txiaj ntsig ntawm txoj kev tshawb fawb no tau pom tias kev kho mob nrog tocilizumab txo qhov kev pheej hmoo ntawm kev ua pa tsis zoo lossis kev tuag ntawm cov neeg mob uas muaj tus kab mob COVID{11}} mob ntsws hnyav [99. Tib cov txiaj ntsig tau tshaj tawm los ntawm Huang et al. qhia tias kev kho mob tocilizumab cuam tshuam nrog kev txo qis hauv kev tuag piv rau kev kho mob tsis zoo hauv cov neeg mob COVID{14}} [100]. Hauv kev sib piv nrog cov kev tshawb fawb yav dhau los, Stone et al. Tsis ntev los no tau tshaj tawm tias Tocilizumab tsis muaj txiaj ntsig los tiv thaiv kev tso ntshav lossis tuag rau cov neeg mob me me hauv tsev kho mob nrog COVID-19 [101].
Interleukin-17 yav dhau los cuam tshuam nrog lub xeev hyperinflammatory hauv cov neeg mob COVID-19. Lub luag haujlwm ntawm kev tiv thaiv IL-17 tau tshaj tawm nyob rau hauv tus neeg mob nrog ankylosing spondylitis kho nrog sekukinumab (ib qho tshuaj tiv thaiv monoclonal uas khi rau IL-17 protein). Raws li txoj kev tshawb fawb no, IL-17 inhibitors tau nthuav tawm raws li lub hom phiaj muaj txiaj ntsig rau kev tiv thaiv kev mob tsis zoo thiab mob ua pa nyuaj hauv COVID-19. Cov txiaj ntsig zoo los ntawm kev tawm tsam IL-17 kuj tau tshaj tawm los ntawm Mareev li al. [102]. Mugheddu et al. tau tshaj tawm tias ob tus neeg mob COVID-19- tus neeg mob zoo uas tseem raug mob psoriasis tau zoo sai sai los ntawm lawv cov kab mob vim yog kev kho mob sekukinumab mus sij hawm ntev [103].
Zuag qhia tag nrho, ntau yam kev txiav tawm thiab kev tshawb fawb tsis tu ncua tsom rau IL receptors. Txawm hais tias muaj txiaj ntsig zoo los ntawm qee qhov ntawm cov kev tshawb fawb no, lwm cov kev tshawb fawb tau muab cov lus pom tsis zoo, ua rau muaj kev sib cav txog qhov tseeb ntawm cov kev cuam tshuam no. Kev tsim qauv zoo dua thiab ntau qhov kev tshawb fawb tuaj yeem qhia qhov tseeb ntawm cov tshuaj no.
9.2 ib. Neutrophil Elastase Inhibitors
Neutrophil Elastase (NE), ib qho serine protease, yog ib qho ntawm cov enzymes proteolytic uas pab txhawb kev ua haujlwm ntawmneutrophils. NE koom nrog hauv kev ua haujlwm neutrophil thiab NET tsim. Tshwj xeeb tshaj yog, NE pab txhawb kev cuam tshuam ntawm SARS-CoV-2 mus rau hauv cov cell thiab tuaj yeem ua rau cov ntaub so ntswg puas ncaj qha. Lub luag haujlwm ntawm NE hauv cov neeg mob nrog ARDS, suav nrog COVID-19, thiab sepsis tau tshaj tawm hauv cov kev tshawb fawb sib txawv [104-107I. Ntxiv mus, hauv kev sim nas qauv, Ogura li al. qhia tias NE deficiency txhim kho myocardial raug mob hauv post-myocardial infarction [108]. Raws li cov ntaub ntawv dhau los, NE inhibition tuaj yeem muaj txiaj ntsig zoo rau COVID-19 [109]. Ntawm qhov tod tes, cov txiaj ntsig tau los ntawm kev tshawb fawb STRIVE ntawm tag nrho ntawm 492 tus neeg kho tshuab qhov cua heterogeneous acute-lung-injury cov neeg mob tau pom cov kev tswj hwm ntawm NE inhibitor sivelestat tsis muaj kev cuam tshuam rau 28-hnub tag nrho-ua rau kev tuag lossis lub tshuab ua pa. - hnub dawb [110].
