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1、COVID-19-is the ACE2 just a foe?1 2 Letter to the editor 3 4 Hrvoje Jakovac,MD,PhD 5 Department of physiology and immunology 6 Medical Faculty,University of Rijeka 7 Brace Branchetta 20 8 51000 Rijeka 9 Croatia 10 11 email:hrvoje.jakovacmedri.uniri.hr 12 phone:00385915624242 13 14 15 16 17 18 19 20

2、21 22 23 24 25 26 27 28 29 30 Downloaded from journals.physiology.org/journal/ajplung(193.202.082.052)on April 10,2020.TO THE EDITOR:I read with great interest and pleasure the recent editorial article Covid-19 infection 31 and mortality A physiologists perspective enlightening clinical features and

3、 plausible interventional 32 strategies by Abassi ZA and colleagues(1).In the article,the authors suggested blockage of 33 angiotensin-converting enzyme 2(ACE2)as a potential strategy for mitigating clinical picture and 34 reducing mortality in SARS-CoV-2 infected subjects.Because the SARS-CoV-2 vir

4、us uses ACE2 as a 35 receptor,this approach could be promising to prevent virus entry into the pneumocytes.But,ACE2 36 inhibition in COVID-19 patients with already developed symptoms could even be detrimental due to 37 the consequent decrease in the production of Angiotensin 1-7,which,as have been s

5、tated by the 38 authors,shows anti-inflammatory and antifibrotic activity via the Mas receptor.Regarding that,the 39 authors also mentioned that the depletion of ACE2 by SARS-CoV-2 binding may be responsible for 40 the more severe clinical presentation of COVID-19 in the group of high-risk patients(

6、1).Indeed,41 previous studies showed the protective effect of ACE2 in the animal models of ARDS(4,7,14),while 42 angiotensin II was found to be a harmful molecule,causing pulmonary edema and fibrosis(8).So,43 inhibition of ACE2 could lead to reduced clearance of the harmful molecule,while the protec

7、tive one 44 would be insufficiently produced.Moreover,suggestions considering ACE2 induction as a possible 45 therapeutic strategy for COVID-19 have recently emerged(11).Besides,an increased level of soluble 46 ACE2 isoform,as a consequence of pre-existing disease(such as inflammatory bowel diseases

8、),has 47 been assumed as a possible protective factor,acting by intercepting viral particles(9,12).Interestingly,48 ACE2 is expressed in respiratory tract only moderately compared to intestinal epithelia(2,3),but 49 respiratory symptomatology is incomparably more severe than intestinal,although amon

9、g COVID-19 50 patients up to 50%of stool specimens were SARS-CoV-2 positive(10),and some patients remained 51 stool-positive after respiratory samples were negative(13).These observations give rise to the 52 possibility that a higher proportion of intact ACE2 molecules provide sufficient protection

10、during 53 infection,and suggest that the role of ACE2 during COVID-19 pathogenesis should be considered 54 relative to viral load.55 By all accounts,in the context of SARS-CoV-2 infection,ACE2 could justifiably be referred to as a 56 double-edged sword.Regarding that,it is worth distinguishing passi

11、ve ACE2 expression,which is 57 undoubtedly the main doorway for viral entry,and total ACE2 activity,which seems to be protective.58 The situation could be further complicated if the SARS-CoV-2 is capable to shed catalytically active 59 ACE2 ectodomains,as is the case with SARS-CoV(5,6),which would l

12、ead to the releasing of active 60 Downloaded from journals.physiology.org/journal/ajplung(193.202.082.052)on April 10,2020.ectodomains in the systemic circulation.If so,in addition to its potential diagnostic relevance,an 61 increase in plasma ACE2 activity may diminish systemic effects of angiotens

13、in II,impairing thus 62 hemodynamics and renal function in critically ill COVID-19 patients.63 Withal,it should be emphasized that angiotensin-converting enzyme inhibitors(ACE-Is)and 64 angiotensin receptor blockers(ARBs)are differently related to ACE2:in contrast to ARBs,ACE-Is 65 deplete its subst

14、rate and consequently reduce the production of the final anti-inflammatory product.66 Moreover,by blocking the receptors,ARBs could divert a larger proportion of generated angiotensin II 67 towards ACE2.These assumptions encourage more detailed stratification of clinical presentation and 68 outcome