9.3. DNase Inhibitors
Cov kev tshawb fawb soj ntsuam tau pom tias daim ntawv thov ntawm DNaseI nyob rau hauv ib txoj kev kho mob rau mob ntsws raug mob vim muaj kab mob ntsws hnyav tau txhim kho cov ciaj sia taus ntawm cov nas los ntawm kev txo qis hauv NET tsim [111,112]. Ntxiv mus, kev kho mob nrog DNase nce
ciaj sia nyob rau hauv cov neeg mob cystic fibrosis (CF). CF yog tus cwj pwm los ntawm kev nthuav qhia ntau ntxiv ntawm DNA (eDNA) hauv cov hlab cua [113]. Tsis ntev los no, Weber et al.reported data on the administration of Dornase alfa, recombinant human DNase-1, for the treatment of five mechanically ventilated patient with COVID-19. Cov txiaj ntsig tau pom tias Dornase alfa tau txais txiaj ntsig zoo los ntawm cov neeg mob [114]. Raws li cov ntaub ntawv kawm no, tam sim no muaj ntau qhov kev sim tshuaj COVID-19 siv Dornase alfa. Decelles et al. tau tshaj tawm cov ntsiab lus ntawm kev kawm raws tu qauv rau kev sim tshuaj ntsuam xyuas ntawm qhov ua tau zoo thiab kev nyab xeeb ntawm aerosolized intra-tracheal Dornase alfa kev tswj hwm ntawm cov neeg mob SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) [115].
9.4.Colchicine ib
Colchicine yog alkaloid extract los ntawm lub caij nplooj zeeg crocus uas tau siv los kho ntau yam kab mob, xws li gout thiab tsev neeg Mediterranean fever (FMF), ntau xyoo [116,117. Colchicine yog ib qho ntawm cov tshuaj ntsuab qub tshaj plaws uas siv rau kev mob pob qij txha. Txog niaj hnub no, cov kev tshawb fawb tseem ceeb thiab kev kho mob qhia tias colchicine muaj cov txiaj ntsig ntawm cov hlab plawv [118]. athero-tiv thaiv muaj peev xwm ntawm colchicine yog raws li nws cov teebmeem ntawm tubulin-colchicine-complex polymerization, nrog rau nws lub peev xwm los suppress pro-inflammatory cytokine (IL-1 thiab IL-18) tso tawm los ntawm kev cuam tshuam nrog Nod-zoo li receptor protein 3 inflammasome protein complex [118,119]. Tsis tas li ntawd, colchicine inhibits NET tsim nyob rau hauv cov neeg mob uas muaj mob Coronary Syndrome (ACS) [120]. Raws li nws cov teebmeem, colchicine tau npaj rau kev tiv thaiv ntawm venous thromboembolism hauv cov neeg mob uas muaj COVID-19 [121,122]. Tsis ntev los no, cov teebmeem ntawm colchicine ntawm lub plawv thiab mob biomarkers tau tshaj tawm nyob rau hauv GRECCO{17}} randomized soj ntsuam sim. Cov txiaj ntsig tau pom tias cov neeg koom nrog uas tau txais colchicine tau txheeb xyuas lub sijhawm zoo rau kev kho mob tsis zoo [123]. Scarsi et al. ntxiv txhawb kev siv colchicine rau kev kho mob ntawm COVID-19 [124]. Tsis tas li ntawd, nyob rau hauv ib qho randomized, ob qhov muag tsis pom kev, cov tshuaj placebo tswj kev sim, Lope et al. tau tshaj tawm tias colchicine txo qhov ntev ntawm ob qho tib si kev kho pa oxygen ntxiv thiab mus pw hauv tsev kho mob [125]. Txoj kev tshawb no tau lees paub cov txiaj ntsig ntawm kev tshawb fawb yav dhau los. Kev rov ua dua ntawm colchicine lossis lwm yam tshuaj yuav, yog li ntawd, yuav pab tau rau hauv kev sib ntaus sib tuaCOVID-19. Txawm li cas los xij, kev tshawb fawb ntxiv yuav tsum tau soj ntsuam thiab sim hauv kev sim tshuaj tom ntej.
9.5 ib. Corticosteroids
Yav dhau los, corticosteroids, raws li kev tswj hwm ntawm cov kab mob hauv lub cev, tau muab rau cov neeg mob hnyav nrog cov txiaj ntsig tsis sib haum [126,127]. Tsis ntev los no, raws li cov ntaub ntawv los ntawm RECOVERY sim (qhov loj, ntau qhov chaw, randomized, qhib-label sim ua hauv tebchaws United Kingdom), corticosteroids tau pom zoo rau cov neeg mob COVID-19. Hauv qhov kev sim no, tag nrho ntawm 2104 tus neeg mob pib dexamethasone, thiab 4321 txuas ntxiv cov kev kho li niaj zaus. Qhov kev sim no tau pom qhov kev tuag ntawm 28 hnub kom qis dua ntawm cov neeg mob uas tau randomized kom tau txais dexamethasone[128]. Ntxiv mus, CoDEX Randomized Clinical Trial qhia tias Dexamethasone tuaj yeem txo qis kev mob ntsws hauv cov neeg mob COVID-19 [129]. Ntawm cov neeg mob uas muaj tus mob hnyav lossis mob hnyav COVID-19, kev siv cov tshuaj dexamethasone tso rau hauv cov hlab ntsha tau nce cov hnub ua pa tsis muaj pa. Txawm hais tias tau txais txiaj ntsig zoo los ntawm qhov kev sim loj tshaj plaws, RECOVERY, thiab CoDEX, cov txiaj ntsig muaj txiaj ntsig zoo rau txhua tus neeg mob COVID{14}} yuav tsum tau kwv yees ua ntej kev kho corticosteroid pib. Kev kho corticosteroid ua ke nrog cytokine cua daj cua dub yog cuam tshuam nrog cov tshuaj insulin tseem ceeb thiab txo qis cov tshuaj insulin los ntawm cov hlwb pancreatic. Qhov kev sib tsoo ob zaug no tuaj yeem ua rau muaj mob hnyav hyperglycemia thiab teeb meem rau lub neej. Cov kev tshawb fawb yav tom ntej ntawm qhov muaj txiaj ntsig ntawm corticosteroids hauvCOVID-19tuaj yeem muab kev nkag siab txog lawv cov txiaj ntsig thiab kev phom sij.
9.6 ib. Lwm yam kev kho mob cuam tshuam uas cuam tshuam rau Neutrophils
Prebiotics thiab probiotics tuaj yeem suav hais tias muaj peev xwm tiv thaiv lossis kho kev cuam tshuam los tshem tawm COVID-19 [130]. Nws tau raug tshaj tawm yav dhau los tias qee cov kab mob, xws li Lactobacillus rhamnosus, lees txais cov haujlwm ntawm probiotics thiab txo cov haujlwm ua haujlwm.neutrophilsob leeg los ntawm inhibiting NET tsim thiab los ntawm downregulating phagocytic kev ua si [131]. Raws li cov ntaub ntawv sau tseg zoo ntawm NETs hauv cov kab mob ntawm COVID-19, qhov inhibition ntawm NETs los ntawm Lactobacillus rhamnosus tuaj yeem ua rau muaj txiaj ntsig zoo rau cov neeg mob COVID-19. Tsis tas li ntawd, kev cuam tshuam microbiota (dysbiosis) thaum lub sijhawm COVID-19 kis thoob qhov txhia chaw tau ua rau muaj kev kis tus kabmob C. difficile (CDI) [132]. Cov tshuaj probiotics tau tshaj tawm ntxiv los txhawb kev tiv thaiv kab mob hauv nruab nrab xws li pseudomembranous colitis vim Clostridium difficile. Zuag qhia tag nrho, nutraceuticals tuaj yeem yog riam phom zais rau lub hom phiaj SARS-CoV-2.