15、among COVID-19 patients receiving RAS modulating drugs.69 Finally,it is reasonable to assume that different ACE2 gene polymorphisms could underlie a huge 70 variety of COVID-19 clinical presentation and outcome,as well as a propensity for infection.71 72 73 References 74 1.Abassi ZA,Skorecki K,Heyma

16、n SM,Kinaneh S,Armaly Z.Covid-19 Infection and Mortality-A 75 physiologists perspective enlightening clinical features and plausible interventional strategies.Am J 76 Physiol Lung Cell Mol Physiol(March 24,2020).doi:10.1152/ajplung.00097.2020.77 2.Hamming I,Timens W,Bulthuis ML,Lely AT,Navis G,van G

17、oor H.Tissue distribution of ACE2 78 protein,the functional receptor for SARS coronavirus.A first step in understanding SARS 79 pathogenesis.J Pathol 203:631637,2004.80 3.Harmer D,Gilbert M,Borman R,Clark KL.Quantitative mRNA expression profiling of ACE 2,a 81 novel homolog of angiotensin converting

18、 enzyme.FEBS Lett 532:107110,2002.82 4.Imai Y,Kuba K,Rao S,Huan Y,Guo F,Guan B,Yang P,Sarao R,Wada T,Leong-Poi H,83 Crackower MA,Fukamizu A,Hui CC,Hein L,Uhlig S,Slutsky AS,Jiang C,Penninger JM.84 Angiotensin-converting enzyme 2 protects from severe acute lung failure.Nature 436:112116,2005.85 5.Jia

19、 HP,Look DC,Tan P,Shi L,Hickey M,Gakhar L,Chappell MC,Wohlford-Lenane C,86 McCray PB Jr.Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia.87 Am J Physiol Lung Cell Mol Physiol 297:L84L96,2009.88 6.Lambert DW,Yarski M,Warner FJ,Thornhill P,Parkin ET,Smith AI,Hooper NM,T

20、urner 89 AJ.Tumor necrosis factor-alpha convertase(ADAM17)mediates regulated ectodomain shedding of 90 Downloaded from journals.physiology.org/journal/ajplung(193.202.082.052)on April 10,2020.the severe-acute respiratory syndrome-coronavirus(SARS-CoV)receptor,angiotensin-converting 91 enzyme-2(ACE2)

21、.J Biol Chem 280:3011330119,2005.92 7.Li Y,Zeng Z,Cao Y,Liu Y,Ping F,Liang M,Xue Y,Xi C,Zhou M,Jiang W.Angiotensin-93 converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the 94 ERK1/2 and NF-B signaling pathways.Sci Rep 6:27911,2016.95 8.Marshall RP,Gohlke P

22、,Chambers RC,Howell DC,Bottoms SE,Unger T,McAnulty RJ,96 Laurent GJ.Angiotensin II and the fibroproliferative response to acute lung injury.Am J Physiol Lung 97 Cell Mol Physiol 286:L156L164,2004.98 9.Monteleone G,Ardizzone S.Are Patients With Inflammatory Bowel Disease at Increased Risk for 99 Covi

23、d-19 Infection?J Crohns Colitis(March 26,2020).doi:10.1093/ecco-jcc/jjaa061.100 10.Wang W,Xu Y,Gao R,Lu R,Han K,Wu G,Tan W.Detection of SARS-CoV-2 in different types 101 of clinical specimens.JAMA(March 11,2020).doi:10.1001/jama.2020.3786.102 11.Wu Y.Compensation of ACE2 Function for Possible Clinic

24、al Management of 2019-nCoV-Induced 103 Acute Lung Injury.Virol Sin(February 7,2020).doi:10.1007/s12250-020-00205-6.104 12.Wysocki J,Satchell K.Soluble angiotensin-converting enzyme 2:a potential approach for 105 coronavirus infection therapy?Clin Sci 134:543545,2020.106 13.Xiao F,Tang M,Zheng X,Liu

25、Y,Li X,Shan H.Evidence for gastrointestinal infection of SARS-107 CoV-2.Gastroenterology(March 3,2020).doi:10.1053/j.gastro.2020.02.055.108 14.Ye R,Liu Z.ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by 109 inhibiting the LPS-TLR4 pathway.Exp Mol Pathol 113:104350,2020.110 Downloaded from journals.physiology.org/journal/ajplung(193.202.082.052)on April 10,2020.