10. Cov lus xaus
Cov kev tshawb fawb yav dhau los ntawm cov txheej txheem pathophysiological ntawm SARS-CoV-2 qhia tias lub cev tiv thaiv kab mob hauv lub cev yog qhov tseem ceeb rau kev cuam tshuam ntawm COVID-19.Neutrophils, "Cinderella" ntawm lub cev tiv thaiv kab mob, koom nrog COVID-19 kab mob (Daim duab 1). NETs tau piav qhia thawj zaug hauv 2004 los ntawm Brinkmann li al. thiab feem ntau tau kawm nyob rau hauv cov mob hnyav heev. Lub pathogenesis ntawm COVID-19 suav nrog ob qho tib si septic thiab aseptic o, thiab kab mob kis ua rau lub cev tsis muaj zog. Tom qab ntawd, qhov kev ua siab loj no ua rau cytokine cua daj cua dub thiab tau cuam tshuam nrog COVID-19 cov teeb meem xws li ARDS, ntau lub cev tsis ua haujlwm, thiab cov xwm txheej thromboembolic. Thaum kawg, kho cov kev cuam tshuam rau lub hom phiajneutrophilstej zaum yuav sawv cev rau cov khoom muaj peev xwm hauv ib qho kev sib koom ua ke kho mob rau cov neeg mob COVID-19.
micronized purified flavonoid feem 1000 mg siv
Cov ntaub ntawv
1.Zu, N; Zhang, D.; Wang, W.; Li, X; Yaj, B.; Nkauj, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R; et al. Novel Coronavirus los ntawm Cov Neeg Mob Pneumonia hauv Suav Teb, 2019.N.Engl.J. Med.2020,382, 727-733. [CrossRef] [PubMed]
2. LEEJ TWG Coronavirus(COVID-19) Dashboard. Muaj nyob online: https://covid19.who.int ( nkag mus rau 28 Lub Peb Hlis 2021).
3. Guo, Y.-R.; Cao, Q.-D.; Hong, ZS.; Tan, YY; Chen, S.-D.; Jin, H.-JL:; Tan, KS; Wang, D.-Y; Yan, Y. Keeb Kwm, Kev Kis 3. thiab Kev Kho Mob Kho Mob ntawm Kab Mob Coronavirus 2019(COVID-19) Kev Tawm Tsam Tawm-ib qho Kev Hloov Kho ntawm Tus Txheej Txheem. Mil Med. Xyoo 2020,7,11. [CrossRef] [PubMed]
4. Zhou, Y.; Yalavarthi, S.; Sib, H.; Gockman, K.; Zuo, M.; Madison, JA; Blair, C.; Weber, UA; Barnes, BJ; Egeblad, M.; ua al. Neutrophil Extracellular Traps hauv COVID-19. JCI Insight 2020, 5, e138999.[CrossRef]
5. Ibanez, C.; Perdomo, J.; Calvo, A.; Ferrando, C.; Reverter, JC; Tassies, D.; Blasi, A. High D Dimers thiab Low Global Fibrinolysis Coexist nyob rau hauv cov neeg mob COVID19: Dab tsi tshwm sim nyob rau ntawd? I. Thromb.Thrombolysis 2020,51,308-312.[CrossRefl[PubMed]
6. Arachchillage, DRJ; Laffan, M.Abnormal Coagulation Parameters Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia. J. Taub. Haemost. 2020, 18, 1233-1234. [CrossRefl [PubMed]
7. Zhou, F; Yus, T; Du, R.; Fan, G.; Liu, Y. Liu, Z; Xiang, J.; Vaj, Y. Nkauj, B.; Gu, X.; et al.Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet 2020,395,1054-1062. [CrossRef]
8. Tang, N.;Li, D.;Wang, X.;Tshav, Z.Txoj kev coagulation tsis zoo cuam tshuam nrog kev pom tsis zoo hauv cov neeg mob uas muaj tus mob Coronavirus mob ntsws. J. Taub. Haemost.2020, 18, 844-847. [CrossRef] [PubMed]
9. Slomka, A.;Kowalewski, M.; Zekanowska, E. Tus Kab Mob Coronavirus 2019(COVID-19): Kev Tshawb Fawb luv luv ntawm Hematological Manifestations. Cov kab mob 2020, 9, 493. [CrossRef]
10. Eljilany, I.; Suzuki, A.-ND-Dimer, Fibrinogen, thiab IL-6 hauv COVID-19 Cov neeg mob uas xav tias muaj Venous Thromboembolism: Kev Tshawb Fawb Txog Kev Tshawb Fawb. HRM 2020, 16, 455-462. [CrossRef] [PubMed]
11. Zhou, Y.; Cai, W.; Jiang, W. Xiao, M.; Li, Y; Tang, N.; Liu, Z.; Yan, X.; Zhao, Y.; Li, T.; ua al. Profile ntawm Natural Anticoagulant, Coagulant Factor thiab Anti-Phospholipid Antibody in Critically Ill COVID-19 Cov neeg mob. I. Thromb.Thrombolysis 2020,50,580-586. [CrossRef]
12. Gazzaruso, C.;Paolozzi, E.;Valenti, C.;Brocchetta, M.; Naldani, D.; Grignani, C.; Salvucci, F.; Marino, F; Coppola, A.; Gallotti, P. Koom haum ntawm Antithrombin thiab Mortality in Patients with COVID-19. Ib Qhov Txuas Txuas Nrog Obesity. Nutr. Metab. Cardiovasc. Dis. Xyoo 2020, 30, 1914-1919. [CrossRef] [PubMed]
13. Gazzaruso, C.; Valenti, C.; ib. Coppola, UA; Gallotti, P. Impact of Convalescent and Nonimmune Plasma on Mortality of Patients with COVlD-19: Lub luag hauj lwm muaj peev xwm rau Antithrombin. Clin. Microbiol. Kab mob. 2020.27. 637-638. [CrossRefl
14. Lerman, YV; Kim, M. Neutrophil Migration nyob rau hauv ib txwm thiab Sepsis mob. Cardiovasc. Hematol. Teeb meem. Lub Hom Phiaj Tshuaj 2015, 15, 19-28. [CrossRef [PubMed]
15. Schymeinsky, J.; Mocsai, A.; Walzog, B. Neutrophil Ua rau ntawm Beta2 Integrins (CD11/CD18): Molecular Mechanisms thiab Clinical Implications. Thromb. Haemmost.2007, 98, 262-273. [CrossRef] [PubMed]
16. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, DS; Weinrauch, Y.; Zychlinsky, A. Neutrophil Extracellular Traps Kill Bacteria. Science 2004, 303, 1532-1535. [CrossRef]
17. Brinkmann, V.; Zychlinsky, A. Kev tua tus kheej muaj txiaj ntsig: Vim li casNeutrophilsTuag Ua NETs. Nat. Rev. Microbiol.2007,5, 577-582. [CrossRef]
18. Hamam, HJ; Khan, MA; Palaniyar, N. Histone Acetylation Txhawb nqa Neutrophil Extracellular Trap Tsim. Biomolecules 2019, 9, 32. [Crossref]
19.Konstantinidis, T; Kambas, K; Mitsios, A.; Panopoulo, M.; Tsironidou, V; Dellaporta, E.; Kouklakis, G; Arampatzioglou, A; Angelidou, ib.; Mitroulis, ib.; ua al. Lub luag haujlwm Immunomodulatory ntawm Clarithromvcin hauv Acinetobacter Baumannii Kab Mob los ntawm Kev Tsim Nyog Neutrophil Extracellular Traps. Antimicrob. Tus neeg sawv cev Chemother. Xyoo 2016, 60, 1040-1048. [CrossRef]
20. Halverson, TWR; Wilton, M. Poon, KKH; Petri, IB; Lewenza, S.DNA yog ib qho tshuaj tiv thaiv kab mob ntawm Neutrophil Extracellular Traps. PLoS Pathog.2015, 11, e1004593. [CrossRef]
21. Martinod, K.; Deppermann, C.Immunothrombosis, thiab Thromboinflammation hauv Tswv Cuab Tiv Thaiv thiab Kab Mob. Platelets 2020, 32, 314-324. [CrossRef]
